Female infertility

The etiology of female infertility can be defined under multiple diseases (Table I) (Forti and Krausz, 1998). However, the most influential physiological compo-nent is the age of a woman. Similarly, genetic propensity, environmental fac-tors, including smoking the cigarettes and substance abuse, malnutrition and over- or underweight play also a great role (The ESHRE Capri Workshop Group, 2002).

Table I. Non-genetic causes of female infertility (based on Forti and Krausz, 1998) Ovulatory dysfunction

Premature ovarian failure (POF) Polycystic ovary syndrome (PCOS) Tubal obstructions

Tubal factor infertility (TFI) Endometriosis

Vaginal and cervical factors Uterus abnormalities Unexplained infertility

15 Ovulatory dysfunction

Impairments in the endocrine system can lead to anovulatory infertility either with , hyper-, or normal levels of gonadotropic hormones. During hypo-gonadotropic hypogonadism, the reduced secretion of pituitary follicle stimu-lating hormone (FSH) and luteinizing hormone (LH) hinder ovulation. This condition is often seen in underweight women but also in excessively exercising female athletes. Elevated levels of FSH indicate ovarian failure, mainly, be-cause of depletion of the oocytes, or, in rare cases, bebe-cause of resistant ovary syndrome (The ESHRE Capri Workshop, 1996; The ESHRE Capri Workshop Group, 2002). When elevated serum FSH level is associated with amenorrhea and hypoestrogenism before the age of 40, the diagnosis of premature ovarian failure (POF) is assigned. Lately a pathophysiologically more precise term, primary ovarian insufficiency (POI), is preferred (Welt, 2008). The new term describes more accurately the state of ovarian condition, since varying degree of ovarian function is still preserved in some of the patients and, moreover, a small proportion of women with POF diagnosis may still spontaneously conceive and deliver (Tsigkou et al., 2008; Welt, 2008). The estimated prevalence of POF in women by the age 40 is approximately 1%. Two major mechanisms of POF are follicle dysfunction and follicle depletion. The etiology of POF, however, re-mains mostly unknown and a variety of possible causes, including genetic, en-vironmental and iatrogenic, have been proposed (Kokcu, 2010). Besides, an autoimmune basis has been detected in almost half of the POF cases as these patients have: (1) associated autoimmune diseases, such as Addison’s disease or thyroid autoimmunity; (2) autoantibodies to steroid-producing cells and/or other ovarian antigens and (3) lymphocytic oophoritis (Hill et al., 1990; Lebovic and Naz, 2004; Carp et al., 2012; Kokcu et al., 2012).

Women with normogonadotropic anovulation reveal serum levels of FSH and LH within normal range. Normogonadotropic anovulation can often be cau-sed by adrenal hyperandrogenism or polycystic ovary syndrome (PCOS) (The ESHRE Capri Workshop, 1996; The ESHRE Capri Workshop Group, 2002).

Although PCOS is the leading endocrine disorder in women, with prevalence up to 15%, there is still a lot unknown in the etiology of this disease. The clinical expression of this syndrome can be variable, generally including oligo- or an-ovulation, hyperandrogenism and polycystic ovaries. These women may suffer from subfertility due to the impact of obesity, hyperinsulinemia or –andro-genism and endocrine irregularities on folliculogenesis and endometrial recep-tivity. Furthermore, because of the factors listed, these patients are more prone to develop pregnancy associated complications, like gestational diabetes or hypertension. Insulin resistance, commonly seen in obese PCOS patients, increases the risk of developing type II diabetes in these women (Fauser et al., 2012). Additionally, autoimmune thyroiditis is significantly more prevalent in PCOS patients than in controls without PCOS (Janssen et al., 2004). Therefore, an autoimmune implication has been suspected in the etiopathogenesis of PCOS cases that are associated with other autoimmune diseases, as these patients are

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also positive for several autoantibodies (Luborsky, 2002; Petríková and Lazúrová, 2012).

Tubal obstructions

Tubal factors account for 25–35% of infertility cases. Causes for damaged fallo-pian tubes include pelvic inflammatory disease (PID), endometriosis and pelvic surgery. As a result, the transport of either spermatozoids or fertilized oocyte is impaired or even impossible (The Practice Committee of the American Society for Reproductive Medicine, 2006b). PID is a widely spread significant sequelae of sexually transmitted diseases (STD) among non-pregnant women of repro-ductive age. Long-term complications due to PID can be tubal factor infertility (TFI), ectopic pregnancy and chronic pelvic pain. Long term complications are mostly associated with the coinfection of Chlamydia trachomatis and Neisseria gonorrhoeae (Sweet, 2011). The induction of proinflammatory cytokines [tu-mor necrosis factor (TNF)-α and interleukin (IL)-1] after chlamydia or gono-cocci infection can damage the epithelium of the fallopian tubes causing thereby loss of function. In addition, hydrosalpinx fluid contains prostaglandins, leuko-trienes and lymphocytes that can eventually have deleterious inflammatory ef-fects also on the uterine environment, influencing thereby negatively implant-ation of an embryo (Meyer et al., 1997; Camus et al., 1999; Maisey et al., 2003;

Bontis and Theodoridis, 2006). Further evidence of deviations in the regulation of local immune response in TFI patients is provided by the significantly higher levels of serum autoantibodies, which may also harm the function of fallopian tubes and endometrium (Van Voorhis and Stovall, 1997; Stern et al., 1998;

Choudhury and Knapp, 2001; Reimand et al., 2001).

Endometriosis, a chronic inflammatory disease characterized by the presence of endometrial glands and stroma outside the uterus, affects up to 10% of repro-ductive age women. The main manifestations are pelvic pain and infertility (Burney and Giudice, 2012). Diverse causes for reduced fertility have been de-scribed in these patients, as they have disturbances in folliculogenesis, funct-ional disorders in fallopian tubes and impaired implantation of the embryo into the endometrium (Halis and Arici, 2004; de Ziegler et al., 2010). Endometriosis is also characterized by inflammatory status of the immune system, for example impaired natural killer cell activity and macrophage function. Overexpression of proinflammatory and embryotoxic cytokines in the peritoneal fluid creates an inflammatory milieu not only in the peritoneum but also in the eutopic endo-metrium (de Ziegler et al., 2010; Burney and Giudice, 2012). Besides, a high concordance of autoimmune diseases is observed in infertile women with endo-metriosis, as well as significantly higher prevalence of autoantibodies against endometrium, ovary and phospholipids, to name a few. Therefore, endometri-osis is sometimes considered as an autoimmune disease (Matarese et al., 2003;

Burney and Giudice, 2012).

17 Unexplained infertility

Unexplained infertility is a diagnosis made by exclusion, when standard investi-gations used in everyday clinical approach (tests of ovulation, tubal patency and semen analysis) are normal in an infertile couple (The Practice Committee of the American Society for Reproductive Medicine, 2006a). The prevalence of unexplained infertility in infertile women varies from 21–26%, increasing with patients age (Maheshwari et al., 2008). The causes for unexplained infertility are heterogeneous. Female age is thought to be the major influencing factor (The ESHRE Capri Workshop, 1996; Maheshwari et al., 2008), but immune system impairments (Putowski et al., 2004; De Carolis et al., 2010), genetic factors (Altmäe et al., 2009) and subclinical endocrinological diseases (Dmowski, 1995) have been suspected as much. In patients with immune sys-tem impairments, discrepancy between the T helper lymphocyte (Th)1-Th2 res-ponses towards the pregnancy not favoring Th1 profile has been detected.

Consequent imbalance in cytokine profile may in one’s turn lead to changes in uterine natural killer cell number and activation status, which may additionally contribute to implantation failure in unexplained infertility patients (Perricone et al., 2008; De Carolis et al., 2010).