Clinica Chimica Acta 508 (2020) 185–190

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Clinica Chimica Acta

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Review

Biochemistry of infertility T
b,d,⁎
T. Wasilewski , M. Łukaszewicz-Zając , J. Wasilewska , B. Mroczko
a b c

a
Centre for Restorative Procreative Medicine, Napromedica, Bialystok, Poland
b
Department of Biochemical Diagnostics, Medical University of Bialystok, Bialystok, Poland
c
Centre for Paediatrics, Allergology, Psychodietetics, and Treatment of Children Diagnosed with Autism, IPM, Bialystok, Poland
d
Department of Neurodegeneration Diagnostics, Medical University of Bialystok, Bialystok, Poland

A R T I C LE I N FO A B S T R A C T

Keywords: Infertility affects approximately 186 million people worldwide and 8–12% of couples of reproductive age.
Infertility Therefore, a comprehensive diagnostic evaluation of infertility is crucial to achieving improvements in targeted
Diagnosis prevention and treatment outcomes. The aim of this review is to explore the biochemistry of infertility in order
Treatment to properly diagnose and treat infertile couples. Recent studies indicate that routine measurement of biochemical
parameters reflecting thyroid dysfunction, immunological disorders, autoimmune mechanisms, insulin re-
sistance and malabsorption of selected micro- and macronutrients are required to assess infertility. Due to the
complexity of this approach, algorithmic protocols that integrate these biochemical parameters in a dynamic test
environment are necessary to provide a more comprehensive diagnostic assessment and more effective treatment
strategy for infertile couples.

1. Introduction Infertility is expected to increase in the future, therefore a com-

Infertility is defined as the failure to achieve a clinical pregnancy
after 12 months or more of regular, unprotected sexual intercourse [1].
It is estimated that infertility may affect around 186 million people
worldwide, while male infertility contributes to more than half of all
cases of global infertility [2]. Some clinical investigations have in-
dicated that infertility affects approximately 8–12% of couples of re-
productive age worldwide [2,3]. It is reported that 33–41% of infertility
cases are due solely to a female factor, male factor accounts for 25–39%
of the problem and 9–39% is due to a combination of both male and
female factors. Moreover, in some regions of the world such as Central
and Eastern Europe, Central and South Asia and sub-Saharan Africa the
rates of infertility are higher, reaching 30% [2–5].
Common etiologies for female infertility are ovulation disorders
such as polycystic ovary syndrome, hypothalamic dysfunction, pre-
mature ovarian insufficiency, tubal infertility, endometriosis and/or
uterine and cervical causes, whereas male infertility is mainly due to
disturbed sperm function, blockages preventing sperm delivery, var-
icocele, hormone imbalance, malignancies, infection, antisperm anti-
bodies [6–10]. In addition, it is estimated that approximately 30% of
infertile couples globally are diagnosed with unexplained or idiopathic
infertility and this clinical problem is defined as a lack of an obvious
cause for a couple's infertility [11].
prehensive diagnostic evaluation of infertility is crucial to achieving
improvement in targeted prevention and treatment outcomes. The goal
of presented review is to highlight the importance of a comprehensive
biochemical parameters evaluation including thyroid dysfunction, im-
munological disorders, autoimmune mechanisms, metabolic dysregu-
lation, as well as malabsorption of selected micro- and macronutrient
(Fig. 1; Table 1) that can impact the fertility to improve diagnosis,
treatment and ultimately outcomes.
1.1. Infertility and thyroid dysfunction
Hypothyroidism may cause menstrual disturbances, infertility as
well as heighten the risk of miscarriage by causing an increase in
thyrotropin-releasing hormone levels (TRH). Hypothyroidism stimu-
lates the secretion of prolactin and/or alters dopamine metabolism,
which may lead to increased prolactin concentration and decreased
dopamine levels. Thus, hypothyroidism, followed by hyperprolacti-
nemia, may cause ovulation disturbances, changes in the luteal phase as
well as amenorrhea or oligomenorrhea [1,12–14]. Furthermore, dopa-
mine may slow down the pulsation of gonadotropin-releasing hormone,
causing an increase in luteinizing hormone levels (LH) [2,12–15].
Elevated concentrations of thyroid stimulating hormone (TSH) and TRH
might regress the dysfunction of corpus luteum by a direct luteotropic

⁎
Corresponding author at: Department of Neurodegeneration Diagnostics, Department of Biochemical Diagnostics, Medical University of Bialystok, ul.
Waszyngtona 15 a, 15-269 Bialystok, Poland.
E-mail address: mroczko@umb.edu.pl (B. Mroczko).

https://doi.org/10.1016/j.cca.2020.05.039
Received 9 April 2020; Received in revised form 18 May 2020; Accepted 20 May 2020
Available online 21 May 2020
0009-8981/ © 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
T. Wasilewski, et al. Clinica Chimica Acta 508 (2020) 185–190

Fig. 1. Biochemical findings in infertile couples resulting from brain, thyroid, gut, genitourinary tract disorders, immune system over activity with molecular
mimicry (autoimmunity) and multisystem metabolic dysregulation leading to gonadal failure and the incapacity to achieve a pregnancy. TRH – Thyrotropin-
releasing hormone, PRL – Prolactin, TSH – Thyroid-stimulating hormone, TPO-Ab – Anti-thyroid peroxidase antibodies, TG-Ab – Anti-thyroglobulin antibodies, TR-
Ab – thyrotropin receptor antibodies, fT4 – free thyroxine, fT3 – free triiodothyronine, HOMA-IR – Homeostatic Model Assessment of Insulin Resistance, HbA1c
–glycosylated (or glycated) haemoglobin. A high-resolution version of this Fig. 1 is available as eSlide.

Table 1
Biochemical parameters in diagnostics of infertility.
Biochemical aspects Parameters References

Thyroid dysfunction TSH – thyroid stimulating hormone [1,9,12–25]

TRH – thyrotropin-releasing hormone
fT4 – free thyroxine
fT3 – free thyroxine
anti-TPO – anti-thyroid peroxidase antibodies
anti-TAG, thyroid antibodies thyroglobulin, anti-TRAb – thyroid receptor antibodies
Immunological disorders IgE – immunoglobulin E [8,26–32,56,57]
IgA – immunoglobulin A
IgG – immunoglobulin G
ASA – anti-sperm antibodies
Can f5 – dog dander allergen
cytokines (interleukin-5, -6, -8, and -10)
Autoimmune mechanism (gluten intolerance) (IgA anti-tTG) antibodies – immunoglobulin A anti-tissue transglutaminase [33–44,58]
Metabolic dysregulation (insulin resistance) fasting glucose [45–51]
fasting insulin
2-hour glucose and 2-hour insulin levels
homeostasis model assessment of insulin resistance (HOMA-IR)
Malabsorption of selected micro- and macronutrients iron, folic acid, zinc, vitamin D, as well as other micro- and macronutrients [52–55]
(vitamins), (vitamins)

186
T. Wasilewski, et al.
effect [12,16]. It has also been proven that hypothyroidism may result
in a decrease in the concentration of sex hormone-binding globulin
(SHBG) and estradiol, a reduction in the metabolic clearance rates of
estrone and androstenedione as well as an increase in the concentration
of the unbound fraction of testosterone and estradiol [1,12,14,15]. In-
adequate treatment of hypothyroidism or subclinical hypothyroidism
(SH) can lead to infertility, miscarriage and adverse obstetrical and
neurodevelopmental outcomes [17].
The diagnosis of hypothyroidism is based on the measurement of
TSH and free thyroxine (T4) concentrations. The incidence of SH in the
population of reproductive age is approximately 4%–8% [18]. The
clinical symptom of hypothyroidism is a decreased level of free thyr-
oxine (FT4) caused by the reduced secretion of thyroid hormones. In
patients with SH, however, serum TSH concentrations are elevated, but
FT4 is within the reference range and usually no typical symptoms of
hypothyroidism are present [12,19]. In the differential diagnosis of
thyroid abnormalities, a TRH stimulation test has been widely used. An
abnormal TRH stimulation test may indicate early-stage SH [12,20].
A study by Eldar-Geva T. et al. has assessed the prevalence of SH
among women with various causes of infertility and proved the relia-
bility of TRH stimulation testing in determining SH in infertile women
[12]. The authors have indicated that the prevalence of SH is sig-
nificantly higher among women with ovulation disorders and abnormal
TRH in comparison to women with normal ovulation, which has been
confirmed by other authors [1,17]. Furthermore, despite the fact that
basal TSH concentrations were within the reference values on recruit-
ment, 2–4 months later those levels were abnormally high in 8% of the
women studied [12]. The authors recommend performing a TRH sti-
mulation test in women with ovulation disorders and normal basal TSH
levels, followed by regular assessments of thyroid function in order to
enable thyroxine treatment in patients with abnormal results [12].
Contradictory results have been presented by other authors, who have
demonstrated that a positive TRH test does not have sufficient diag-
nostic sensitivity and specificity to identify SH. They concluded that a
TRH stimulation test was not helpful in identifying patients with SH and
should not be part of the initial screening in this group of patients [21].
However, a TRH stimulation test is a widely used screening tool for SH
in subfertile patients in clinical practice [21].
A study by Poppe and Velkeniers has indicated that thyroid dys-
function interferes with normal ovarian function and is more frequent
in women with positive anti-thyroid peroxidase (anti-TPO) antibodies
[1]. The association between the presence of anti-TPO antibodies and
miscarriage may also result from the impact of autoimmune diseases on
existing cellular abnormality, which directly affects the ability to con-
ceive [1]. Despite the fact that anti-TPO antibodies are not used in the
diagnosis of SH [17], the authors suggest systematic screening of TSH,
FT4 and anti-TPO antibodies in all women diagnosed with infertility
[1].
Thyroid dysfunction has been proven to be linked to reproductive
disorders in men. Studies by Trummer H et al. [22,23] have assessed the
impact of thyroid dysfunction on male infertility. The authors per-
formed a TRH test, measured the levels of thyroid hormones (TSH, FT4,
FT3), thyroid antibodies such as anti-TPO, thyroid antibodies thyr-
eoglobulin (TAG) and thyroid receptor (TRAb) antibodies, sex steroid
hormones and established correlations between the obtained results
and semen analyses. The authors revealed that neither hypo- nor hy-
perthyroidism had an impact on semen parameters. However, elevated
anti-TPO antibodies were significantly correlated with a reduction in
the motility of spermatozoa. They concluded that the routine assess-
ment of thyroid hormones and antibodies in infertile men was not re-
commended, while SH detected as a result of TRH testing was a rare
finding in infertile men [23].
In conclusion, the recommendations of the ‘2017 Guidelines of the
American Thyroid Association for the Diagnosis and Management of
Thyroid Disease During Pregnancy and the Postpartum’ indicate that it
is reasonable to assess TSH concentrations in infertile women trying to
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Clinica Chimica Acta 508 (2020) 185–190
conceive [24,25]. In addition, pregnant women who are anti-TPO or
anti-TAG antibody positive should have serum TSH concentration
measured at the time pregnancy is confirmed and every 4 weeks
through mid-pregnancy [24].
1.2. Infertility and immunological aspects
Immunological infertility is diagnosed in cases of spontaneous
production of antibodies which interact with antigens occurring on
either male or female gametocytes. These antibodies might bind to
seminal proteins or structures present on the sperm or oocyte. However,
anti-sperm antibodies (ASA) have been observed more frequently than
anti-oocyte antibodies [8,26]. Semen is defined as a complex fluid
containing sperm, cells and components, which could sensitise the fe-
male genital tract. The immune rejection of male semen in the female
reproductive tract might be explained by the failure of natural tolerance
leading to a local and/or systemic immune response. Some clinical in-
vestigations have indicated that active immune mechanism is able to
induce elevated levels of anti-seminal/sperm antibodies. Therefore,
isoimmunisation is associated with infertility [8]. In a study by Ulcova-
Gallova et al. seminal sperm-agglutinating antibodies, intra-acrosomal
proteins, sperm head abnormalities and levels of selected cytokines
were measured in the semen of men from infertile couples. Sperm-ag-
glutinating antibodies as well as IgA, IgG levels were found to be higher
in the seminal plasma of asthenospermatic and oligoasthenospermatic
men in comparison with normospermatic men, while high cytokine
levels were revealed for interleukin-5, −6, −8, and −10. The authors
concluded that immunological causes were a very important risk factor
of male infertility [27]. Commonly, human seminal plasma (HSP) hy-
persensitivity has to be differentiated from an allergic reaction to latex,
spermicidal agents, local anesthetics or components of lubricants [28].
It is suggested that prostate-specific antigen is the main antigen al-
though other proteins might also be involved in this heterogenous
disorder. There are no known risk factors for developing HSP hy-
persensitivity, but it has been proven that women who develop systemic
symptoms are more frequently atopic [29]. Symptoms might occur after
the first intercourse in almost 50% of cases [29]. The diagnosis of
human seminal plasma allergy as anaphylaxis caused by immediate
hypersensitivity to human seminal plasma is based on history, presence
of serum specific immunoglobulin E (IgE) antibodies in the serum and
skin tests. Most affected females are younger than 40 years, presenting
with a family history of atopy [28]. An example are women with ele-
vated serum IgE antibodies sensitised to dog dander (Can f 5) who are
predisposed to an allergic reaction following contact with semen during
a sexual intercourse [30] and in whom the allergic reaction can pro-
gress to generalised urticaria, dyspnea or anaphylactic shock [28].
These reactions can result from cross-reactivity between a dog dander
allergen and human prostate-specific antigen (PSA) [31]. The sequence
of amino acids of allergen Can f 5 is, in 55–60%, similar to the sequence
of amino acids of human PSA (prostate-specific antigen). Can f 5, a
28 kDa protein, a prostatic kallikrein, also named androgen-dependent
arginine esterase; serine protease has been isolated from the urine of
male dogs and is considered one of the major dog allergens [32]. In-
dividuals who are sensitised to Can f 5 may only tolerate female or
castrated dogs.
1.3. Infertility and autoimmune mechanisms (gluten intolerance)
Coeliac disease (CD), also referred to as immune mediated entero-
pathy, is a genetically-based immune intolerance to gluten affecting all
ages which is characterised by the destruction of the small intestinal
villi and malabsorption. It is estimated that CD is a relatively frequent
disorder with the overall prevalence of around 1:300 in Western Europe
[33]. This condition is a systemic disease which affects mainly the small
intestine as well as the liver, the brain, the thyroid, the skin and the
reproductive tract. It has been proven that a gluten-free diet results in
T. Wasilewski, et al.
the healing of the mucosa and resolution of malabsorptive states, while
untreated CD is a risk for delayed puberty, infertility, amenorrhea and
precocious menopause [33]. Therefore, the pathogenesis of this disease
might be related to reproductive disorders and needs further clarifica-
tion. The prevalence of CD among women with unexplained infertility
ranges from approximately 2.5–3.5% to 10.3% for subclinical CD (la-
tent), diagnosed solely on the basis of positive serological findings [34].
Patients with unexplained infertility are more likely to be diagnosed
with CD in comparison with the general population, as found in a meta-
analysis by Tersigni et al. [35].
Transglutaminase (TG) is expressed in different cells in the body,
including endometrial cells as well as stromal and trophoblast placental
cells and may be a target of maternal anti-transglutaminase antibodies
[36]. Several ways of placental damage in celiac disease have been
identified in an experimental murine model, e.g. direct binding of anti-
TG antibodies to trophoblasts leading to apoptotic damage and dis-
ruption of endometrial angiogenesis by anti-Tg antibodies on en-
dothelial cells (anti-angiogenic effect) [37].
There are no recommendations concerning the screening of female
patients with infertility for CD, although some authors have indicated
that each woman with unexplained infertility should be screened for
this disorder [38]. Moreover, clinical and epidemiological studies show
that female patients with CD face a higher risk of spontaneous abortion,
delivery of a low-birth-weight newborn and reduced duration of lac-
tation [33]. The diagnosis of CD is based on the identification of im-
munoglobulin A anti-tissue transglutaminase (IgA anti-tTG) antibodies,
endomysial antibodies and the determination of total IgA, while posi-
tive serological results should lead to intestinal biopsy [34]. A study by
Karaca et al. has demonstrated that CD may also cause a decrease in
male fertility by affecting sperm motility and androgen levels [39].
Studies performed by Gunn et al. have revealed that CD is not more
common in women with unexplained infertility than those with an
identifiable cause of infertility [40]. Contradictory findings have been
presented by Singh et al. who indicated an association between CD and
infertility [41]. They concluded that the disorder was more prevalent in
women with ‘all-cause’ infertility and 'unexplained' infertility in com-
parison with the general population, which has been confirmed by
other authors [42,43]. Additionally, a study by Rajput et al. has in-
dicated that in anaemic patients suffering from infertility of un-
explainable etiology should be tested for CD, in whom dietary mod-
ifications can resolve the problem of infertility [44].
1.4. Infertility and metabolic dysregulation (insulin resistance)
Polycystic ovary syndrome (PCOS) is a multisystem disease which is
associated with important reproductive morbidity due to the high
prevalence of anovulatory infertility, preeclampsia, gestational diabetes
and spontaneous abortion [45]. Glucose metabolism abnormalities in
patients with PCOS have been widely investigated. PCOS is one of the
most common causes of anovulatory infertility, while hyperinsulinemia
leads to the increased production of androgens and presence of insulin
resistance (IR) in women [46,47]. A study by Wei at al. found that in
patients with PCOS, body mass index (BMI), fasting glucose, fasting
insulin, 2-hour glucose and 2-hour insulin levels as well as the home-
ostasis model assessment of insulin resistance (HOMA-IR) values were
higher than in the control group of infertile subjects [46]. In addition,
the prevalence of impaired glucose tolerance (IGT), diabetes mellitus
(DM) and/or impaired fasting glycemia (IFG) were observed more
frequently in women with PCOS in comparison to the control group,
which has been confirmed by other authors [48]. Furthermore, women
with glucose intolerance were found to have higher BMI, waist cir-
cumference, free testosterone, fasting insulin, 2-hour post-load insulin,
total cholesterol, LDL cholesterol, triglyceride and lower sex hormone
binding globulin and insulin-mediated glucose uptake (IMGU) than
women with normal glucose tolerance [48]. The authors indicated that
IMGU was the most powerful predictor for glucose intolerance after
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Clinica Chimica Acta 508 (2020) 185–190
adjustment for age, BMI, waist circumference and hyperandrogenemia,
whereas the 2-hour oral glucose tolerance test (OGTT) was the best
screening tool for glucose intolerance and diagnosis of DM in women
with PCOS. Moreover, Ehrmann et al. have suggested that IR and hy-
perinsulinemia in PCOS patients might be associated with increased
levels of plasma homocysteine, which may influence short-term re-
productive outcomes and long-term cardiovascular complications as-
sociated with insulin-resistant PCOS [49,50]. Therefore, the authors
concluded that women with PCOS are at an increased risk for IR, glu-
cose intolerance and DM compared with controls, while insulin re-
sistance is the most important factor associated with glucose intoler-
ance [46,48].
Insulin and androgen can promote early folliculogenesis. Therefore,
in patients with PCOS, the presence of hyperinsulinemia and hyper-
androgenemia may lead to the appearance of multiple antral follicles. A
study by Dickerson et al. has indicated a significant positive correlation
between HOMA and BMI as well as between free androgen index (FAI)
and testosterone [51].
In conclusion, PCOS may be associated with metabolic disturbances
and the hypothalamic-pituitary-ovarian axis function disorders. This
condition is a major cause of female infertility and may be associated
with hyperandrogenemia, hyperinsulinemia/insulin resistance (IR),
increased estrone, luteinizing hormone (LH) and follicle-stimulating
hormone (FSH) ratio imbalance, which leads to infertility [45].
1.5. Infertility and malabsorption of selected micro- and macronutrients
(vitamins)
Some clinical investigations have suggested that vitamin D may play
a key role in the regulation of testicular hormone production, seminal
parameters and male fertility. The expression of vitamin D receptors
and metabolising enzymes have been demonstrated in the testis and
spermatozoa [52,53]. However, experimental research studies have not
demonstrated an undisputed relationship between vitamin D status and
testicular hormone production, although the majority of published
studies support that vitamin D might have a positive impact on human
male fertility potential, particularly through better sperm motility. In
addition, optimal vitamin D concentrations seems to be related to better
pregnancy outcomes [52,54].
1.6. Infertility and other biochemical parameters
It has also been suggested that abnormal levels of seminal bio-
chemical components could be associated with semen alterations and
infertility [55]. The authors have revealed that albumin, total protein
(TP) and gamma-glutamyl transpeptidase (GGT) activity was sig-
nificantly higher in patients with sperm motility ≤ 5th percentile,
while men with sperm vitality ≤ 5th percentile showed increased al-
bumin concentration and creatine kinase (CK) activity. In addition, the
presence of germ cells in semen was concomitant with high values of
ferritin, whereas alkaline phosphatase (ALP) activity and folic acid (FA)
levels were decreased in hyperviscous semen. Moreover, the con-
centrations of albumin and ferritin were significantly higher in infertile
patients in comparison to men with unknown reproductive potential.
The authors concluded that some biochemical components may be as-
sociated with human seminal pathological conditions [55].
2. Conclusion
Infertility is defined as the failure to achieve a clinical pregnancy
after 12 months or more of regular, unprotected sexual intercourse.
This condition may affect around 186 million people worldwide and it
is expected to increase in the future. Presented review highlights the
importance of a comprehensive biochemical parameters evaluation
including thyroid dysfunction, immunological disorders, autoimmune
mechanisms, metabolic dysregulation, as well as malabsorption of
T. Wasilewski, et al.
selected micro- and macronutrient that can impact the fertility to im-
prove diagnosis, treatment and ultimately outcomes.
Acknowledgements
The present project was supported by the Medical University of
Bialystok, Poland.
Declaration of Competing Interest
None declared.
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