2015 Group Project 4

From Embryology
2015 Student Projects 
2015 Projects: Three Person Embryos | Ovarian Hyper-stimulation Syndrome | Polycystic Ovarian Syndrome | Male Infertility | Oncofertility | Preimplantation Genetic Diagnosis | Students
2015 Group Project Topic - Assisted Reproductive Technology
This page is an undergraduate science embryology student and may contain inaccuracies in either description or acknowledgements.

Male Infertility

Infertility is defined as the inability to achieve a clinical pregnancy after 12 months of unprotected sexual intercourse. [1] Male infertility is the inability for a male to successfully impregnate a fertile female. Infertility is an ever increasing issue that affects one in six Australian couples as reported in the Australian Government Department of Health, National Women's Health Policy. [2] Of these couples who are considered infertile, one in five experience problems that lie solely with the male.

Background Information

1. <pubmed>24356336</pubmed> This review article introduces the development of male germ cells prenatally and postnatally, as well as the factors which causes the abnormalities and fertility preservation.

2. <pubmed>6793629</pubmed>

Male infertility disorders

Causes of Infertility

Due to the increasing rates of male infertility worldwide, researchers have been focusing on aetiological factors for its treatment and prevention. There are numerous causes of male infertility, however, the most common causes are those that relate to the correct development and adequate supply of spermatazoa to result in pregnancy, or inefficient transport of spermatazoa. The three key parameters for assessing male infertility are spermatazoa count, viability and motility.[3]

Physiology of fertility in Males

Normal reproductive functioning in males is controlled by gonadotropin releasing hormone (GnRH), androgens and gonadatropins. The correct metabolism and functioning of all three types of hormones is essential to the normal and efficient production of spermatazoa, as well as over all reproductive health. GnRH is synthesised and released by the hypothalamus, which stimulates the anterior pituitary to release two gonadatropins: follicle stimulating hormone (FSH) responsible for spermatogenesis in the Sertoli cells and luteinizing hormone (LH) responsible for stimulating the release of androgens by the Leydig cells. Testosterone, the primary androgen, is released into the testes and aids FSH by further promoting spermatogenesis. Furthermore, testosterone is vital to the normal development of many accessory reproductive organs, including the accessory glands. A negative feedback loop of testosterone and inhibin (secreted by Sertoli cells) acts on the anterior pituitary, either decreasing or stimulating the release of FSH and LH. [4]

Major Causes of Male Infertility

Varicocele

Varicocele is one of the leading causes of infertility in males and affects one third of individuals classified as infertile. Varicocele is the abnormal dilation of the internal spermatic veins and creamasteric veins from the panpiniform plexus as a result of back flow of blood. This downward flow of blood into the panpiniform plexus is due to the absence or presence of incomplete valves within the veins. [5] As previously mentioned, the three key markers of spermatozoa quality and of male infertility, spermatazoa viability, count and motility, are also heavily associated with varicocele. [6] Other causes of varicocele include an increase in programmed cell death (apoptosis), increased scrotal temperature of approximately 2.5 degrees Celcius and reduced androgen secretion leading to testosterone deprivation. [7] Testosterone is one of the hormones that play a major role in the correct physiological functioning of the male reproductive system. It is therefore evident that a deprivation of testosterone severely affects the rate of production of spermatazoa, their maturation as well as the male reproductive systems ability to effectively ejaculate semen (related to the development of accessory glands).

Male Reproductive Cancers

Male reproductive cancers, including prostate cancer and testicular cancer, have been shown to dramatically decrease the quality of semen prior to treatment, being comparable with that of infertile and subfertile men. [8] A link between testicular cancer and male infertility has been established by the identification of Testicular Dysgenesis Syndrome (TDS). The improper or abnormal development of the testicles associated with TDS has direct links to Sertoli and Leydig cell disfunction leading to failure of gonocyte maturation and therefore insufficient or low production of mature spermatazoa; one of the key indicators of male infertility. [9]. Furthermore, the presence of tumors in the male reproductive system have systemic effects including immunological and cytotoxic effects on the germinal epithelial leading to reduction in the quality of sperm produced and changes in the processes of spermatogenesis. [10] Finally, it has also been suggested that the fever and malnutrition associated with cancer may lead to alterations in spermatogenesis, a large decrease in spermatazoa concentration and evem azoospermia, the absence of motile spermatazoa. [11]

Chromosomal Abnormalities

Chromosomal Abnormalities are responsible for approximately 5% of all cases of male factor infertility and result in azoospermia (absence of spermatazoa) and oligozoospermia (low spermatazoa concentration). [12] Aneuploidy is the presence of an incorrect number of chromosomes and is the most common error of chromosomal abnormality resulting in infertility. [13] Klinefelter syndrome occurs in approximately 5% of severe oligozoospermic and 10% of azoospermic men and causes the cessation of spermatogenesis at the primary spermatocyte stage. [14] Another aneuploidy associated with male infertility is Y-chromosome microdeletions, present in 10-15% of azoospermic and 5-10% of severe oligozoospermic men, that can result in lack of spermatazoa in ejaculate (AZFa deletion), arrest of spermatogenesis at primary spermatocyte stage (AZFb deletion) and low concentration of spermatazoa (AZFc deletion). [15][16]

Damage to DNA

DNA damage in the germ cell population of males has been shown to be a contributing factor to many adverse clinical outcomes including poor semen quality, low fertilisation rates and impaired pre-implantation development; an outcome significant in the use of Assisted Reproductive Technologies when treating infertility. [17] The integrity of spermatazoa can be negatively impacted by deficits in the DNA repair pathways resulting in decrease in germ cell survival and the production of spermatazoa. [18] It has been demonstrated that common inherited variants within genes that encode enzymes utilised in the mismatch repair pathway have a negative relationship with the maintenance of genome integrity, meiotic recombination and even gametogenesis, therefore increasing the risk of DNA damage in spermatazoa and male infertility. [19] Finally, it has been demonstrated that an increase in age is associated with increased spermatazoa DNA damage resulting in a decline in semen volume, spermatazoa motility and morphology and over all semen quality. [20]

Lifestyle Factors

There are numerous lifestyle factors that are associated with a decrease in male fertility that often cause irreversible damage to processes in gametogenesis. Tobacco smoking has been seen to increase risk of male infertility by up to 30% due to the competitive binding of cadmium to DNA polymerase, replacing zinc and causing damage to the testes. [21] It was also suggested by the same study that excessive alcohol intake has an adverse affect on spermatazoa quality and chromosome number. [22] Another lifestyle factor that produces adverse clinical outcomes to male infertility is obesity and its association with hypogonadatropic hypogonadism; a condition characterised by a decrease in functional activity of the gonads (hormone production and therefore gametogenesis). [23] Studies conducted on animals demonstrates that a sensitivity to leptin in the hypothalamus as a result of obesity, decreases Kiss1 expression, therefore decreasing the release of gonadatropin releasing hormone (GnRH) and ultimately resulting in hypogonadatropic hypogonadism. [24] Studies have demonstrated vigorous physical exercise such as bicycle riding and horse riding, has been associated with urogenital disorders including erectile dysfunction, torsion of the spermatic cord and infertility. [25]



--Z3462124 (talk) 09:53, 27 August 2015 (AEST)

Diagnosis

Male infertility is a widespread condition. There are different diagnostic techniques to detect male infertility, from medical histories, physical examinations to sophisticated tests such as blood tests, ultrasounds and semen analysis. Most cases, there are no obvious signs showing infertility. Sexual intercourse, erections and ejaculations occur usually without any difficulty; the quantity and sperm count of the ejaculated semen are not noticeable with the naked eye.

Physical examination

The physical examination focuses on the size and consistency of the genitals (testicles, epididymus and vas deferens) but also the overall body build. Noting the distribution of body hair and presence or absence of gynecomastia, which is the enlargement of male breasts due to the imbalance of hormones or hormone therapy. In some cases, by examining the size and consistency of the scrotum it is possible to palpate whether or not the epididymis may have hardened from a possible inflammation. Other cases may suggest obstruction within the ducts,this is determined by observing and examining the prostate size and consistency, checking for the presence of cysts or enlarged seminal vesicles.[26] Varicoceles are the most common abnormal finding in infertile men, typically diagnosed by physical examination of Valsalca manoeuvre. It is performed by forceful attempts of exhalation against closed airways by closing one's mouth and pinching their nose while pressing out. This strain increases their intrathoracic pressure and causes the venous return to the heart to decrease and increases the peripheral venous pressure.[27]

Varicoceles can be diagnosed by conducting Valsalva manoeuvre. [28] They can be classified into three grades:

  • Grade 1: only palpable during Valsalva manoeuvre
  • Grade 2: palpable without Valsalva manoeuvre
  • Grade 3: visible without Valsalva manoeuvre

Semen Analysis

Although the semen parameters of fertile men can vary, semen analysis is an initial and crucial laboratory test when determining male infertility. [29] Every 2 to 4 weeks, at least two semen samples should be collected. 2 to 4 days prior to the collection is the abstinence period; this is important as it will increase the sperm destiny by 25%. Semen samples are obtained by masturbation or by using a latex free, spermicide free condom during intercourse.

Semen samples are required to liquefy before being studied under the microscope.

Testicular Colour Dopple Ultrasound

High resolution color Doppler ultrasound is a noninvasive means of simultaneously imaging and evaluating the blood flow to the testes in infertile men. It is not generally performed as a routine examination, however physical examination may miss intrascrotal abnormalities readily detected by dopple ultrasound. Non-palpable intrascrotal abnormalities includes testicular and epididymal lesions and tumour. [30]


<pubmed>25038770</pubmed>

<pubmed>21243017</pubmed>

<pubmed>16903932</pubmed>

Prevention

1. <pubmed>17304390</pubmed> Smoking

2. <pubmed>20090219</pubmed> Alcohol and cigarette smoking

3. <pubmed>25277121</pubmed> Alcohol

4. <pubmed>24306102</pubmed> Prevalence of low ejaculate volume in overweight and obese men, but still needs further investigation to understand role of weight loss in fertility.

5. <pubmed>26067627</pubmed> "High BMI is negatively associated with semen characteristics and serum levels of AMH (Anti-Mullerian Hormone)"

Treatments

Current treatments for male infertility aim to eliminate the causative factors mentioned above. These may involve improving the male's fertility using drug therapies or surgical procedures, however many assisted reproductive technologies have been introduced and have proven successful. Both methods of treatment have shown evidence of efficacy, thus having great implications on infertile couples worldwide.

Improving Fertility

In order to effectively treat male infertility, it is imperative to correctly identify the specific cause and contributing factors. Currently, the different treatment strategies used or investigated tend to the specific aetiological factors for male infertility. Apart from theoretically allowing natural conception, these treatments also have an implication on the assisted reproductive technologies (ARTs) that are currently available. Some ARTs allow for the male's genetic material to be passed onto the offspring, contingent upon a successful sperm extraction/retrieval such as intracytoplasmic sperm injection (ICSI). Although only a spermatozoon (single sperm) is required for this particular procedure, these treatment methods ultimately aim to "maximize the sperm retrieval yield" [31].

Injectable Hormones & Fertility Drugs

Hormonal imbalance is a non-obstructive cause for male infertility. The efficiency of spermatogenesis depends on stimulation and regulation mainly by gonadotropins, GnRH and testosterone, without which may cause infertility. Males that have a deficiency in these hormones are being targeted by research involving injectable hormones such as human chorionic gonadotropin (hCG) and human menopausal gonadotropin (hMG), and Clomiphene citrate, a fertility drug. hCG and hMG are gonadotropins that are used to treat male hypogonadotropic hypogonadism (MHH), a condition associated with infertility causing an underproduction of sperm or testosterone, or both [32]. These gonadotropins have been utilised in infertile males to stimulate the synthesis of testosterone and sperm directly, bypassing the pituitary gland that normally releases gonadoptropins LH and FSH. LH triggers Leydig cells to release testosterone, and FSH plays a vital role in spermatogenesis maintenance as it promotes Sertoli cell maturation [31].

Additionally, clomiphene citrate also increases secretion of GnRH from the hypothalamus, and FSH and LH from the pituitary gland by blocking feedback inhibition of serum estradiol [31]. Normally, males have more testosterone levels than estrogen however those with MHH and consequent infertility, may have the opposite [33]. This was investigated in a study conducted in 2013 by Hussein et al. showing that hCG, hMG and clomiphene citrate are suitable treatments particularly for azoospermia, increasing levels of FSH, LH and total testosterone [31]. Therefore the administration of these substances may correct abnormal hormone levels that contribute to male infertility, thus stimulates spermatogenesis to increase spermatozoa count, motility and viability.

Antioxidants

Reactive oxygen species (ROS) formed during oxidation plays a vital role in sperm function, particularly in capacitation, acrosome reaction, hyperactivation and sperm-oocyte fusion [34]. In low concentrations, ROS are essential for the synthesis of energy, and contribute to signal transduction pathways within the cell. Usually ROS levels are regulated by natural antioxidants within the seminal plasma [34]. However an influx of ROS and/or a deficiency in antioxidants due to abnormal sperm or environmental stress, can lead to oxidative stress. Spermatozoal cell membranes contain high amounts of polyunsaturated fatty acids that consist of several electron-containing double bonds. The electrons of these fatty acids contribute to the formation of ROS and oxidative stress, thus causing a disruption in the flexibility of the spermatozoal membrane and diminishing the motility and sustainability of sperm [35]. This may result in sperm membrane lipid peroxidation, DNA fragmentation, and apoptosis [34]. The following are a few antioxidants that have been proven to treat oxidative stress, hence improves male fertility.

1. Lycopenes

Lycopenes are a type of cartenoid that is found in various fruits and vegetables such as tomatoes and watermelon. Despite it being a source of vitamin A, it also possesses strong antioxidant properties that quenches (deactivates) a high energy form of oxygen [36]. Although the exact mechanism of lycopenes is yet to be known, they have a role inneutralizing ROS and hindering their activity, achieved by their ability to donate an electron to free radicals [35]. As a result of this antioxidation pathway, lipid peroxidation is inhibited allowing for spermatozoal membranes to be retained and protected from further damage. Lycopenes have also been suggested to increase natural antioxidant enzymes indirectly, and also decrease the production of pro-inflammatory agents.

Proposed Mechanisms of Lycopene Treatment for Idiopathic Male Infertility.jpeg

Proposed Mechanisms of Lycopene Treatment for Idiopathic Male Infertility [37]


2. Cerium dioxide nanoparticles (CNPs)

Cerium dioxide nanoparticles have been used extensively in the health care industry as potential pharmacological agents to treat various conditions from cancer to male infertility. These products are formed by cerium combining to oxygen obtaining a strong crystalline structure [38]. CNPs have the ability to interchange Ce 3+ and Ce 4+ ions that are present on its surface, leading to defects in oxygen within its crystal lattice structure. These regions on the surface of CNPs are ‘reactive sites’ to attract free radicals [39]. Therefore, the electronic structure of CNPs, and thus its antioxidant properties make this material a promising therapeutic for male infertility caused or affected by oxidative stress.


2. <pubmed>26097523</pubmed> The research discussed in this article discusses the advantages of using cerium dioxide nanoparticles (CNPs) to treat male infertility due to its antioxidant effects. The research team experimented on male rats to observe CNP effects on male health and infertility as oxidative stress plays a key role in preventing proper spermatogenesis.


3. <pubmed>PMC4023371</pubmed> Research article also focuses on the effects of oxidative stress on male fertility. It discusses the use of lycopenes as a possible treatment for infertility disorders due to its antioxidant properties, as well as contributing to gap junction communication, modulation of gene expression, regulation of the cell cycle and immunological aspects.


4. <pubmed>15867002</pubmed> Using an antioxidant and vitamins C and E to decrease rates of DNA fragmentation caused by ROS


5. <pubmed>16110353</pubmed> Using Astaxanthin to treat fertility by preventing oxidative damage. Measured its effects by semen analysis, blood serum levels of hormones (LH, FSH and testosterone) = can also use for 'diagnosis'


6. <pubmed>25890347</pubmed> This research focuses on a cause for male infertility - varicocele, an enlargement of the pampiniform venous plexus (varicose vein) within the scrotum, with the influence of ROS can lead to atrophy of the testicle. It has been suggested that protein alteration in the seminal plasma and spermatozoa occur in this condition thus the proteins can act as potential biomarkers to diagnose infertility. If diagnosed, males can undergo surgery to treat this.


7. <pubmed>25885464</pubmed> Discusses the success rate of the microsurgery rat model to treat varicocele that is a causative factor for male infertility. Relates to article number 6

Assisted Reproductive Technologies (ARTs)

References

  1. The World Health Organisation,. (2015). Human Reproductive Programme | Sexual and Reproductive Health. Retrieved 4 September 2015, from http://www.who.int/reproductivehealth/topics/infertility/definitions/en/
  2. The Department of Health,. (2011). Department of Health | Fertility and infertility. Health.gov.au. Retrieved 2 September 2015, from http://www.health.gov.au/internet/publications/publishing.nsf/Content/womens-health-policy-toc~womens-health-policy-experiences~womens-health-policy-experiences-reproductive~womens-health-policy-experiences-reproductive-maternal~womens-health-policy-experiences-reproductive-maternal-fert
  3. <pubmed>21243017</pubmed>
  4. Stanfield, L. C. Pearson New International Edition Principles of Human Physiology Fifth Edition
  5. Marmar, L.J. (2001) Varicocele and Male Infertility Part II: The pathophysiology of varicoceles in the light of current molecular and genetic information. Human Reproduction Update, Vol. 7, No. 5 pp. 461-472 retrieved 2nd September 2015, from http://humupd.oxfordjournals.org/content/7/5/461.long
  6. Cocuzzo, M. Cocuzzo, M. A. Bragais, F. M/ P. Agarwal, A. (2008) The role of varicocele repair in the new era of assisted reproductive technologies. Clinics Vol. 63, No. 6 retrieved 2nd September 2015, from http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1807-59322008000300018&lng=en&nrm=iso&tlng=en
  7. Marmar, L.J. (2001) Varicocele and Male Infertility Part II: The pathophysiology of varicoceles in the light of current molecular and genetic information. Human Reproduction Update, Vol. 7, No. 5 pp. 461-472 retrieved 2nd September 2015, from http://humupd.oxfordjournals.org/content/7/5/461.long
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  26. <pubmed>21243017</pubmed>
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  31. 31.0 31.1 31.2 31.3 <pubmed>22958644</pubmed>
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  38. Xu, C., & Qu, X. (2014). Cerium oxide nanoparticle: a remarkably versatile rare earth nanomaterial for biological applications. NPG Asia Materials, 6(3), e90. http://dx.doi.org/10.1038/am.2013.88
  39. <pubmed>26097523</pubmed>

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