Genetic Counseling and Diagnostic Guidelines for Couples with Infertility And/Or Recurrent Miscarriage
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medizinische genetik 2021; 33(1): 3–12 Margot J. Wyrwoll, Sabine Rudnik-Schöneborn, and Frank Tüttelmann* Genetic counseling and diagnostic guidelines for couples with infertility and/or recurrent miscarriage https://doi.org/10.1515/medgen-2021-2051 to both partners prior to undergoing assisted reproduc- Received January 16, 2021; accepted February 11, 2021 tive technology. In couples with recurrent miscarriages, Abstract: Around 10–15 % of all couples are infertile, karyotyping is recommended to detect balanced structural rendering infertility a widespread disease. Male and fe- chromosomal aberrations. male causes contribute equally to infertility, and, de- Keywords: female infertility, male infertility, miscarriages, pending on the defnition, roughly 1 % to 5 % of all genetic counseling, ART couples experience recurrent miscarriages. In German- speaking countries, recommendations for infertile cou- ples and couples with recurrent miscarriages are pub- lished as consensus-based (S2k) Guidelines by the “Ar- Introduction beitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften” (AWMF). This article summarizes the A large proportion of genetic consultation appointments current recommendations with regard to genetic counsel- is attributed to infertile couples and couples with recur- ing and diagnostics. rent miscarriages. Infertility, which is defned by the WHO Prior to genetic counseling, the infertile couple as the inability to achieve a pregnancy after one year of must undergo a gynecological/andrological examination, unprotected intercourse [1], afects 10–15 % of all couples, which includes anamnesis, hormonal profling, physical thus rendering infertility a widespread disease, compara- examination and genital ultrasound. Women should be ex- ble to, e. g., high blood pressure or depression. Histori- amined for the presence of hyperandrogenemia. Men must cally, the female partner has been the focus of diagnos- further undergo a semen analysis. Based on the overall re- tics and counseling, but the causes of infertility are well sults, hyper- or hypogonadotropic hypogonadism can be known to be equally distributed between the male and fe- diagnosed in both sexes. male partners. In fact, in one-third of all infertility cases, Female genetic diagnostics for infertility comprise both partners contribute to the pathogenesis [2]. Since karyotyping, analysis of the FMR1 premutation and a gene 5–10 % of female infertility cases and 5–20 % of male in- panel including genes associated with congenital hypo- fertility cases have identifable genetic roots in currently gonadotropic hypogonadism (CHH) or congenital adrenal established diagnostic analyses [3, 4], such diagnostics hyperplasia. Male genetic diagnostics for infertility com- and respective counseling should account for both part- prise karyotyping, screening for AZF microdeletions, CFTR ners equally. Due to novel technologies such as next gen- analysis and a gene panel including genes associated eration sequencing (NGS) and an increasing number of with CHH. Also, gene panels are increasingly being used known monogenic causes of both male and female infer- to causally clarify specifc phenotypes such as defective tility, more diagnostics increase the complexity of genetic sperm morphology/motility or azoospermia. As infertile counseling and informed consent for those couples. couples have an increased risk for chromosomal aber- In contrast to couples who present with infertility, cou- rations, a chromosomal analysis should also be ofered ples with recurrent miscarriages regularly do not have any difculty achieving a pregnancy but fail to maintain it. *Corresponding author: Frank Tüttelmann, Institute of Reproductive Genetics, University of Münster, Vesaliusweg 12-14, 48149 Münster, Overall, miscarriages occur frequently, as 5 % of all cou- Germany, e-mail: [email protected] ples of reproductive age experience recurrent (at least two) Margot J. Wyrwoll, Institute of Reproductive Genetics, University of miscarriages [5]. The percentage of couples meeting the Münster, Vesaliusweg 12-14, 48149 Münster, Germany, e-mail: WHO defnition of recurrent miscarriage (three or more [email protected] miscarriages before 20 weeks gestation) is estimated to Sabine Rudnik-Schöneborn, Institute of Human Genetics, Medical University Innsbruck, 6020 Innsbruck, Austria, e-mail: be 1 % [3]. Most miscarriages take place within the frst [email protected] trimester and are the result of numerical chromosomal Open Access. © 2021 Wyrwoll et al., published by De Gruyter. This work is licensed under the Creative Commons Attribution 4.0 International License. 4 | M. J. Wyrwoll et al., Review genetics infertility & miscarriage aberrations. In most cases, the fetus is not further exam- Female hyper- and hypogonadotropic ined, leaving the specifc cause undetermined. hypogonadism Although both infertility and miscarriages are com- mon, these issues remain socially taboo. Therefore, con- For genetic testing it is important to distinguish hyper- and cerned couples often feel exclusively afected by this prob- hypogonadotropic hypogonadism. Hypergonadotropic lem and avoid discussing the topic with their peers, which hypogonadism is characterized by elevated gonadotropins puts these couples under additional pressure; therefore, (FSH/LH) in the presence of normal or reduced estrogen genetic counseling of infertile couples or couples with mis- levels and point toward a primary ovarian dysfunction. carriages also requires an associated educational compo- Hypogonadotropic or hypothalamic hypogonadism (re- nent. On top of that, afected couples often sufer enor- duced FSH/LH and reduced estrogen levels) is very rare in mous psychological stress. Furthermore, the age of the females and is mostly caused by a reduced secretion of the female partner constitutes a critical factor for conceiv- gonadotropin releasing hormones (GnRH). Genetic causes ing a child naturally. Notably, the average age of women are complex and include congenital hypogonadotropic receiving treatments at fertility centers in Europe is 35 hypogonadism (CHH) and metabolic dysfunctions of the years [6], resulting in lower pregnancy and higher miscar- pituitary gland. riage rates when compared with the normal fertile popula- tion. This review provides an overview of important genetic Hyperandrogenemia conditions and the recommended diagnostic algorithms for couples with recurrent miscarriages or infertile cou- Important diferential diagnoses of hyperandrogenemia ples requesting assisted reproductive technology (ART). are polycystic ovary syndrome (PCOS) and congenital The corresponding recommendations were published in adrenal hyperplasia (CAH). Women with PCOS present German-speaking countries as S2k Guidelines by the “Ar- with cycle abnormalities and clinical signs of hyperandro- beitsgemeinschaft der Wissenschaftlichen Medizinischen genemia. Following the Rotterdam criteria, the diagnosis Fachgesellschaften” (AWMF) [4, 7]. For a more in-depth of PCOS can be established if testosterone levels are in- overview, both guidelines have been summarized in arti- creased and SHBG levels are reduced, along with specifc cles concerning the female [8–10] and male [10, 11] con- ultrasound changes of the ovaries (more than 12 antral fol- siderations. licles of less than 10 mm in diameter in each ovary). More than 50 % of patients show an insulin resistance, which can best be detected with the HOMA index. If hyperandrogenemia is associated with high 17-OHP Gynecological examinations for and DHEAS, this points toward an adrenal androgen pro- reduced fertility duction as seen in CAH. Classical CAH, most often caused by severe biallelic mutations of the CYP21A2 gene, is nowa- Diagnostic algorithms generally start with determining days generally detected by newborn screening for early the patient’s personal disease history including pedigree treatment. Non-classical or late-onset CAH presents like information (anamnesis) followed by clinical and labo- PCOS, with cycle abnormalities, subfertility and hyperan- ratory examinations. Anamnesis and physical examina- drogenemia. The most frequent 21-hydroxylase defciency tions should address pubertal development, signs of hypo- is suspected in the case of elevated 17-OHP and relative re- gonadism or cortisol excess. Anomalies of the inner geni- duction of cortisol. Final diagnosis is generally established tal tract can be sufciently detected by a vaginal sono- by molecular genetic analysis. graphy. The endocrine basics include measuring LH, FSH, TSH, prolactin, testosterone, DHEAS, SHBG, free andro- Anti-Müllerian hormone gen index, estradiol and Anti-Müllerian hormone (AMH). If there are anovulatory cycles, a single progesterone mea- AMH is synthesized by primordial follicles and plays a surement should be obtained at about day 21 in an as- role in determining ovarian activity. The activity of AMH is sumed cycle. If there are abnormal fndings in the en- inversely correlated with age and shows considerable in- docrine basics, further diagnostic steps proceed, e. g., terindividual diferences. Reduced AMH levels are of poor 17-OH progesterone (17-OHP) measurements in the pres- predictive value regarding fertility but are used to estimate ence of hyperandrogenemia. the ovarian reserve in the context of ART. Besides genetic M. J. Wyrwoll et al., Review genetics infertility & miscarriage | 5 factors leading to primary or premature ovarian insuf- mic men with increased FSH levels and reduced