Review articles
 

By Dr. Dipak K Sahoo
Corresponding Author Dr. Dipak K Sahoo
KTRDC, University of Kentucky, Cooper & University Drives - United States of America 40546-0236
Submitting Author Dr. Dipak K Sahoo
REPRODUCTION

Thyroid hormones, Testes, Antioxidant defence system, Oxidative stress, Protection, Antioxidants

Sahoo DK. Testicular Protection From Thyroid Hormone Mediated Oxidative Stress. WebmedCentral REPRODUCTION 2013;4(5):WMC004252
doi: 10.9754/journal.wmc.2013.004252

This is an open-access article distributed under the terms of the Creative Commons Attribution License(CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
No
Submitted on: 12 May 2013 11:24:50 PM GMT
Published on: 13 May 2013 05:17:02 AM GMT

Abstract


Testis is very rich in unsaturated fatty acids with poor antioxidant defense system and due to presence of a potential reactive oxygen species (ROS)-generating systems, it is much more vulnerable to oxidative damage than other tissues. Thyroid hormones are well known to regulate steroidogenesis and spermatogenesis, thereby, affecting male fertility. In the presence of disturbed thyroid conditions, in hyperthyroidism as well as hypothyroidism testis is much more susceptible to oxidative stress. The increase of testicular oxidative stress marked by elevated MDA or TBARS levels, lipid hydroperoxide, hydrogen peroxide or protein carbonyl contents along with disturbed antioxidant enzyme levels happens during L-thyroxine or tri-iodothyronine induced hyperthyroidism. The reduction of testicular oxidative stress can be achieved either by increasing glutathione contents through administration of melatonin or by vitamin E and/or curcumin or by elevating of levels of antioxidant defence enzymes like SOD, CAT or GPx through administration of vitamin E and/or curcumin. In contrast, during hypothyroidism, the extent of testicular oxidative stress is marked by elevation in rat testicular mitochondrial membrane protein carbonylation, lower GSH contents and decreased antioxidant enzyme levels. Hypothyroidism-induced oxidative stress condition could not be reversed with T3 treatment. Furthermore, such oxidative stress condition is not nullified still after withdrawal of reversible goitrogen PTU. Besides, in case of transient hypothyroidism, the oxidative stress condition is prevailed as marked by decreased antioxidant enzymes like SOD, CAT, GPx and GR levels and that might be responsible for triggering germ cell apoptosis in transient hypothyroid rats results in reduction in sperm count.

Introduction


For the last few years infertility rates have increased exponentially in both men and women where at least the central cause of infertility is attributable to biological reasons and only 10% is attributed to psychological and emotional reasons. Infertility statistics 2011 and 2012 indicate that at least over 90 million people across the world are unable to conceive children for one reason or another (http://www.breathingtherightway.com/infertility/infertility-statistics-2011-and-2012). Male fertility markers have been identified and studied extensively in order to understand the molecular mechanisms that can direct sub-fertility or infertility and permit an accurate diagnosis and design of therapeutic protocols. Among these markers, oxidative stress and poor antioxidant defence status in testis as well as in semen has emerged as a promising field (Sanocka et al., 1997; Choudhury et al., 2003; Agarwal et al., 2003). High concentrations of ROS play an important role in the pathophysiology of damage to human spermatozoa (Sharma and Agarwal, 1996). Thyroid hormones are well known to regulate steroidogenesis and spermatogenesis, thereby, affecting male fertility (Sahoo, 2011; Jannini et al., 1995; Mendis-Handagama and Ariyaratne, 2005). Hence, thyroid hormones have a vital role in regulating testicular antioxidant defence system and thereby influencing the testicular physiology (Sahoo, 2011).

Testicular Antioxidant defence system


Aerobes protect themselves from the oxidative stress generated due to the ROS (reactive oxygen species) by neutralizing them by their well-evolved antioxidant defences (Halliwell and Gutteridge, 2001). Testicular cells are well equipped with both small molecular weight antioxidants like reduced glutathione, ascorbic acid, vitamin E, uric acid, ubiquinone and carotenoids; and antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), that efficiently neutralize ROS (Figure-1; Sahoo, 2011). Spermatozoa and seminal plasma contain a battery of ROS scavengers, including enzymes such as SOD and catalase, and also a variety of substances with antioxidant activities (Dandekar et al, 2002; Sheweita et al, 2005).

Reduced glutathione (GSH)

Reduced glutathione (GSH) is the major non-enzymatic antioxidant and the most abundant non-protein thiol source of cell (Irvine, 1996; Sies, 1999) and it plays an important role in many biological processes of cells, including synthesis of proteins, DNA and protection against oxidative damage (Sies, 1999). The testis has high concentration of GSH, which plays an important role in spermatogenesis  (Meister and Anderson, 1983; Knapen et al., 1999; Sahoo et al., 2007). A glutathione deficiency can lead to instability of the mid-piece, resulting in defective sperm motility (Hansen et al, 1996; Ursini et al., 1999). Cells with high level of intracellular GSH are protected against oxidative damage caused by ROS. GSH either non-enzymatically reacts with ROS (Anderson, 1998) or directly scavenges them by neutralizing OH? (Sies, 1986). Thiols such as thioredoxins (small disulphide-containing proteins) and reduced glutathione (GSH) can neutralize a hydroxyl radical or a vitamin C radical (Sahoo et al., 2007).

Vitamin E

Vitamin E specifies a group of lipid soluble compounds, tocopherols and tocotrienols that act as antioxidants defending the organism against lipid oxidation. a-Tocopherol, the most abundant and active vitamin E family member is a chain-breaking antioxidant that prevents the propagation of free radical reactions (Mardones et al., 2002). Vitamin E as a lipid soluble plays a major protective role against oxidative stress and prevents the production of lipid peroxides by scavenging free radicals (particularly strong scavenger of hydroxyl radicals) in biological membranes (Sundararajan et al., 2006). Vitamin E also plays a vital role in protecting the sperm from morphological damage by binding endoperoxides, hence affecting the percentage of normal and motile sperm cells (Marin-Guzman et al., 1997; Sonmez et al., 2007). Vitamin E deficiencies cause testicular degeneration in chickens, rats, hamsters, dogs, cats, pigs, boars and monkeys and resulted in a reduction in sperm production (Marin-Guzman et al., 1997). Brzezinska-Slebodzinska et al. (1995) suggested that dietary vitamin E serves as an antioxidant in boar semen. In vitro studies also show that vitamin E is a major chain-breaking antioxidant in the sperm membrane and it appears to have a dose-dependent protective effect (Hull et al, 2000).

Vitamin C

Vitamin C (ascorbic acid) is another important chain-breaking antioxidant contributing up to 65% of the antioxidant capacity of the seminal plasma. Vitamin C also contributes to the support of spermatogenesis at least in part through its capacity to reduce α-tocopherol and maintain this antioxidant in an active state. Vitamin C is itself maintained in a reduced state by a GSH-dependent dehydroascorbate reductase, which is abundant in the testes (Paolicchi et al, 1996). Deficiency of vitamins C leads to a state of oxidative stress in the testes that disrupts both spermatogenesis and the production of testosterone.

Superoxide dismutase (SOD)

Superoxide dismutase (SOD) dismutates superoxide radicals into hydrogen peroxide (H2O2). Mammals have three isozymes of SOD namely, SOD1 which encodes mostly cytosolic CuZnSOD having Cu and Zn metal cofactors; SOD2 encodes mitochondrial isoform MnSOD containing Mn, while SOD3, encodes the extracellular form, ECSOD (structurally similar to CuZnSOD containing Cu and Zn as metal cofactors) (Fujii et al, 2003). A key role of SOD in protection of testicular cells against heat stress-induced apoptosis has been demonstrated in vivo and in vitro (Ikeda et al, 1999; Kumagai et al, 2002). SOD also prevents premature hyper-activation and capacitation induced by superoxide radicals before ejaculation (Lamirande et al, 1995). On the contrary, transgenic male mice expressing higher levels of MnSOD are infertile, but the mechanism for this is unknown. Since SOD only dismutates superoxide anion to hydrogen peroxide, the resulting hydrogen peroxide may also cause a toxic effect in testicular cells (Fujii et al., 2003). ECSOD is present at high levels in the epididymis (Mruk et al. 2002) as well as is localized in the nuclei in the seminiferous tubules of testis (Ookawara et al. 2002). Erectile function is improved by transferring the SOD3 gene to the penis in aged rats (Bivalacqua et al. 2003).

Hydrogen peroxide metabolizing enzymes

Hydrogen peroxide produced from superoxide radicals in turn is efficiently neutralized by catalase (CAT) and glutathione peroxidase (GPx). Catalase is also known to activate nitrous oxide (NO)-induced sperm capacitation, in a complex mechanism involving H2O2 (Lamirande et al, 1997). GSH serves as the substrate for glutathione peroxidase (GPx) as well as glutathione S-transferase (GST).  Glutathione peroxidase (GPx) oxidizes GSH to GSSG and GSSG is reduced back to GSH by glutathione reductase (GR) (Halliwell and Gutteridge, 2001). GPx may be of Selenium dependent or Selenium independent types. Selenium dependent glutathione peroxidases (Se-D GPxs) are the foremost selenoprotein-containing gene family in mammals (Esworthy et al., 2001). Among the different types of selenium dependent hydroperoxide reducing isozymes, phospholipids hydroperoxide glutathione peroxidase (PH-GPx/ GPx-4; EC1.11.1.12) and classic cellular glutathione peroxidase (cGPX/GPx-1; EC 1.11.1.9) are mainly found in testis (Sahoo and Roy, 2012). PHGPx is a monomeric seleno-enzyme present in different mammalian tissues in soluble and bound form (Tramer et al., 2002). The GPX4 protein represents about 50 % of the capsule material, that embeds the helix of mitochondria in the mid-piece of spermatozoa (Ursini et al, 1999). A correlation between male infertility and a GPX4 defect has actually been reported (Imai et al, 2001). Selenium-dependent glutathione peroxidases contribute to a part of the total GPx activity. Other GPx activities in mammalian systems are selenium-independent and the Se-independent GPx (Se-I GPx) component of GST alfa class (Accession: IPR003080GST_alpha) is accountable for GPx activity in testis (Sahoo and Roy, 2012; Doyen et al., 2006; Institoris et al., 1995). GPX5 is a non-selenium enzyme under the non-selenium dependent GPX group and is found to be highly associated with the male reproductive system. GPX5 is expressed exclusively in the epididymis and is secreted and present in the caput and cauda epididymis lumens (Rejraji et al, 2002). It constitutes 6% of the secretory epididymal proteins (Fouchecourt et al, 2000). The binding of GPX5 to sperm membrane has also been reported. Thus, the protection of the sperm membrane against peroxidation is a possible function of this epididymis-specific isoform (Vernet et al, 1999).

Alteration of testicular antioxidant parameters by hyperthyroidism


Tissues in hyperthyroid rats exhibit high vulnerability to oxidative challenge (Venditti et al., 1997; Sahoo and Chainy, 2007). L-thyroxine (Mogulkoc et al., 2005a; 2005b; Sahoo et al., 2008b) or tri-iodothyronine (Choudhury et al., 2003; Sahoo et al., 2005; 2007) was administered in rats to induce hyperthyroidism experimentally and oxidative stress parameters as well as antioxidant defence profile were measured. Since thyroid hormones in general activate all the systems in the body, hyperthyroidism inevitably causes lipid peroxidation in different tissues depending on its severity (Sahoo and Chainy, 2007; Chattopadhyay et al., 2007; 2010; Sahoo, 2011; Venditti et al., 1997). Hyper-metabolic state in hyperthyroidism results in increase in free radical production (Venditti et al., 1997; Das and Chainy, 2001; 2004). Testis is very rich in unsaturated fatty acids (particularly 20:4 and 22:6) with poor antioxidant defense system (Sahoo et al., 2008c; Peltola, 1992) and due to presence of a potential reactive oxygen species (ROS)-generating systems, it is much more vulnerable to oxidative damage than other tissues.

Changes in oxidative stress parameters

It was reported that different thyroid hormone isomers used in induced hyperthyroidism led to different degrees of oxidative stress.  Most of the studies confirm the increase of testicular oxidative stress as marked by elevated MDA levels during L-thyroxine induced hyperthyroidism (Mogulkoc et al., 2005a) or by increased TBARS, lipid hydroperoxide, hydrogen peroxide or protein carbonyl contents during L-thyroxine or tri-iodothyronine induced hyperthyroidism (Choudhury et al., 2003; Sahoo et al., 2005; 2007; Sahoo et al., 2008b).

Changes in antioxidant defence parameters

Small antioxidant molecules

Interestingly while short-term L-thyroxine administration to hypothyroid rats causes an increased testicular GSH contents (Mogulkoc, 2005b), T3 treatment for three days to hypothyroid rats causes an elevation of oxidized (GSSG) and a decline in reduced (GSH) glutathione contents resulting in a decreased reduced to oxidized glutathione ratio (Choudhury et al., 2003). However, T3 treatment for five days enhances testicular GSH contents both in both mitochondrial (MF) and post-mitochondrial (PMF) fractions (Sahoo et al., 2007). The reduced to oxidized glutathione ratio (GSH: GSSG) remains higher in both MF and PMF fractions during L-thyroxine or tri-iodothyronine induced hyperthyroidism (Sahoo et al., 2007; Sahoo et al., 2008b). Ascorbic content is also elevated in crude homogenate of hyperthyroid rat testis by one to five days T3 treatment (Sahoo et al., 2007).

Antioxidant Enzymes

During acute hyperthyroid state, testis exhibits lower SOD activity and higher activities of CAT, GPx, GR and G6PD enzymes (Sahoo et al., 2005; 2007). Moreover, L-thyroxine induced hyperthyroid rats also exhibit decreased testicular SOD, CAT activities with elevated GPx activity (Sahoo et al., 2008b). In testicular PMF and MF, both Se-dependent and Se-independent GPx are enhanced, respectively by around 20% and 30% in response to L-thyroxine (Sahoo, 2012). Se-I-GPx activity is elevated only in MF due to triiodothyronine treatment in rat testis (Sahoo et al., 2007). Increase in both Se-D and Se-I-GPx levels in response to L-thyroxine induced hyperthyroidism (Sahoo, 2012) and Se-I-GPx elevation in response to triiodothyronine treatment (Sahoo et al., 2007) may be an adaptive response to neutralize toxic hydrogen peroxides generated due to impairment of normo-oxidant status of the organ. Such type of altered testicular antioxidant defence parameters and oxidative stress conditions by hyperthyroidism hampers fertility as evidenced by reduced viable and total sperm counts (Sahoo et al., 2005; 2007; 2008b).

Treatments

By curcumin treatment

Curcumin (1,7-bis [4-hydroxy-3-methoxyphenyl]-1,6-heptadiene-3,5-dione) is the principal curcuminoid found in turmeric, and is generally considered as its most active constituent (Sharma et al., 2005). Both phenolic and -diketone functional groups of curcumin have remarkable free radical scavenging activities (Cohly et al., 1998, Reddy and Lokesh, 1994) and it was reported to inhibit superoxide anion and hydroxyl radical generation by preventing oxidation of Fe2+ to Fe3+ through Fenton reaction (Reddy and Lokesh, 1994). The elevated LPx and PC of the testis in response to T4 get reduced to the nomal level by curcumin (Sahoo et al., 2008b). Treatment of curcumin to T4-treated rats results in elevation of SOD level in post-mitochondrial fraction (PMF) and mitochondrial fraction (MF) and CAT in PMF. However, curcumin is unable to change GPx activity alone but together with vitamin E it elevates the GPx in PMF of T4-treated rat testis (Sahoo et al., 2008b). Curcumin decreases the increased Se-D-GPx (GPx-1 and GPx-4) in MF and Se-I-GPx in PMF of hyperthyroid rats to normal level like untreated control rats that might happen in response to less oxidative stress condition after curcumin treatment (Sahoo, 2012). The less oxidative stress condition is also due to the increased levels of GSH contents in testes of curcumin fed rats (Sahoo et al., 2008b). This may be because of the triggered GSH biosynthesis as studies in cell culture suggest that curcumin can increase cellular glutathione levels by enhancing the transcription of the two Gcl genes, i.e. Gclc and Gclm for glutamate cysteine ligase, the rate-limiting enzyme in glutathione synthesis (Dickinson et al., 2004).

By vitamin E treatment

Treatment of vitamin E to T4-treated rats results in elevation of SOD level in post-mitochondrial fraction (PMF) and mitochondrial fraction (MF) and CAT in PMF. Vitamin E does not change GPx activity alone but in together with curcumin increases the GPx in PMF of T4-treated rat testis (Sahoo et al., 2008b). Vitamin E treatment causes reduction of increased Se-D-GPx (GPx-1 and GPx-4) in MF and Se-I-GPx in PMF of hyperthyroid rats to normal levels as a result of decreased oxidative stress due to vitamin E treatment (Sahoo, 2012). Vitamin E also elevates GSH to GSSG ratio (GSH:GSSG) when given to T4-treated rats (Sahoo et al., 2008b).

By melatonin treatment

Melatonin, which is mainly secreted from the pineal gland in the body, reduces oxidative stress by its free radical eliminating and direct antioxidant effects (Akbulut et al., 1999; Reiter et al., 2003). Due to hyperthyroidism, the significant increased level of MDA in testis is inhibited to a large extent by the increase in levels of GSH (an indicator of antioxidant system activity) as a result of melatonin administration (Mogulkoc et al., 2005a). Such result demonstrates that the oxidative stress brought about by hyperthyroidism was hindered to a great degree by melatonin’s increasing antioxidant system activities. Exogenous melatonin administration in addition to endogenous melatonin secretion strengthens effectively the antioxidant defense system of the body (Mogulkoc et al., 2005a). 

Alteration of testicular antioxidant parameters by hypothyroidism


Hypothyroidism also alters the oxidant generation and testicular antioxidant defence system as it is linked to a hypo-metabolic state. Effect of persistent and transient hypothyroidism on testicular antioxidant defence system during development and maturation has been evaluated (Sahoo et al., 2008a)

Changes in oxidative stress parameters

Oxidative stress parameters such as malondialdehyde (MDA) level decreases (Mogulkoc et al., 2005b) in hypothyroid rat testes, however the levels of hydrogen peroxide and protein carbonyl contents remain increased in the crude homogenate (Choudhury et al., 2003). In addition, the mitochondrial LPx and protein carbonylation contents remain elevated in the testis during persistent hypothyroidism (Choudhury et al., 2003). The extent of oxidative damage marked by elevation in mitochondrial membrane protein carbonylation was also reported in hypothyroid rat testis (Chattopadhyay et al., 2010). Marked increased protein carbonylation in hypothyroid immature rat testis also states about the prevalence of oxidative stress during hypothyroidism (Sahoo and Roy, 2012).

Changes in Antioxidant defence parameters

Small antioxidant molecules

Rat testicular reduced glutathione (GSH) levels are lower in testicular tissues of the hypothyroid rats (Mogulkoc et al., 2005b). On the other hand, oxidized glutathione (GSSG) content remains elevated as a result of which reduced to oxidized glutathione ratio (GSH: GSSG) of testis decreases during hypothyroidism (Choudhury et al., 2003). Moreover, persistent hypothyroidism causes disturbed redox status in immature rat testis (Sahoo and Roy, 2012).

Antioxidant Enzymes

SOD and CAT activities get reduced and GPX activity gets elevated in the PMF of testis in the hypothyroid rats (Choudhury et al., 2003). Hypothyroidism also reduces the rat testicular GST levels (Choudhury et al., 1992-2003). In contrast, persistent hypothyroidism causes elevation in SOD and CAT activities with decreased GPx and GR activities (Sahoo et al., 2008a). Persistent hypothyroidism reduces both Se-D-GPx and Se-I-GPx in testicular MF and PMF fractions (Sahoo, 2012). The decrease in Se-D GPx (GPx-1 and GPx-4) as well as Se-I-GPx in the testis suggests that antioxidant enzymes like SOD and CAT have predominant role to combat oxidative stress than GPx in hypothyroid rats as indicated by elevated SOD and CAT levels (Sahoo et al., 2008a). An altered antioxidant defence system marked by elevated SOD, CAT, and GR activities, with decreased GPx and GST activities occurs in hypothyroid immature rat testis (Sahoo and Roy, 2012). GPx is primarily responsible for H2O2 removal in testicular mitochondria that does not contain catalase. The metabolic pathway of testosterone biosynthesis requires protection against peroxidation and will be affected by a decrease in the GPx activity (Chandra et al., 2000). The lower serum testosterone level in hypothyroid rats (Sahoo et al., 2008a; Sahoo and Roy, 2012) also corroborates the fact. This compromised testicular antioxidant status contributes to poor growth and development by affecting the spermatogenesis and steroidogenesis in rats before puberty as indicated by reduced germ cell number due to increased apoptosis (Sahoo, 2013), complete absence of round spermatids, decreased seminiferous tubule diameter, and decreased testosterone level (Sahoo and Roy, 2012). Such type of altered testicular physiology by hypothyroidism is reflected in adulthood with hampered fertility as evidenced by reduced total viable germ cells (Sahoo et al., 2006) and sperm counts (Sahoo et al., 2008a).

Treatment

Withdrawal of hypothyroid state/ transient hypothyroid condition

In spite of decreased mitochondrial LPx in transient hypothyroidism, it is associated with reduced testicular SOD, CAT, GR and GPx activities (Sahoo et al., 2008a). In transient hypothyroidism, the declined GPx in MF is found to be due to the reduction in Se-D-GPx activity only (Sahoo, 2012). The significant decrease in Se-D-GPx and Se- I GPx in PMF of testis suggests the prevailed oxidative stress in hypothyroid rats (Sahoo, 2012). Studies on germ cells of transient hypothyroid rats also further demonstrate that the germ cells are under oxidative stress as exhibited by lower GSH contents, decreased CAT and SOD activities (Sahoo et al., 2006) and higher LPx contents (Sahoo et al., 2006). Such prevalence of oxidative stress marked by decreased antioxidant enzymes such as SOD, CAT, GPx and GR levels in both mitochondrial as well as post-mitochondrial fractions (Sahoo et al. 2008a; Sahoo and Roy, 2012) might be responsible for triggering germ cell apoptosis in transient hypothyroid rats (Sahoo, 2013) that results in reduction in sperm count (Sahoo et al. 2008a).

Treatment with T3 (tri-iodothyronine) adminstration

When PTU induced hypothyroid rats are treated with T3 (tri-iodothyronine) hormone, it causes elevation in catalase and decline in glutathione peroxidase activity without altering superoxide dismutase and glutathione reductase activities in testicular post-mitochondrial fractions (Choudhury et al., 2003). Increased pro-oxidant level and reduced antioxidant capacity renders the hypothyroid mitochondria susceptible to oxidative injury and the extent of damage is more evident in the membrane fraction, reflected in higher degree of oxidative damages inflicted upon membrane lipids and proteins (Chattopadhyay et al., 2010). While membrane proteins were more susceptible to carbonylation, thiol residue damage is evident in matrix fraction. Reduced levels of glutathione and ascorbate further weaken the antioxidant defenses and impair testicular functions (Chattopadhyay et al., 2010). Such hypothyroid condition disturbed intra-mitochondrial thiol redox status leads to testicular dysfunction. Hypothyroid rat testis mitochondrial matrix exhibiting lower glutathione and ascorbate contents is not nullified with the T3 treatment (Chattopadhyay et al., 2010).

Conclusion


Both the compounds curcumin and vitamin E are known as efficient scavenger of reactive oxygen species (Inano et al., 2000; Aydilek, et al., 2004). However, their effects on antioxidant enzymes are quite different. Both these antioxidants are reported to decrease L-thyroxine induced oxidative stress as shown by reduced lipid peroxide and protein carbonyl contents in the testis (Sahoo et al., 2008b). Both vitamin E and curcumin are efficient in protecting testis from oxidative stress generated by T4 mainly by restoring antioxidant enzymes to the level of euthyroid animals up to some extent; however, vitamin E is more efficient than curcumin as it restores the normal testicular physiology by elevating total sperm count and increasing percentage of live sperm impaired by hyperthyroid state (Sahoo et al., 2008b). Similarly, melatonin decreases hyperthyroid induced testicular oxidative stress to some extent with increasing testicular glutathione contents (Mogulkoc et al., 2005a).

The reduction of testicular oxidative stress is either by increasing glutathione contents through administration of melatonin (Mogulkoc et al., 2005a) or by vitamin E and/or curcumin (Sahoo et al., 2008b) or by elevating levels of antioxidant defence enzymes like SOD, CAT or GPx through administration of vitamin E and/or curcumin (Sahoo et al., 2008b).

Hypothyroidism-induced oxidative stress condition could not be reversed with T3 treatment (Chattopadhyay et al., 2010). Furthermore, the oxidative stress condition is not nullified still after withdrawal of reversible goitrogen PTU and in case of transient hypothyroidism the prevalence of oxidative stress marked by decreased antioxidant enzymes like SOD, CAT, GPx and GR levels (Sahoo et al. 2008; Sahoo and Roy, 2012) might be responsible for triggering germ cell apoptosis (Sahoo, 2013) that results in reduction in sperm count. Further, more studies are needed to find out the role of different antioxidants for protecting testis from oxidative stress caused by hypothyroidism.

References


1. Agarwal, A., Saleh, R.A and Bedaiwy, M. A. (2003). Role of reactive oxygen species in the pathophysiology of human reproduction. Fertil. Steril. 79: 829-843.
2. Akbulut GK, Gonul B, Akbulut H. Differential effects of pharmacological doses of melatonin on malondialdehyde and glutathione levels in young and old rats. Gerontology 1999; 45:67–71.
3. Anderson, M. E. (1998). Glutathione: an overview of biosynthesis and modulation. Chem. Biol. Interact. 111: 1-14.
4. Aydilek, N., Aksakal, M. and Karakilcik, A. Z. (2004). Effects of testosterone and vitamin E on the antioxidant system in rabbit testis. Andrologia 36: 277-281.
5. Bivalacqua TJ, Armstrong JS, Biggerstaff J, Abdel-Mageed AB, Kadowitz PJ, Hellstrom WJ, Champion HC. Gene transfer of extracellular SOD to the penis reduces O22N and improves erectile function in aged rats. Am J Physiol Heart Circ Physiol. 2003; 284: 1408–1421.
6. Brzezinska-Slebodzinska, E., Slebodzinski, A. B., Pietras, B. and Wieczorek, G. (1995). Antioxidant effect of vitamin E and glutathione on lipid peroxidation in boar semen plasma. Biol. Trace Elem. Res. 47: 69-74.
7. Chandra, R., Aneja, R., Rewal, C., Konduri, R., Das, K. and Agarwal, S. (2000). An opium alkaloid – papaverine ameliorates ethanol-induced hepatotoxicity: diminution of oxidative stress. Ind. J. Clin. Biochem.15: 155-160.
8. Chattopadhyay, S., Sahoo, D.K., Roy, A., Samanta, L. and Chainy, G.B.N. (2010). Thiol redox status critically influences mitochondrial response to thyroid hormone-induced hepatic oxidative injury: A temporal analysis. Cell Biochemistry and Function 28(2): 126-134.
9. Chattopadhyay, S., Sahoo, D.K., Subudhi, U. and Chainy, G.B.N. (2007). Differential expression profiles of antioxidant enzymes and glutathione redox status in hyperthyroid rats: a temporal analysis. Comp. Biochem. Physiol. C 146: 383-391.
10. Choudhury, S., Chainy, G. B. N, and Mishro, M. M. (2003). Experimentally induced hypo- and hyperthyroidism influence on the antioxidant defence system in adult rat testis. Andrologia 35: 131-140.
11. Choudhury, S., Samanta, L. and Chainy, G. B. N. (1992-2003). Inhibition of testicular glutathione S-transferase activity by altered thyroid status. J. Zool. Soc. India 44-55: 11-18.
12. Cohly, H. H. P, Taylor, A., Angel, M. F. and Salahudeen, A. K. (1998). Effect of turmeric, turmerin and curcumin on H2O2-induced renal epithelial (LLC-PK1) cell injury. Free Rad.  Biol.  Med. 24: 49-54.
13. Dandekar, S. P., Nandkarni, G. D., Kulkarni, V. S. and Punekar, S. (2002). Lipid peroxidation and antioxidant enzymes in male infertility. J. Postgrad. Med. 48: 186-190.
14. Das, K. and Chainy, G. B. N. (2001). Modulation of rat liver mitochondrial antioxidant defence system by thyroid hormone. Biochim. Biophys. Acta 1537: 1-13.
15. Das, K. and Chainy, G. B. N. (2004) Thyroid hormone influences antioxidant defence in adult rat brain. Neurochem. Res. 29: 1755-1766.
16. Dickinson, D. A., Levonen, A. L., Moellering, D. R., Arnold, E. K., Zhang, H., Darley-Usmar, V. M. and Forman, H. J. (2004). Human glutamate cysteine ligase gene regulation through the electrophile response element.  Free Rad. Biol. Med. 37: 1152-1159.
17. Doyen, P., Vasseur, P. and Rodius F. (2006). Identification, sequencing and expression of selenium-dependent glutathione peroxidase transcript in the freshwater bivalve Unio tumidus exposed to Aroclor 1254. Comparative Biochemistry and Physiology, Part C, vol. 144, no. 2, 122–129.
18. Esworthy, R. S., Aranda, R., Mart´?n, M. G., Binder, J. H., Doroshow, S.W. and Chu, F. F. (2001). Mice with combined disruption of Gpx1 and Gpx2 genes have colitis. The American Journal of Physiology 281 (3) G848–G855.
19. Fouchecourt, S., Metayer, S., Locatelli, A., Dacheux, F and Dacheux, J. L. (2000). Stallion epididymal fluid proteome: qualitative and quantitative characterization; secretion and dynamic changes of major proteins. Biol Reprod., 62: 1790-1803.
20. Fujii, J., Iuchi, Y., Matsuki, S. and Ishii, T. (2003). Cooperative function of antioxidant and redox systems against oxidative stress in male reproductive tissues. Asian J Androl., 5: 231-242.
21. Halliwell, B. and Gutteridge, J. M. C. (2001). Free radicals in Biology and Medicine. 3rd Ed.; Oxford University Press, New York.
22. Hansen, J. C and Deguchi, Y. (1996) Selenium and fertility in animals and man – a review. Acta.Vet. Scand., 37(1): 19–30.
23. Hull, M. G., North, K., Taylor, H., Farrow, A and Ford, W. C. (2000) Delayed conception and active and passive smoking. The Avon Longitudinal Study of Pregnancy and Childhood Study Team. Fertil. Steril., 74(4): 725–733.
24. Ikeda, M., Kodama, H., Fukuda, J., Shimizu, Y., Murata, M., Kumagai, J. and Tanaka, T. (1999). Role of radical oxygen species in rat testicular germ cell apoptosis induced by heat stress. Biol. Reprod. 61: 393-399.
25. Imai, H., Suzuki, K., Ishizaka, K., Ischinose, S., Oshima, H., Okayasu, I., Emoto, K., Umeda, M. and Nakagawa, Y. (2001). Failure of the expression of phopholipid hydroperoxide glutathione peroxidase in the spermatozoa of human infertile males. Biol. Reprod. 64: 674-683.
26. Inano, H., Onoda, M., Inafuku, N., Kubota, M., Kamada, Y., Osawa, T., Kobayashi, H. and Wakabayashi, K. (2000). Potent preventive action of curcumin on radiation-induced initiation of mammary tumorigenesis in rats. Carcinogenesis 21: 1835-1841.
27. Institoris, E., Eid, H., Bodrogi, I. and Bak, M. (1995). Glutathione related enzymes in human testicular germ cell tumors and normal testes. Anticancer Research 15 (4) 1371–1374.
28. Irvine, S. (1996). Glutathione as a treatment for male infertility. J. Reprod. Fertil. 1: 6-12.
28. Jannini, E. A., Ulisse, S. and d’Armiento, M. (1995). Thyroid hormone and male gonadal function. Endocr. Rev. 16: 443-459.
29. Knapen, M. F., Zusterzeel, P.L., Peters, W. H. and Steegers, E. A. (1999). Glutathione and glutathione-related enzymes in reproduction. A review. Eur. J. Obstet. Gynecol. Reprod. Biol. 82: 171-184.
30. Kumagai, A., Kodama, H., Kumagai, J., Fukuda, J., Kawamura, K., Tanikawa, H., Sato, N. and Tanaka, T. (2002). Xanthine oxidase inhibitors suppress testicular germ cell apoptosis induced by experimental cryptorchidism. Mol. Hum. Reprod. 8: 118-123.
31. Lamirande E, Leclerc P, Gagnon C (1997). Capacitation as a regulatory event that primes spermatozoa for the acrosome reaction and fertilization. Mol. Hum. Reprod., 3(3): 175–194.
32. Lamirande, E and Gagnon C. (1995). Capacitation-associated production of superoxide anion by human spermatozoa. Free Radic. Biol. Med., 18(3): 487–495.
33. Mardones, P., Strobel, P., Miranda, S., Leighton, F., Quinones, V., Amigo, L., Rozowski, J., Krieger, M. and Rigotti, A. (2002). α-Tocopherol metabolism is abnormal in scavenger receptor class B type I (SR-BI)-deficient mice. J. Nutr. 132: 443-449.
34. Marin-Guzman, J., Mahan, D. C., Chung, Y. K., Pate, J. L. and Pope, W. F. (1997). Effects of dietary selenium and vitamin E on boar performance and tissue responses, semen quality, and subsequent fertilization rates in mature gilts. J. Anim. Sci. 75: 2994-3003.
35. Meister, A. and Anderson, M. E. (1983). Glutathione. Ann. Rev. Biochem. 52: 711-760.
36. Mendis-Handagama, S. M. and Ariyaratne, S. H. B. (2005). Leydig cells, thyroid hormones and steroidogenesis. Ind. J. Exp. Biol. 43: 939-962.
37. Mendis-Handagama, S. M. and Ariyaratne, S. H. B. (2005). Leydig cells, thyroid hormones and steroidogenesis. Ind. J. Exp. Biol. 43: 939-962.
38. Mogulkoc, R., Baltaci, A. K., Oztekin, E., Aydin, L. and Tuncer, I. (2005a). Hyperthyroidism causes lipid peroxidation in kidney and testis tissues of rats: protective role of melatonin. Neuro. Endocrinol. Lett. 26: 806-810.
39. Mogulkoc, R., Baltaci, A.K. Oztekin, E. Ozturk, A. and Sivrikaya, A. (2005b). Short term thyroxine administration leads to lipid peroxidation in renal and testicular tissues of rats with hypothyroidism. Acta Biol. Hung. 56: 225-232.
40. Mruk, D. D., Silvestrini, B., Mo, M. and Cheng, C. Y. (2002). Antioxidant superoxide dismutase- a review: its function, regulation in the testis, and role in male fertility. Contraception 65: 305-311.
41. Ookawara, T., Kizaki, T., Takayama, E., Imazeki, N., Matsubara, O.,Ikeda, Y., Suzuki, K., Li, Ji, L., Tadakuma, T., Taniguchi, N. and Ohno, H. (2002). Nuclear translocation of extracellular superoxide dismutase. Biochem. Biophy. Res. Commun. 296: 54-61.
42. Paolicchi, A., Pezzini, A., Saviozzi, M., Piaggi, S., Andreuccetti, M., Chieli, E., Malvaldi, G. and Casini, A.F. (1996). Localization of a GSH-dependent dehydroascorbate reductase in rat tissues and subcellular fractions. Arch Biochem Biophys., 333: 489–495.
43. Peltola, V., Huhtaniemi, I. and Ahotupa, M. (1992). Antioxidant enzyme activity in the maturing rat testis. J. Androl. 13: 450-455.
44. Reddy, A. C. P. and Lokesh, B. R. (1994). Effect of dietary turmeric (Curcuma longa) on iron-induced lipid peroxidation in rat liver. Food Chem. Toxicol. 32: 279-283.
45. Reiter RJ, Tan DX, Mayo JC, Sainz RM, Leon J, Czarnocki Z. Melatonin as an antioxidant: biochemical mechanisms and pathophysiological implications in humans. Acta Biochim Pol 2003; 50: 1129–1146.
46. Rejraji, H., Vernet, P. and Drevet, J. R. (2002). GPX5 is present in the mouse caput and cauda epididymis lumen at three different locations. Mol. Reprod. Dev. 63: 96-103.
47. Sahoo, D.K. (2011). Effects of Thyroid Hormone on Testicular Functions and Antioxidant Defence Status. Biochemistry: An Indian Journal 5 (6).
48. Sahoo, D.K. (2012). Alterations of testicular selenium-dependent and independent glutathione peroxidase activities during experimentally L-thyroxine induced hyperthyroidism and n-propyl thiouracil induced hypothyroidism in adult rats. Research & Reviews in BioSciences 6(3).
49. Sahoo, D.K. (2013). Increased germ cell apoptosis during testicular development and maturation by experimentally induced transient and persistent hypothyroidism. WebmedCentral ENDOCRINOLOGY 2013; 4(5): WMC004235.
50. Sahoo, D.K. and Chainy, G.B.N. (2007). Tissue specific response of antioxidant defence systems of rat to experimentally induced hyperthyroidism. Natl. Acad. Sci. Lett., Vol.30, No. 7 & 8: 247-250.
51. Sahoo, D.K. and Roy, A. (2012). Compromised Rat Testicular Antioxidant Defence System by Hypothyroidism before Puberty. International Journal of Endocrinology 2012: Article ID 637825, 11 pages. doi:10.1155/2012/637825.
52. Sahoo, D.K., Roy, A. and Chainy, G.B.N. (2006). PTU-induced neonatal hypothyroidism modulates antioxidative status and population of rat testicular germ cells. Natl. Acad. Sci. Lett., Vol.29, No. 3 & 4: 133-135.
53. Sahoo, D.K., Roy, A. and Chainy, G.B.N. (2008b). Protective effects of Vitamin E and curcumin on L-thyroxine-induced rat testicular oxidative stress. Chem. Biol. Interact. 176: 121-128.
54. Sahoo, D.K., Roy, A. and Chainy, G.B.N. (2008c). Rat testicular mitochondrial antioxidant defence system and its modulation by aging. Acta Biologica Hungarica 59 (4): 413-424.
55. Sahoo, D.K., Roy, A., Bhanja, S. and Chainy, G.B.N. (2005). Experimental Hyperthyroidism-induced Oxidative stress and Impairment of Antioxidant Defence System in Rat Testis. Ind. J. Exp. Biol. 43: 1058-1067.
56. Sahoo, D.K., Roy, A., Bhanja, S. and Chainy, G.B.N. (2008a). Hypothyroidism impairs antioxidant defence system and testicular physiology during development and maturation. Gen. Comp. Endocrinol. 156: 63-70.
57. Sahoo, D.K., Roy, A., Chattopadhyay, S. and Chainy, G.B.N. (2007). Effect of T3 treatment on glutathione redox pool and its metabolizing enzymes in mitochondrial and post-mitochondrial fractions of adult rat testes. Ind. J. Exp. Biol. 45: 338-346.
58. Sanocka, D., Miesel, R., Jedrzejczak, P., Chelmonskasoyta, A. and Kurpisz, M. (1997). Effect of reactive oxygen species and the activity of antioxidant systems on human semen; association with male infertility. Int. J. Androl. 20: 255-264.
59. Sharma, R. A., Gescher, A.J. and Steward, W. P. (2005). Curcumin: The story so far. Eur J. Cancer. 41: 1955-1968.
60. Sharma, R. K and Agarwal, A. (1996). Role of reactive oxygen species in male infertility. Urology. 48: 835-850.
61. Sheweita, S. A., Tilmisany, A. M and Al-Sawaf, H. (2005). Mechanisms of male infertility: role of antioxidants. Curr Drug Metab., 6: 495-501.
62. Sies H (1986). Biochemistry of oxidative stress. Angew. Chem. Int. Ed. Engl. 25: 1058-1071.
63. Sies, H. (1999). Glutathione and its role in cellular functions. Free Rad. Biol. Med. 27: 916-921.
64. Sonmez, M., Yuce, A. and Turk, G. (2007). The protective effects of melatonin and Vitamin E on antioxidant enzyme activities and epididymal sperm characteristics of homocysteine treated male rats. Reprod. Toxicol. 23: 226-231.
65. Sundararajan, R., Haja, N. A., Venkatesan, K., Mukherjee, K., Saha, B. P., Bandyopadhyay, A. and Mukherjee, P. K. (2006). Cytisus scoparius Link- A natural antioxidant. BMC Complementary and Alternative Medicine 6: 8.
66. Tramer, F., Micali, F., Sandri, G., Bertoni, A., Lenzi, A., Gandini, L. and Panfili, E. (2002). Enzymatic and immunochemical evaluation of phospholipid hydroperoxide glutathione peroxidase (PHGPX) in testes and epididymal spermatozoa of rats of different ages. Int. J. Androl. 25: 72-83.
67. Ursini, F., Heim, S., Kiess, M., Maiorino, M., Roveri, A., Wissing, J. and Flohe, L. (1999). Dual function of the selenoprotein PHGPX during sperm maturation. Science 285: 1393-1396.
68. Venditti, P., Balestrieri, M., Di Meo, S. and De Leo, T. (1997). Effects of thyroid state on lipid peroxidation, antioxidant defences and susceptibility to oxidative stress in rat tissues. J. Endocrinol. 155: 151-157.
69. Vernet, P., Rock, E., Mazur, A., Rayssiguier, Y., Dufaure, J. P. and Drevet, J. R. (1999). Selenium-independent epididymis-restricted glutathione peroxidase-5 protein  (GPX5) can back up failing Se-dependent GPxs in mice subjected to selenium deficiency. Mol. Reprod. Dev. 54: 362-370.
70. Sahoo, D.K., Roy, A., Bhanja, S. and Chainy, G.B.N. (2005). Experimental Hyperthyroidism-induced Oxidative stress and Impairment of Antioxidant Defence System in Rat Testis. Ind. J. Exp. Biol. 43: 1058-1067.

Source(s) of Funding


None

Competing Interests


No competing interests.

Disclaimer


This article has been downloaded from WebmedCentral. With our unique author driven post publication peer review, contents posted on this web portal do not undergo any prepublication peer or editorial review. It is completely the responsibility of the authors to ensure not only scientific and ethical standards of the manuscript but also its grammatical accuracy. Authors must ensure that they obtain all the necessary permissions before submitting any information that requires obtaining a consent or approval from a third party. Authors should also ensure not to submit any information which they do not have the copyright of or of which they have transferred the copyrights to a third party.
Contents on WebmedCentral are purely for biomedical researchers and scientists. They are not meant to cater to the needs of an individual patient. The web portal or any content(s) therein is neither designed to support, nor replace, the relationship that exists between a patient/site visitor and his/her physician. Your use of the WebmedCentral site and its contents is entirely at your own risk. We do not take any responsibility for any harm that you may suffer or inflict on a third person by following the contents of this website.

Reviews
3 reviews posted so far

I am very much thankful to Prof. Kaur for critically evaluating the paper “Sahoo DK. Testicular Protection From Thyroid Hormone Mediated Oxidative Stress. WebmedCentral REPRODUCTION 2013;4(5):WMC004... View more
Responded by Dr. Dipak K Sahoo on 19 May 2013 01:48:14 AM GMT

Review of the article
Posted by Mrs. C Sahu on 15 May 2013 03:44:00 PM GMT

I am very much grateful to Dr. Sahu for critically evaluating the paper “Sahoo DK. Testicular Protection From Thyroid Hormone Mediated Oxidative Stress. WebmedCentral REPRODUCTION 2013;4(5):WMC00425... View more
Responded by Dr. Dipak K Sahoo on 19 May 2013 01:49:34 AM GMT

Report or Book Chapter
Posted by Dr. Mohammad Othman on 13 May 2013 10:51:30 AM GMT

I am very much thankful to Dr. Othman for critically evaluating the paper “Sahoo DK. Testicular Protection From Thyroid Hormone Mediated Oxidative Stress. WebmedCentral REPRODUCTION 2013;4(5):WMC004... View more
Responded by Dr. Dipak K Sahoo on 19 May 2013 01:49:08 AM GMT

Comments
0 comments posted so far

Please use this functionality to flag objectionable, inappropriate, inaccurate, and offensive content to WebmedCentral Team and the authors.

 

Author Comments
0 comments posted so far

 

What is article Popularity?

Article popularity is calculated by considering the scores: age of the article
Popularity = (P - 1) / (T + 2)^1.5
Where
P : points is the sum of individual scores, which includes article Views, Downloads, Reviews, Comments and their weightage

Scores   Weightage
Views Points X 1
Download Points X 2
Comment Points X 5
Review Points X 10
Points= sum(Views Points + Download Points + Comment Points + Review Points)
T : time since submission in hours.
P is subtracted by 1 to negate submitter's vote.
Age factor is (time since submission in hours plus two) to the power of 1.5.factor.

How Article Quality Works?

For each article Authors/Readers, Reviewers and WMC Editors can review/rate the articles. These ratings are used to determine Feedback Scores.

In most cases, article receive ratings in the range of 0 to 10. We calculate average of all the ratings and consider it as article quality.

Quality=Average(Authors/Readers Ratings + Reviewers Ratings + WMC Editor Ratings)