How is male infertility caused by Y chromosome microdeletions?

By (embryologist), (embryologist) and (biochemist).
Last Update: 08/17/2022

Genetic material and genes are packaged into units called chromosomes, which are arranged in pairs. In each pair of chromosomes, one comes from the father, while the other comes from the mother. Each person has 22 pairs of homologous chromosomes and two sex chromosomes: XX for females and XY for males.

Therefore, only men have the Y chromosome. Microdeletions in this Y chromosome can lead to severe defects in spermatogenesis.

Y chromosome microdeletions

Although male infertility has causes such as infectious diseases or endocrine irregularites, it can have also a genetic basis. In this case, Y chromosome microdeletions are a genetic cause of male infertility (one of the most frequent genetic abnormalities, along with Klinefelter's syndrome).

The Y chromosome has a region called AZF (azoospermia factor). The presence of deletions in this chromosomal region is related to problems in spermatogenesis. A microdeletion is the loss of a small part of genetic material.

Thus, microdeletions in the AZF region lead to serious alterations in sperm production, such as azoospermia and severe oligozoospermia.

Azoospermia is the absence of spermatozoa in the ejaculate. Oligospermia refers to a low concentration of spermatozoa per milliliter of semen (less than 15 mil/ml).

Y chromosome microdeletion types

Microdeletions in the Y chromosome can have different repercussions, depending on where you find them within the AZF. Initially, these zones were named AZFa, AZFb and AZFc. However, subsequent discoveries showed that AZFb and AZFc partially overlap. In this way:

  • AZFa: relates to Sertoli cell-only syndrome. Males with AZFa microdeletions may have small testes and be azoospermic.
  • AZFb or AZFb/c: more associated with the absence of spermatozoa in their final form, since there is a halt in the formation process.
  • AZFc: a male with microdeletions in this region can present with both azoospermia and oligospermia.

In the case of oligozoospermic men, it may be advisable to freeze semen samples, as the sperm count could progressively decline towards azoospermia (at which point a testicular biopsy should be performed to try to recover sperm directly from the testicle).

Diagnosis

Men with Y chromosome related infertility often receive the diagnosis when they come to an infertility clinic after trying for a pregnancy that does not happen. They can be otherwise asymtompatic.

On physical examination these males may have a smaller testicular size, but this parameter may also be normal. Therefore, what usually leads the specialist to do further studies of the male is the result of a semen analysis of azoospermia or severe oligospermia.

The possibility of finding Y chromosome microdeletions is greater when the male presents with azoospermia as opposed to oligospermia. In any case, the diagnosis is made following a blood draw from the male. From this, the genetic test is performed to see if there any Y chromosome microdeletions.

Finally, if the patient is diagnosed with microdeletions in the Y chromosome, he should receive appropriate genetic counseling before trying for pregnancy. Mainly because their male offspring will inherit the microdeletions and, therefore, the fertility problems.

Prognosis and treatment

In general, the reproductive prognosis of males with Y chromosome-related infertility vaires on where the deletion is on the Y chromosome:

  • AZFa or AZFb/c: the prognosis is poor, since it is usually difficult to find spermatozoa and testicular biopsy would not be indicated.
  • AZFc: in this more frequent case, it is perhaps possible to find sperm by testicular biopsy or even in the ejaculate.This can then be used to fertilize the couple's oocytes through assisted reproduction techniques.

Assisted procreation, as any other medical treatment, requires that you rely on the professionalism of the doctors and staff of the clinic you choose. Obviously, each clinic is different. Get now your Fertility Report, which will select several clinics for you out of the pool of clinics that meet our strict quality criteria. Moreover, it will offer you a comparison between the fees and conditions each clinic offers in order for you to make a well informed choice.

Y chromosome microdeletions don´t have any treatments as such. However, in the event that it is possible to obtain sperm (in the ejaculate or through a testicular biopsy), these can be used to try for a pregnancy through the IVF technique known as intracytoplasmic sperm injection(ICSI).

In the case of oligozoospermic males with Y chromosome microdeletions, it is possible for the couple to become pregnant naturally even though it poses many difficulties. Additionally, semen freezing may be recommended. In this way, these men will be able to become biological fathers in the future by assisted reproduction techniques, even though their sperm count may gradually progress towards azoospermia.

However, as previously mentioned, it is very important that patients diagnosed with microdeletions in the Y chromosome receive appropriate genetic counseling. This should be before seeking gestation, since the genetic alteration will be transmitted to male offspring.

Alternatively, patients with microdeletions in the Y chromosome can also become parents by resorting to sperm donation or adoption

FAQs from users

Is IVF the treatment for Y chromosome microdeletions?

By Silvia Azaña Gutiérrez B.Sc., M.Sc. (embryologist).

In vitro fertilization (IVF), specifically by intracytoplasmic sperm injection (ICSI), may be the solution for patients with Y chromosome microdeletions to have children.

However, ICSI can only be performed if sperm can be obtained from the male (either from the ejaculate or by testicular biopsy), which is more frequent in the case of microdeletions in the AZFc region of the Y chromosome.

In this case, it is very important that patients also receive genetic counseling, as the male offspring will inherit the paternal Y chromosome microdeletions.

On the other hand, in the event that sperm cannot be obtained, patients with Y chromosome microdeletions can opt for sperm donation or adoption to become parents.

Is a natural pregnancy possible with Y chromosome microdeletions?

By Silvia Azaña Gutiérrez B.Sc., M.Sc. (embryologist).

Yes, it would be possible if the male has oligozoospermia and his partner has no fertility problems. However, due to oligozoospermia, natural conception is hindered.

Therefore, many patients with microdeletions in the Y chromosome in whom sperm can be recovered (in the ejaculate or by testicular biopsy) resort to assisted reproductive techniques in order to become parents.

However, it is important to remember that male offspring will inherit Y chromosome microdeletions, so appropriate genetic counseling will be necessary before seeking gestation.

What is azoospermia due to microdeletions in the Y chromosome?

By Silvia Azaña Gutiérrez B.Sc., M.Sc. (embryologist).

Azoospermia is a seminal disorder defined as the absence of spermatozoa in the male ejaculate.

Azoopermia can be obstructive (when sperm are produced but do not come out in the ejaculate due to an obstruction) or secretory (when no sperm are produced).

In the case of azoospermia due to microdeletions in the Y chromosome, it is a secretory azoospermia because these microdeletions involve serious alterations in spermatogenesis, that is, in the production of spermatozoa and, therefore, it is possible that no spermatozoa are found in the ejaculate.

Klinefelter syndrome is another genetic cause of male infertility. If you want to learn more about this syndrome, we recommend visiting the following article: Klinefelter syndrome (XXY syndrome).

We have mentioned ICSI as the assisted reproduction treatment that can help some patients with microdeletions in the Y chromosome to have children. You can read more about this technique in this article:What is ICSI?

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References

Colaco S, Modi D. Consequences of Y chromosome microdeletions beyond male infertility. J Assist Reprod Genet. 2019 Jul;36(7):1329-1337. (view)

Colaco S, Modi D. Genetics of the human Y chromosome and its association with male infertility. Reprod Biol Endocrinol. 2018 Feb 17;16(1):14. (view)

Fan Y, Silber SJ. Y Chromosome Infertility. 2002 Oct 31 [Updated 2019 Aug 1]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. (view)

Li X, Li X, Sun Y, Han J, Ma H, Sun Y. Effect of Y Chromosome Microdeletions on the Pregnancy Outcome of Assisted Reproduction Technology: a Meta-analysis. Reprod Sci. 2021 Sep;28(9):2413-2421. (view)

Oz O. Evaluation of Y chromosome microdeletions and chromosomal anomalies in infertile men. Horm Mol Biol Clin Investig. 2021 Mar 8;42(3):279-283. (view)

Peña VN, Kohn TP, Herati AS. Genetic mutations contributing to non-obstructive azoospermia. Best Pract Res Clin Endocrinol Metab. 2020 Dec;34(6):101479. (view)

Punjani N, Kang C, Schlegel PN. Clinical implications of Y chromosome microdeletions among infertile men. Best Pract Res Clin Endocrinol Metab. 2020 Dec;34(6):101471. (view)

Rives N. Y chromosome microdeletions and alterations of spermatogenesis, patient approach and genetic counseling. Ann Endocrinol (Paris). 2014 May;75(2):112-4. (view)

FAQs from users: 'Is IVF the treatment for Y chromosome microdeletions?', 'Is a natural pregnancy possible with Y chromosome microdeletions?' and 'What is azoospermia due to microdeletions in the Y chromosome?'.

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Authors and contributors

 Neus Ferrando Gilabert
Neus Ferrando Gilabert
B.Sc., M.Sc.
Embryologist
Bachelor's Degree in Biology from the University of Valencia (UV). Postgraduate Course in Biotechnology of Human Assisted Reproduction from the Miguel Hernández University of Elche (UMH). Experience managing Embryology and Andrology Labs at Centro Médico Manzanera (Logroño, Spain). More information about Neus Ferrando Gilabert
 Silvia Azaña Gutiérrez
Silvia Azaña Gutiérrez
B.Sc., M.Sc.
Embryologist
Graduate in Health Biology from the University of Alcalá and specialized in Clinical Genetics from the same university. Master in Assisted Reproduction by the University of Valencia in collaboration with IVI clinics. More information about Silvia Azaña Gutiérrez
License: 3435-CV
Adapted into english by:
 Michelle Lorraine Embleton
Michelle Lorraine Embleton
B.Sc. Ph.D.
Biochemist
PhD in Biochemistry, University of Bristol, UK, specialising in DNA : protein intereactions. BSc honours degree in Molecular Biology, Univerisity of Bristol. Translation and editing of scientific and medical literature.
More information about Michelle Lorraine Embleton

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