Infertility: new potential pathways involved

Author: Silvia De Francia
Date: 29/05/2012


Lavoro comune di Federica Collino, Silvia De Francia, Antonina Germano, Simona Perga, Monica Pradotto.

Despite numerous studies, clear comprehension of mechanisms of infertility are poorly understood. Purpose of the present investigation is to indicate pathways potentially involved in infertility, in order to promote new links between fields outwardly unconnected.


Aromatase seems to play a pivotal role in women already compromized for fertility. In PCOS affected women, for example, further increase in androgens levels via GnRH inhibition, leads to an infertility aggravation. In endometriosis affected women, furthermore, aromatase, expressed in endometrium (while in unaffected tissue is not expressed) leads to an increase in estrogens levels, inducing to an infertility aggravation. In both cases (PCOS and emdometriosis) are recommended aromatase inhibition drugs use; however aromatase inhibition drugs can entail a subclinical hypothyroidism development with normal levels of T3 and T4 and TSH level increase (Exemestane-induced subclinical hypothyroidism : a case report, 2008). At this purpose, furthermore, different studies underline that hypothyroidism leads to an aromatase function increase, while T3 and T4 administration lead to its reduction (Effects of tri-iodothyronine on alternative splicing events in the coding region of cytochrome P450 aromatase in immature rat Sertoli cells, 2001; Effect of thyroid hormone on CYP19 expression in ovarian granulosa cells from gonadotropin-treated immature rats, 2004; Short term hypothyroidism affects ovarian function in the cycling rat, 2010).
Infertility related disease and thyroid pathologies, then, especially hypothyroidism, seem to be related via aromatase pathway.


Normal pregnancy and childbirth are associated with significant haemostatic changes, the mechanisms of which remain poorly understood despite numerous studies. However, overall these changes create a procoagulant state, possibly in preparation for the haemostatic challenge of delivery. The concentration of the majority of clotting factors (including fibrinogen, factors VII, VIII, X, XII and von Willebrand factor) increase, and there is a decrease in physiological anticoagulants, including thrombomodulin and protein C inhibitor (Coagulation in pregnancy, 2010).


Various abnormalities of coagulation and fibrinolysis occur in patients with thyroid diseases, and may range from subclinical laboratory abnormalities to clinically significant disorders of coagulation and, rarely, major haemorrhage or
thromboembolism. Hyperthyroidism is hypothesized to increase the risk of various venous thromboembolic events, including venous, cerebral and superior sagittal sinus thrombosis, as highlighted by some case reports in the scientific literature. Compared with control subjects, increased values of von Willebrand factor, factor VIII factor IX, antithrombin, plaminogen activator inhibitor 1 (PAI-1) and decreased values of factor X, tissue plasminogen activator (t-PA) and TAFI were observed in patients with hyperthyroidism (Blood coagulation, fibrinolytic activity and lipid profile in subclinical thyroid disease: subclinical hyperthyroidism increases plasma factor X activity, 2006; Hyperthyroidism is associated with shortened APTT and increased fibrinogen values in a general population of unselected outpatients, 2009). Hypercoagulable responses resulting from a number of mutations that lead to thrombosis of the uteroplacental vessels, spiral artery vasculopathies, and impaired placental perfusion are all associated with abnormal development of the fetus, pregnancy losses, and obstetrical complications (Inherited thrombophilia and gestational vascular complications, 2003).

Inherited abnormalities of fibrinogen

Inherited abnormalities of fibrinogen (Fg) can be subdivided into quantitative defects in which there is a complete absence of fibrinogen (afibrinogenemia) or a reduced amount of fibrinogen (hypofibrinogenemia), and qualitative defects in which the fibrinogen produced does not function normally (dysfibrinogenemia). Patients can also have low levels of dysfunctional fibrinogen (hypodysfibrinogenemia). Afibrinogenemia is an autosomal recessive disorder with an estimated prevalence of 1 in 1 million. Hypofibrinogenemia can be inherited in an autosomal recessive or dominant fashion.
Dysfibrinogenemia is an autosomal dominant disorder with an unknown incidence. Women who have quantitative defects of fibrinogen are at increased risk of miscarriage, placental abruption, and postpartum hemorrhage. The ability of fibrinogen to form a stable fibrin network is important in maintaining placental integrity. Molecular defects that result in dysfibrinogenaemia are usually caused by a single base mutation that results in the substitution of a single amino acid. Other dysfibrinogenaemias are the result of stop codons (resulting in a truncated molecule) or small base deletions or additions that alter normal fibrinogen structure. A database of known molecular defects can be found on the World Wide Web (Fibrinogen Variants). The murine model FG-/- of congenital afibrinogenemia thus seems to be very suitable to investigate mechanistic
features of spontaneous miscarriage in humans with this genetic defect, and, even more important, to define the role of Fg in supporting a successful outcome of pregnancy.
In cases of pregnancies of
FG-/- mice, obvious genital bleeding was observed at any time between Embryonic day (E)7 to E9, and miscarriage occurred before E10. These pregnancies were rescued by administration of Fg, and normal vaginal deliveries occurred.
The role of Fg in supporting a successful pregnancy certainly involves its function as a hemostatic agent, by assuring that normal bleeding during development of immature vessels is effectively controlled. In addition, Fg is required in a less appreciated role, by assisting in formation of a stable fibrinoid layer that is
essential for anchoring the spongiotrophoblast layer to the decidua. This process may involve the interaction of stromal FN, itself bound to collagen at the surface of decidual cells at the implantation site, with its integrin receptors, on invading spongiotrophoblast cells.
Stromal Fg, supplied by the vasculature of the mother, may also bind to fibronectin (FN) and/or integrin, stabilizing the fibrinoid layer. FXIII, which is supplied by maternal plasma and by macrophage-derived mononuclear cells in the decidua, is capable of further stabilizing the fibrinoid layer via crosslinking of FN to Fg and of FN to decidua-derived collagen (Fibrinogen stabilizes placental-maternal attachment during embryonic development in the mouse, 2002).

5 alpha-reductase

Stewart PM et al. first reported an increased ratio of 5α-reduced cortisol and androgen metabolites in the urine of women with PCOS compared with weight-matched controls and proposed the hypothesis that increased cortisol clearance may cause a compensatory rise in ACTH levels to normalize serum cortisol but at the expense of increased adrenal androgens ("Cortisol metabolism in human obesity: impaired cortisone-->cortisol conversion in subjects with central adiposity, :"). Subsequent studies replicated these results; Chin D. et al. (Increased 5alpha-reductase and normal 11beta-hydroxysteroid dehydrogenase metabolism of C19 and C21 steroids in a young population with polycystic ovarian syndrome, 2000) studied a small cohort of nine adolescents and young women with PCOS, Tsilchorozidou T et al. studied 18 lean PCOS and compared them to BMI-matched controls (Altered cortisol metabolism in polycystic ovary syndrome: insulin enhances 5alpha-reduction but not the elevated adrenal steroid production rates, 2003), and Robinson S et al. reported increased 5α-reductase activity in PCOS (Which hormone tests for the diagnosis of polycystic ovary syndrome?, 1992). A role for 5α-reductase in PCOS has also been supported by Fassnacht M, who demonstrated a significant increase in 5α-reduced androgen metabolites in women with PCOS compared with controls after an oral DHEA load (Beyond adrenal and ovarian androgen generation: Increased peripheral 5 alpha-reductase activity in women with polycystic ovary syndrome, 2003"), and by Goodarzi MO, who found that a polymorphism of the SRD5A2 gene that modestly reduces the activity of the enzyme protects from PCOS (Variants in the 5alpha-reductase type 1 and type 2 genes are associated with polycystic ovary syndrome and the severity of hirsutism in affected women, 2006"). The cause of the increased 5α-reductase activity remains unknown. The metabolic abnormalities (obesity, central adiposity, insulin resistance, hyperinsulinemia) frequently seen in PCOS patients are tightly linked to increased cortisol secretion. Also PCOS is associated with autoimmune thyroid disease (AITD). Future intervention studies aimed at inhibiting 5α-reductase activity or improving insulin sensitivity are required to further our knowledge of the pathogenesis of PCOS.

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