Genetic causes of infertility.

What is infertility?

Infertility is referred to when a couple cannot get pregnant despite 12 months of regular (3-4 times a week) intercourse unprotected (3). Infertility factors include both female factorsas well as men's (4).

Female factors include:

• ovulation disorders,

• damage to or obstruction of the fallopian tubes,

• endometriosis,

• defects in the structure or function of the uterus,

• premature cessation of ovarian function,

• cervical factor.

The male factors are:

• poor semen quality,

• obstruction of the vas deferens,

• aspermia,

• no ejaculation.

Doctors also draw attention to so-called idiopathic infertility, i.e. of unknown aetiology, which is diagnosed in approximately 30% cases.

Genetic factors influencing infertility

Infertility does not always occur from the very beginning of trying for offspring. Sometimes couples who already have a child or children conceived naturally discover difficulties when trying for another pregnancy. It is then a question of nisecondary infertility.

For primary infertility, which prevents pregnancy from the very first attempts, much of the blame may lie with the genes. This applies to both women and men (5).

Genetic causes of female infertility can be discussed in the case of:

In men, genetic disorders causing infertility are evident in the form of impaired sperm production.

• gonadal dysgenesis,

• recurrent miscarriages,

• premature extinction of ovarian function.

Recurrent miscarriages

A miscarriage is the termination of a clinically confirmed pregnancy no older than 20 weeks. It is estimated that around 20% women have experienced at least once in their lives miscarriages.

Recurrent miscarriages are diagnosed when at least 3 consecutive pregnancies have ended spontaneously before 20 weeks (6).

Even 50% spontaneous miscarriages are due to an abnormal fetal karyotype, which is sometimes caused by defective genes present in the parents (7). Often these alterations are small and not easy to detect, but in parents carrying defective genes, not only does the likelihood of miscarriage increase, but also the risk of fetal malformations. Therefore, in the case of recurrent miscarriages, it is worth performing a full genetic testing panel in consultation with an experienced clinical geneticist.

Premature extinction of ovarian function

This is one of the fairly common genetic causes of female infertility. It is believed that Premature expiry of ovarian function (POF/POI) occurs in 1 in 100 women before the age of forty and in 1 in 1,000 women under the age of thirty. POF/POI may be evidenced by the occurrence of menstrual irregularities, and ultrasound shows a low number of ovarian follicles and reduced ovarian volume (8).

Women suffering from POF/POI go through menopause much earlier - the causes of this condition can be varied and are usually related to mutations within the X chromosome. Other causes include:

• autoimmune factors,
• mechanical damage to the ovaries (e.g. during surgery),
• radio or chemotherapy.

Hormone replacement therapy is used for treatment.

POI

It is important to remember that this is not a causal treatment, but a symptomatic one, and the name has been changed from POF to POI because in some patients menstruation, and therefore fertility, can return.

Gonadal dysgenesis

Gonadal dysgenesis (9) is a defect of the reproductive system in which the ovaries in women or testes in men are abnormally formed. In women it can be associated with Turner syndrome and in men it occurs in the course of Klinefelter syndrome. It can also be a variant of male hermaphroditism.

If infertility due to gonadal dysgenesis is diagnosed in a patient, the procedure is followed in vitro using an unrelated donor egg. If the cause is testicular dysgenesis, insemination or IVF can be performed using anonymous donor sperm.

Sperm production disorders

The male factor can cause infertility even in 50% couples, and abnormal semen parameters are the most common factor. Abnormalities in sperm production often have their origin in gene-related abnormalities (10):

• mutation of the CFTR gene in men leads to obstruction of the vas deferens or absence of sperm in the semen,

• A regin AZF microdeletion of the Y chromosome results in a very low or zero sperm count in semen,

• mutation of the AR gene can in turn cause androgen insensitivity syndrome and abnormalities in sexual characteristics.

Genetic factors for infertility are often invisible at first glance. Their correct diagnosis is important not only for the course of infertility treatment, but also for the health of future offspring, as some of the mutations may be passed on to them.

Substantive consultation:

Grzegorz Ziółkowski, MD - Specialist gynaecologist-obstetrician

Bibliography:

1. Koperwas, M., & Głowacka, M. (2017). The problem of infertility among women and men-epidemiology, risk factors and public awareness. Aspects of health and disease, 2(3), 31-49.
2. WDOWIAK, Artur, SADOWSKA, Monika, BAKALCZUK, Szymon, et al. Causes of male infertility. Psychosocial aspects of perception of health and beauty. Lublin: Wincentego Pol Wyższa Szkoła SpołecznoPrzyrodnicza im. Wincentego Pola w Lublinie, 2016, p. 123-141.
3. Szamatowicz M. Infertility. In: Obstetrics and gynaecology. Ed. Bręborowicz G.H. Warsaw: Wyd. Lekarskie PZWL 2005; 737-754.
4. Koperwas, M., & Głowacka, M. (2017). The problem of infertility among women and men-epidemiology, risk factors and public awareness. Aspects of health and disease, 2(3), 31-49.
5. MIANOWSKA, Klaudia, LEWICKA, Magdalena, SULIMA, Magdalena, et al. Evaluation of the karyotype of infertile couples. EJMT, 2015, vol. 3, p. 8.
6. BRANCH, D. Ware, GIBSON, Mark, et SILVER, Robert M. Recurrent miscarriages. N Engl J Med, 2010, vol. 363, p. 1740-47.
7. Zawiła, Karolina. "Recurrent miscarriages diagnosis and treatment. A model of care for the miscarrying patient." (2015).
8. STACHOWIAK, Grzegorz, ZAJĄC, Agnieszka, et WILCZYŃSKI, Jacek. Premature extinction of ovarian function. Menopausal Review/Przeglad Menopauzalny, 2012, vol. 11, no 2.
9. McCann-Crosby, B., Mansouri, R., Dietrich, J. E., McCullough, L. B., Sutton, V. R., Austin, E. G., ... & Macias, C. G. (2014). State of the art review in gonadal dysgenesis: challenges in diagnosis and management. International journal of pediatric endocrinology, 2014(1), 1-17.
10. SZATANIK, Karolina. Male infertility-disorders of spermatogenesis. 2014.