The Genetics of Female and Male Infertility

Background: An estimated 17% of all couples worldwide are involuntarily childless (infertile). The clinically identifiable causes of infertility can be found in the male or female partner or in both. The molecular pathophysiology of infertility still remains unclear in many cases but is increasingly being revealed by genetic analyses.

Methods: This review article is based on pertinent publications retrieved by a selective literature search.

Results: The clinical diagnostic evaluation of an infertile couple may yield an indication for genetic analysis. Women with premature ovarian insufficiency should undergo chromosomal analysis and study of the FMR1 gene. If congenital adrenal hyperplasia is suspected, the CYP21A2 gene should be investigated. In men, genetic diagnosis is based primarily on the findings of semen analysis. Klinefelter syndrome and deletions of the Y-chromosomal azoospermia factors may severely limit sperm production. In both male and female partners, the analysis of a gene panel selected on the basis of the individual indication may identify the cause of infertility, e.g., hypogonadotropic hypogonadism, premature ovarian insufficiency, or severe disturbances of spermatogenesis. In some cases, genetic analysis can help determine the likelihood of success of sperm retrieval via testicular biopsy in men, and the potential indication for oocyte cryopreservation in women.

Conclusion: Genetic causes, disease patterns, and the related investigations are becoming increasingly important in the diagnostic evaluation of infertile couples and have implications for further treatment, for the children of the affected couple, and for other family members.

Cite this as: Tüttelmann F, Wyrwoll MJ, Steingröver J, Wieacker P: The genetics of female and male infertility. Dtsch Arztebl Int 2025; 122: 115–20. DOI: 10.3238/arztebl.m2024.0259

Infertility has some unique features that set it apart from other diseases. First, its status as a disease is called into question, depending on the (health) political agenda. One example of this is the term “unfulfilled desire to have children” which is treated in fertility clinics (in Germany called “Kinderwunschzentrum”, literally translated “Desire-to-have-children Center”). In these clinics, those affected have to pay a substantial part of the associated treatment costs themselves. An alternative term used is “involuntary childlessness“ which does mainly apply to couples and not to individuals which is unique in the entire field of medicine. Accordingly, only a couple can initially be diagnosed with infertility.

However, the use of the term “infertility” is also problematic since in some cases the absence of a spontaneous pregnancy can be overcome by medically assisted reproduction (MAR). Consequently, a woman or a man is only then completely infertile if no egg or sperm cells (oocytes, spermatozoa) are present or the reproductive cells are inherently not fit to conceive a child. The World Health Organization (WHO) defines couple infertility as the failure to achieve a pregnancy after 12 months of regular unprotected sexual intercourse. This applies to one in six adults worldwide—corresponding to about 17% of all couples (1)—and thus is one of the most common diseases of all.

The clinical diagnostic evaluation reveals causes on the part of the female partner of the infertile couple (e.g., menstrual cycle disorders), the male partner (most commonly, impaired sperm quality) or both in about 30%, respectively. A fundamental distinction must be made between fertility impairments as a consequence of a primary disease and isolated fertility impairments in otherwise healthy persons.

In about 10% of all affected couples, all clinical findings are normal. Even if a clinically identifiable cause can be determined, e.g., azoospermia, i.e. a complete absence of sperm cells in the ejaculate, the underlying (molecular) causes remain obscure in the majority of cases (2), because the pathomechanisms are still poorly understood. In many case, this impedes evidence-based, individualized treatment decision-making so that more research in this field is needed (3). At this point, genetic causes, disease patterns and relevant testing gain in importance.

Methods

Our narrative overview is based on a selective search of the PubMed database for articles published in the last ten years, up to May 2024. We also considered the literature cited in the identified articles, other reference publications and reviews, as well as the German (S2k-level) clinical practice guideline “Diagnosis and Treatment Before Assisted Reproductive Treatments” (4).

Clinical forms of infertility

The causes of impaired fertility can be located at the level of:

• the hormonal control of the gonads
• the gonads themselves
• the postgonadal transport structures
• the fertilization, or
• the implantation.

Figure 1 provides an overview of the most common disorders.

Figure 1

Causes of impaired fertility by organ system and overview of the most common conditions

Infertility as a part of a general disease

Many chronic/multisystem disorders are associated with impaired fertility. Examples include Wilson’s disease and thalassemia which can lead to infertility in women and men, especially if left untreated. Thus, treating the underlying disease is the primary approach to achieve the goal of spontaneous fertility. Infertility is part of the clinical spectrum in a number of syndromal diseases, for example in Noonan syndrome which is associated with cryptorchidism and male infertility (5). While there is no causal therapy available in most of the cases, MAR can be an option depending on the clinical findings. MAR is preceded by counselling and, if necessary, genetic testing to determine the risk of recurrence of the underlying disease and infertility in the offspring.

Hypogonadotropic hypogonadism

Among the genetic diseases associated with infertility, hypogonadotropic hypogonadism is of particular importance. Cardinal symptoms include the lack of gonadotropin production (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) as well as the resulting infertility and absence of puberty. Hypogonadotropic hypogonadism can occur isolated, in combination with an impaired sense of smell/anosmia (Kallmann syndrome), or as part of a syndromal disease (e.g., Bardet-Biedl syndrome). The diagnosis is established based on clinical findings, typically on the absence of puberty, and the results of relevant hormone testing.

Hypogonadotropic hypogonadism is a rare disease with a prevalence of less the 1 in 5000 among men and less than 1 in 10 000 among women (6). Today, more than 50 monogenic causes of hypogonadotropic hypogonadism are known. The genetic diagnostic rate is approximately 50% (7). Hormone replacement therapy for the treatment of infertility, which aims to stimulate the ovaries or testis (LH + FSH or gonadotropin-releasing hormone [GnRH] analogs) and must not involve the use of sex hormones (estrogens, testosterone), can lead to spontaneous fertility in many affected individuals.

Clinical diagnosis in isolated infertility

In the case of unwanted childlessness and prior to starting MAR, a gynecological or uro-andrological diagnostic evaluation should be performed according to the current German clinical practice (S2k-level) guideline (4). In each of the two partners, this includes:

• a comprehensive medical history
• a physical examination
• sex hormone testing
• an ultrasound scan
• of the internal genitalia in women
• of the scrotal contents, in particular the testes, in men.

In men, semen analysis is an additional test that guides the diagnostic workup.

The indications for genetic testing are based on the findings of the workup, in particular in patients where no cause can be identified in the medical history or clinical examinations, e.g. a history of cancer treated with chemotherapy or radiotherapy. Figure 2 shows the diagnostic algorithm (4). Of particular note are the broad clinical spectra, ranging, for example, in women from primary or premature ovarian insufficiency (POI) to premature menopause and in men from the complete absence of sperm in the ejaculate (azoospermia) to completely normal ejaculate parameters (normozoospermia). As recommended in the guidelines, even if all findings are normal, both partners should be offered a chromosomal analysis before starting MAR. For the sake of readability, in the following text the abbreviated form in accordance with the guideline of the Association of the Scientific Medical Societies in Germany (AWMF, Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften) is used for all recommendations on genetic testing; what is always meant is “should /ought to/may be offered”, where “should” indicates a strong recommendation, “ought to” a recommendation and “may” an open recommendation.

Figure 2

Diagnostic algorithm adapted from the AWMF clinical practice guideline “Diagnosis and Treatment Before Assisted Reproductive Treatments”

Genetic causes and diagnostic evaluation in women

Chromosomal variations: Turner syndrome, trisomy X and translocations

About 40% of infertile women experience ovarian dysfunction, characterized by elevated FSH levels and reduced anti-Müllerian hormone (AMH) levels. This constellation is an indicator of a diminished ovarian reserve consistent with POI (8). After other causes have been ruled out, a chromosomal analysis should be performed. A rare cause of hypergonadotropic hypogonadism is Turner syndrome which is characterized by a short stature and other abnormalities, such as heart defects and renal malformations. The karyotype is 45,X (monosomy X) or there is mosaicism, e.g., 45,X/46,XX. In women with the karyotype 45,X, the chances of eggs being present are extremely low (9). In the case of mosaicism, the chances increase in parallel with the proportion of 46,XX cells (10). Women with Turner syndrome can get pregnant after egg donation. In about 3% of women with POI, trisomy X (47,XXX) is detected. However, the phenotype is highly variable and many affected women get pregnant spontaneously (11).

Balanced structural chromosomal rearrangements (mainly translocations, but also inversions, etc.) are more common in both infertile women and men compared to the general population. While such chromosomal variations usually do not manifest any symptoms of disease in the carrier, they are associated with a significantly increased risk of the formation of unbalanced (aneuploid) germ cells and embryos. Clinical manifestations of these abnormalities include infertility due to implantation failure, repeated miscarriages and an increased risk of having a child with typically severe mental and physical developmental disorders. For this reason, it is important to inform couples in which one of the two partners is a carrier of a translocation or similar chromosomal variation about the associated risks for the pregnancy and the offspring and about the possibility of prenatal diagnosis and preimplantation genetic diagnosis (PND/PGD).

Monogenic causes

Approximately 2% of the cases with sporadic POI and 10–15% of the women with a relevant family history are carriers of a premutation of the X-chromosomal FMR1 gene, a CGG trinucleotide repeat expansion between 55 and 200 (12). If inherited from the mother, the size of the expansion can further increase. CGG repeats >200 are referred to as full mutations and lead to fragile X syndrome, characterized by intellectual disability. Therefore, the length of the FMR1 CGG repeats should be analyzed in women with suspected POI and affected women should be informed about the risks for their offspring.

In POI, especially the younger the women affected are, there are numerous other genes in which variants can be the cause of disease (13). A causal diagnosis can me established based on an analysis performed using a suitable gene panel (Table, according to [14]). Noteworthy with regard to monogenic causes is the overlap of female and male infertility due to disorders of meiosis. In women, this results in POI, in men in limited or absent production of sperm.

Table

Genes relevant to the diagnosis of selected disorders leading to female and/or male infertility

A mild form of Congenital adrenal hyperplasia (CAH) can be the underlying cause of hyperandrogenemia and resultant acne, hirsutism, secondary oligo- or amenorrhea, and infertility (late-onset CAH). Hyperandrogenemia is attributable to impaired steroid metabolism in the adrenal glands which is caused by variants in the CYP21A2 gene in over 90% of the affected women (15). The severe classical forms of CAH, which are associated with virilization of female fetuses and possibly salt loss, are inherited in an autosomal recessive manner. The mild forms can also be caused by individual heterozygous variants and are often only diagnosed when infertility is investigated. If a patient presents with one or more of the above mentioned symptoms, at least a sequence analysis of the CYP21A2 gene should be performed; other genes are significantly less frequently affected (Table). Spontaneous fertility can be achieved with corticosteroid treatment; if not, MAR is indicated. Affected couples should be informed about the risk of severe forms of CAH in their offspring and the option of preventive corticosteroid treatment during pregnancy which, however, is experimental.

Maternal effect genes (MEGs) encode egg-specific factors that control the early embryonic development (16). Variants in these genes are associated with different phenotypes that lead to female infertility (Table). These include fertilization disorders, early disorders or arrest of embryonic development, hydatidiform moles, implantation failure, and recurrent miscarriage. In addition, affected women are at a higher risk of having a child with a multi-locus imprinting disorder (MLID) (17). Presumably due to the many different phenotypes, maternal effect genes have so far not been systematically analyzed; thus, the associated infertility is very likely underdiagnosed. The recurrence risks vary with the underlying disorder. The recurrence risk for hydatidiform mole is generally between 1% and 9%, but it is almost 100% in the case of biallelic inactivation of the NLRP7 gene.

Genetic causes and diagnostic evaluation in men

Chromosomal variations: Klinefelter syndrome, XX males and translocations

The lower the sperm count in men, the more frequently chromosomal variants are found. In oligozoospermia (total sperm count in the ejaculate <39 million), translocations play a special role—with the same consequences as in women. In men with a very low sperm count (severe oligozoospermia of less than 5 million sperm; crypto- or azoospermia, only few or no sperm), Klinefelter syndrome is the most likely cause (18). In most cases, the karyotype is 47,XXY, but mosaicism also occurs. Patients with Klinefelter syndrome usually present with azoospermia; the chance of retrieving sperm by means of testicular biopsy with testicular sperm extraction (TESE) is about 50% (19).

Klinefelter syndrome affects approximately one in 500 men in the general population. Even though it is likely that being diagnosed with Klinefelter syndrome causes psychological stress, the advantages of the diagnosis outweigh the disadvantages in most cases. One advantage is that bone density can be monitored on a regular basis so that testosterone replacement therapy can be initiated, if necessary. Many men also feel relieved when the cause of infertility has been identified, so that they no longer need to feel guilty. In contrast, so-called XX males (karyotype 46,XX) are significantly rarer. In more than 90% of XX males, this is the result of a translocation of the SRY gene, which allows the embryo to develop into a male fetus despite the absence of the Y chromosome. In contrast to men with Klinefelter syndrome, it is not possible to retrieve sperm in XX males by means of TESE, and a testicular biopsy should not be performed.

Y chromosomal microdeletions

In addition to chromosomal analysis, all men with severe oligo- or azoospermia should undergo azoospermia factor (AZF) testing; the AZFs are located in the long arm of the Y chromosome (20). AZF microdeletions cannot be detected by conventional chromosomal analysis; yet, they are the cause of the condition in up to 4% of men with azoospermia. The AZF region consists of the three segments AZFa, AZFb and AZFc. AZFc deletion is with 70–80% the most common type and the TESE success rate is about 50%. Affected men should be informed about the inheritance of the Y-chromosomal AZF deletion and the associated infertility in sons. Microdeletions of the AZFa (0.5–9%), AZFb (1–7%) and AZFbc (1–20%) regions are rarer and the TESE success rates are virtually zero; therefore, a testicular biopsy is not indicated in these cases (20).

Monogenic causes

As a result of intensified research efforts and technological advances, new genes associated with disorders of spermatogenesis have been described over the past few years on a regular basis. A number of genes associated with many different phenotypes are now known with sufficient supporting evidence and can be investigated by analyzing a corresponding gene panel (Table) (21). The resulting genetic diagnoses are of particular clinical relevance for the differentiation between obstructive and non-obstructive azoospermia. In obstructive azoospermia, the chances for a successful TESE amount to almost 100%, while they are 0% in some cases of non-obstructive azoospermia and 50% on other cases, depending on the underlying genetic cause. This means that genetic testing can predict the chances of success of a testicular biopsy (22). If a pathogenic variant in the CFTR gene is identified, there is a calculated risk of 1–2% for a child with cystic fibrosis, based on the heterozygote frequency of 4% in the general German population. The risk depends on the carrier status of the female partner. Affected persons must be informed about this connection and relevant testing must be offered.

In the case of highly abnormal sperm motility and/or sperm morphology (astheno- or teratozoospermia), conditions commonly associated with a reduced sperm count, monogenic causes are also a possibility (Table); to date, however, these have had hardly any clinical consequences on the further management. However, the fact that the mere identification of the genetic cause is of great value to those affected should not be neglected, even if there is no treatment available for it.

If all ejaculate parameters are normal, the unexplained couple infertility may be due to pathogenic variants in the PLCZ1 gene and in genes such as the CATSPER2 gene, which encode subunits of the CatSper ion channel and is only found in sperm (23). MAR by means of intracytoplasmic sperm injection (ICSI) is the only treatment option available to affected men to father a child.

Consequences beyond fertility

Infertility is increasingly being linked to other health risks, including a higher risk of cancer (24). A common genetic predisposition for infertility and cancer can be assumed due to the fact that infertile persons carry significantly more frequently disease-relevant variants in at least 25 different cancer risk genes (25, 26) and an increased cancer risk is found in their relatives, too (27). Examples of this include the BRCA1 and BRCA2 DNA repair genes, in which variants are associated with a greatly increased risk of breast, ovarian and prostate cancer. Disease-relevant variants in these genes were found in 2% of women in an infertile cohort (26). In other studies, infertility is found to be associated with an increase in metabolic and cardiovascular risks—for example, an odds ratio of 1.8 for hypertension in infertile women—through to an overall lower life expectancy (3, 28). However, the reasons for these associations are still poorly understood. In addition to genetic factors, lifestyle differences between fertile and infertile persons may play a role, e.g., with regard to smoking and/or higher alcohol consumption.

Not only the health of the couple, but also the health of their offspring conceived using MAR should be taken into account. For example, children conceived by means of ICSI have a risk of 5–7% for congenital diseases and malformations (29, 30) compared to the so-called base risk of 3–5% for spontaneously conceived children. In addition, children conceived using MAR and in particular ICSI appear to have higher cardiovascular risks as well as fertility impairments in male offspring (31, 32). Given that the underlying mechanisms are largely unknown, there is an urgent need to collect further data.

Outlook

New molecular diagnostic methods supplement the conventional tests and are clinically and therapeutically relevant for preserving fertility in patients with POI with the help of oocyte cryopreservation, as well as predicting the success of a testicular biopsy/TESE and MAR. In the future, it will presumably be useful to test for all genes known to be associated with female and male infertility early on in the diagnostic process.

Funding

This review article was produced in the context of the “Male Germ Cells” Clinical Research Unit, funded by the German Research Foundation (DFG, Deutsche Forschungsgemeinschaft) (DFG CRU326, project number 329621271), the Junior Scientist Research Center “ReproTrack.MS”, funded by the German Federal Ministry of Education and Research (BMBF, Bundesministerium für Bildung und Forschung) (BMBF 01GR2303), and with support of the DFG Walter Benjamin program (project identifier WY 215/1–1).

Conflict of interest statement

FT received financial support from Bayer AG and the Gates Foundation (research grants). He received reimbursement of travel costs and congress fees as well as lecture fees from IBSA and Organon.

The remaining authors declare that they have no conflict of interest.

Manuscript received on 29 June 2024, revised version accepted on 19 December 2024

Translated from the original German by Ralf Thoene, M.D.

Corresponding author
Prof. Dr. med. Frank Tüttelmann

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