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date: 26 July 2021

Male Reproductive Function and Fecundityfree

Male Reproductive Function and Fecundityfree

  • Michael T. MbizvoMichael T. MbizvoThe Population Council Reproductive Health Program
  •  and Tendai M. ChiwareTendai M. ChiwareWorld Health Organization

Summary

Male reproductive function entails complex processes, involving coordinated interactions between molecular structures within the gonadal and hormonal pathways, tightly regulated by the hypothalamic–pituitary gonadal axis. Studies in men and animal models continue to unravel these processes from embryonic urogenital development to gonadal and urogenital ducts function.

The hypothalamic decapeptide gonadotropin-releasing hormone is released into the hypophyseal portal circulation in a pulsatile fashion. It acts on the gonadotropes to produce the gonadotropins, the main trophic hormones acting on the testis to regulate sperm production. This endocrine control is complemented by paracrine and autocrine regulation arising from the testis, where germ cells originate, modulated by growth factors and local regulators arising within the testis. The process of spermatogenesis, originating in seminiferous tubules, is characterized by stem cell proliferation and differentiation, meiotic divisions, expression of transcriptional regulators, through to morphological changes which include cytoplasm reorganization and flagellum development. Metabolic processes and signal transduction pathways facilitate the functional motion and transport of sperm to the site of fertilization. The normal sperm structure or morphology acquired during spermatogenesis, epididymal maturation, sperm capacitation including motility, and subsequent acrosome reaction are all critical events in the acquisition of sperm fertilizing ability. Generation of the male gamete is assured through adequate gonadal function, involving complex differentiation processes and regulation, during spermiogenesis and spermatogenesis. Sperm functional changes are acquired during epididymal transit, and functional motion is maintained in the female reproductive tract, involving activation of signaling processes and transduction pathways. Infertility can arise in the male, from spermatogenic failure, sperm functional quality, obstruction and other factors, but causes remain unknown in a large proportion of affected men. Semen analysis, complemented by the clinical picture, remains the mainstay of male infertility investigation. Assisted reproductive technology has proved useful in instances where the cause is not treatable. Complications from sexually transmitted infections could lead to male infertility, by impairing sperm quality, production, or transport through the reproductive tract.

Male fecundity denotes the biological capacity of men to reproduce, based on ability to ejaculate normal sperm. Lifestyle, environmental, and endocrine disruptors have been implicated in reduced male fecundity.

Interactions between vascular, neurological, hormonal, and psychological factors confer normal sexual function in men. Nocturnal erections begin in early puberty, occurring with REM sleep. Sexual health is an integral part of sexual and reproductive health, while sexual dysfunction, in various forms, is also experienced by some men.

Methods of contraception available to men are few, and underused. They include condoms and vasectomy.

Enhanced knowledge of male reproductive function and underlying physiological mechanisms, including sperm transit to fertilization, can be catalytic in improvements in assisted reproductive technologies, male infertility diagnosis and treatment, and development of contraceptives for men.

The article reviews the processes associated with male reproductive function, dysfunction, physiological processes and infertility, fecundity, approaches to male contraception, and sexual health. It further alludes to knowledge gaps, with a view to spur further research impetus towards advancing sexual and reproductive health in the human male.

Subjects

  • Sexual & Reproductive Health

Introduction

The Hypothalamic–Pituitary–Gonadal Axis

The male hypothalamic–pituitary–gonadal (HPG) axis comprises of a finely controlled system engaged in the development and maintenance of spermatogenesis and androgen biosynthesis (Corradi, Corradi, & Greene, 2016; Fink, 1988; O’Shaughnessy, 2014). Gonadotropin-releasing hormone (GnRH) is a decapeptide hormone previously known as luteinizing hormone releasing hormone (Corradi et al., 2016; Fink, 1988). Pulsatile secretion of GnRH by the hypothalamus into the hypophyseal portal circulation acts on the pituitary gonadotropes to stimulate synthesis and secretion of the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (Corradi et al., 2016; Fink, 1988). These glycoproteins have subunits associated through noncovalent interactions to increase beta LH and FSH subunit messenger RNA levels and the transcriptional activity of gene promotion (Fink, 1988; Griswold, 1998).

LH and FSH sustain gonadal testosterone production and spermatogenesis (Corradi et al., 2016; Fink, 1988). Testosterone synthesized in the Leydig cells of the testis exerts a direct negative feedback control of LH secretion, an indirect action on FSH secretion in seminiferous tubules through inhibin feedback, and decreases hypothalamic GnRH secretion into the hypophyseal portal circulation (Corradi et al., 2016; Shiraishi & Matsuyama, 2017). FSH is essential for the determination of testicular Sertoli cell number, induction, and maintenance of spermatogenesis by the Sertoli cells (Corradi et al., 2016; Griswold, 2018; O’Shaughnessy, 2014). This steroid hormone binds to specific receptor sites in target cells to activate transcription and production of new mRNA, which is translated in the cytoplasm to produce new proteins that modify cell function (Bernie, Mata, Ramasamy, & Schlegel, 2015). LH stimulates the secretion of gonadal steroidogenesis, converting cholesterol to testosterone, through Leydig cell activity (Corradi et al., 2016).

The timed pulsatile response by the pituitary and Leydig cells to their respective stimulators avoids desensitization to the stimulus, which can occur with continued exposure, for potential use in male fertility regulation. With adequate testosterone levels, the pituitary decreases the production and release of LH via negative feedback, thus decreasing GnRH and LH as well as testosterone. Negative feedback of FSH occurs by gonadal peptide hormones inhibin and activin. Sertoli cells secrete both inhibin A and B, and FSH secretion is suppressed by inhibin B, modulating the FSH stimulation of activin (Corradi et al., 2016). Activin is a dimer of inhibin B subunits with autocrine and paracrine function. Activin is regulated by inhibin and follistatin. It regulates testicular development, modulating germ cell development and Sertoli cell proliferation (Risbridger & Cancilla, 2000; Wijayarathna & de Kretser, 2016). Follistatin produced by the pituitary bind activin and further decrease their function (Corradi et al., 2016).

Figure 1 depicts the regulation of testicular function through pulsatic GnRH secretion to release LH and FSH, which in turn have an effect on gonadal testosterone production and spermatogenesis.

Figure 1. Schematic representation of the reproductive system of the male.

Adapted from Fink (1988) and Griswold (1998).

Pulsatile GnRH secretion from the hypothalamus is essential for maintaining reproductive function. Neuroendocrine function of the HPG axis begins in early fetal development, as early as 13 weeks. Hypothalamic GnRH neurons are fully functional by birth. There is a perinatal surge of androgen production and then tonic suppression until later in childhood when low pulse frequency and amplitude GnRH secretion occurs. The neuroendocrine trigger for puberty is still not fully understood in males and females. Onset of puberty is marked by a sleep directed reactivation of the HPG axis with increased amplitude of LH pulses resulting in gonadal sex steroid production. As puberty progresses, production of gonadotropins throughout the day results in sexual development (Corradi et al., 2016). Increasing levels of testosterone and potent dihydrotestosterone (DHT) cause deepening of the voice, secondary sex hair distribution, enlargement of the testes, growth of the penis, and increase in libido. High levels of testosterone and aromatization to estrogen allow for development of muscle mass, bone maturation, and accelerated bone growth until closure of the epiphyses of the long bones (Corradi et al., 2016). In adulthood, pulsatile GnRH secretion continues to stimulate production of LH and FSH to sustain testosterone production, spermatogenesis, and virilization. Failure of GnRH secretion or action, as well as gonadotropin secretion, result in hypogonadotropic hypogonadism. This can be primary (elevated LH, FSH, and low testosterone) or secondary (low or normal LH, FSH, and low testosterone), both as a result of congenital or acquired disorders (Corradi et al., 2016).

LH and FSH act within the testes to produce 95% of total circulating testosterone in post-pubertal men, the endocrine product, and mature sperm, the exocrine product (Corradi et al., 2016). Testosterone in the circulation is either protein-bound (98%) or free (2%). Free testosterone is considered the biologically active form that is peripherally converted to other steroids including estradiol by the enzyme aromatase and DHT by the enzyme 5α‎-reductase. Only 5% of testosterone is converted to DHT (Corradi et al., 2016). DHT is more potent than testosterone and mediates many important androgen functions. DHT binds the androgen receptor with two to three times more affinity than testosterone, while testosterone is dissociated from the androgen receptor five times faster than DHT (Grino, Griffin, & Wilson, 1990). DHT plays a pivotal role in the formation of male genitalia during embryogenesis and in the growth of the prostate and hair follicles in the adult male (Kang, Imperato-McGinley, Zhu, & Rosenwaks, 2014). A deficiency in the enzyme 5α‎-reductase in infancy results in a small phallus and internal testes. With puberty, mature testosterone levels cause enlargement of the penis, male appearance, and normal male reproductive function (Corradi et al., 2016; Kang et al., 2014). Circulating estradiol (over 80%) as a result of aromatization of testosterone plays an important role in bone metabolism, body fat, and sexual function in men (Finkelstein et al., 2013). Male hypogonadism results in hypoestrogenism and high testosterone. This leads to increased LH from reduced feedback to the pituitary (Corradi et al., 2016).

Spermatogenesis

Sertoli cells, the main mediator of androgen action and spermatogenesis, occupy 17–20% of the seminiferous tubules in an adult man (Neto, Bach, Najari, Li, & Goldstein, 2016). Spermatogenesis entails the process of generation of the male gamete through distinct phases of development and mitosis of the undifferentiated spermatogonia, spermatocyte development through meiosis, differentiation of the spermatids during spermiogenesis, and release of spermatids during spermiation. It is a complex process of differentiation requiring several cell types, hormones paracrine factors, genes, and epigenetic regulators (van den Driesche, Sharpe, Saunders, & Mitchell, 2014). Sertoli cells play a central role in the embryology of the testis by secreting hormones and proteins necessary for its development (Neto et al., 2016). During puberty there is a cessation of mitosis of the Sertoli cells, formation of tight junctions between adjacent Sertoli cells, and progression of germ cells through meiosis and differentiation into spermatozoa (Griswold, 1998).

Spermatogenesis is initiated in the seminiferous tubules of the testis. They facilitate the progression of germ cells to spermatozoa by direct contact and the regulation of the environment milieu within the seminiferous tubules (Griswold, 1998; van den Driesche et al., 2014). The primordial germ cells arise from the extra-embryonic tissues surrounding the yolk sac, migrate to the gonadal ridge, and differentiate into gonocytes (Neto et al., 2016; Pask, 2016). The gonocytes enter in arrest and in the G0 phase of the cell cycle and remain mitotically inactive until after birth. Between birth and 6 months of age the gonocytes further differentiate into spermatogonia, which remain quiescent until the age of 5–7 years old when they undergo mitosis and increase in number. At puberty, spermatogonia, which are diploid progenitors, begin the differentiation to spermatozoa as well as self-renewal, maintaining life-long continuous production of spermatozoa (Neto et al., 2016). A population of undifferentiated spermatogonial stem cells is maintained to ensure adequate numbers of spermatogonia for undergoing spermatogenesis whose micro regulation includes microRNA signaling (van den Driesche et al., 2014). They are located in the basal compartment of the seminiferous tubule in close contact with the Sertoli cell (Neto et al., 2016). Primary spermatocytes are produced by mitotic division of type B spermatogonia, marking the completion of the proliferative portion of spermatogenesis. They are the first germ cells to cross the blood–testis barrier to the adluminal compartment, where they are immunologically isolated and proceed to meiosis where they are in different stages of prophase 1 (Neto et al., 2016). Following meiosis 1, two secondary spermatocytes (haploid chromosomes, 2N DNA) are formed. During meiosis 2, a single secondary spermatocyte becomes two haploid (1N DNA) round spermatids (Neto et al., 2016).

Spermiogenesis then occurs, which is the maturation process with no further cellular divisions. A series of cytoplasmic and nuclear changes occur in which one round spermatid becomes one spermatozoon. The acrosome is formed from the Golgi apparatus and perinuclear theca. The nucleus becomes more condensed and migrates to an eccentric position. Poor DNA packing results in DNA fragmentation and decreases fecundity (Neto et al., 2016). The sperm tail arises from the centriole, gradually elongating the spermatid shape, and is formed of microtubules disposed in a 2+9 formation. Once fully developed, the spermatid is detached from the Sertoli cells and released into the tubule lumen in a process known as spermiation. This is dependent on FSH and testosterone (Neto et al., 2016). Whereas FSH acts to support spermatogenic output by increasing the number of Sertoli cells, the action of testosterone is necessary to achieve the process of spermatogenesis (Griswold, 1998). Thus, while Sertoli cells are the target of FSH, they have numerous androgen receptors, indicating that they are regulated by FSH and the paracrine functions of testosterone. In addition, in combination with Leydig cell-derived growth factors, Sertoli cells support spermatogenesis (Griswold, 1998).

Sperm Functional Motion, Morphology, and Fertilizing Ability

The process by which human spermatozoa mature, become activated and acquire functional motion capacity to transit to the site of fertilization, undergo the acrosome reaction, and interact with the oocyte to achieve fertilization, has been described over several years (Abou-haila & Tulsiani, 2009; Puga Molina et al., 2018; Visconti, Krapf, de la Vega-Beltran, Acevedo, & Darszon, 2011), although there is still lack of full understanding, especially of in vivo differential trigger processes. Following spermatogenesis, sperm are morphologically complete although functionally immature (Freitas, Vijayaraghavan, & Fardilha, 2017). Sperm remain immortal within the epididymis until released, and begin to swim during activation and capacitation, acquired during epididymal transit and maintained in the female reproductive tract, following activation of key signal transduction pathways (Freitas et al., 2017). The functional changes during sperm capacitation are a result of a combination of sequential and concomitant signaling processes (Visconti et al., 2011). There are still profound gaps between the rapid knowledge gained through the advent of in vitro fertilization (IVF) systems, and the in vivo situation pertaining to sperm transit in the female reproductive tract.

In vivo, ejaculation of a sizeable, morphologically normal, and motile sperm population is an essential part of the fertilization process. Sperm motility acquisition is a critical component of human sperm function and subsequent fertility. Thus, normal sperm structure, energy metabolism, epididymal maturation, and capacitation constitute critical events in the acquisition of sperm fertilizing ability, whereas the underlying molecular processes are not fully unraveled. The motion capacity is aided by a metabolic glycolytic process controlled by intracellular adenyl cyclase-cyclic adenosine monophosphate (cAMP) and adenosine triphosphate (ATP) enzyme systems, during which phosphorylation also occurs, with both pathways essential for human sperm function and successful fertilization (du Plessis, Agarwal, Mohanty, & van der Linde, 2015). While competent sperm motion is necessary for penetration of the cervical mucus, migration through the uterus into the fallopian tubes, and penetration of the oocyte vestments, several in vitro studies (Morales, Overstreet, & Katz, 1988; Suarez & Pacey, 2006; Wang, Lee, Leung, Surrey, & Chan, 1993) have shown enhanced velocity, including hyperactivated motility, following addition of biological substances that include follicular fluid, serum, progesterone, adenosine analogues, and methylxanthines (Cohen-Dayag, Tur-Kaspa, Dor, Mashiach, & Eisenbach, 1995; Mbizvo, Burkman, & Alexander, 1990; Mbizvo, Johnston, & Baker, 1993; Nassar et al., 1999; Suarez, 2008). A review by Freitas et al. (2017) discusses further advances that attempt to unravel signaling pathways involved in human sperm functional motion and key messages involved in hyperactivation, aided by signaling mechanisms within the female reproductive tract. There is a controlling role of ATPase activity, calcium ion concertation, and phosphorylation of protein increase in cAMP (Freitas et al., 2017). Wang et al. (1993) assessed the relationship of human sperm hyperactivation and acrosome reaction and observed a significant correlation rate with in vitro human oocytes fertilization rates.

Methylxanthines such as pentoxifylline are known to inhibit phosphodiesterase activity in living cells, which leads to an increase in intracellular cAMP, through the glycolytic pathway, as a second messenger to enhance sperm motility. Intracellular calcium influx modulation has also been shown to affect sperm motion (Nassar et al., 1999). Selective recruitment of functionally mature spermatozoa, through chemotaxis, during which sperm respond by chemo attraction to follicular factors to aid acrosome reaction and fertilization, has been postulated (Cohen-Dayag et al., 1995). Hyperactivated sperm motility, characterized by high curvilinear velocity, and amplitude, is considered a part of the capacitation processes, through chemotactic signals to propel sperm through mucus in the oviductal lumen and the matrix of the cumulus oophorus (Cohen-Dayag et al., 1995; Suarez, 2008; Visconti et al., 2011). It is characterized by a rise in flagellar Ca2+, acting through the calmodulin/calmodulin kinase pathway, although much is still unknown about the trigger sources in human sperm. Quality of sperm motility is among key functional parameters for assessing sperm capacity for fertilization and male fertility. Human sperm are morphologically differentiated in the testis, prior to gaining fertilizing sperm ability through capacitation. Sperm morphology evaluation has been one of the most commonly used tests in the assessment of fertility in men. Several studies have reviewed sperm morphology in the context of fertility diagnostic thresholds, pathophysiology, and analytical tests for assisted reproductive technology (ART) (Auger, Jouannet, & Eustache, 2016; Cooper, 2016; Gatimel, Moreau, Parinaud, & Leandri, 2017).

Morphology of sperm serves as an important marker of testicular function, spermiation, and fertility potential. In an earlier study, Coetzee, Kruge, and Lombard (1998) reviewed literature on the predictive value of sperm morphology as an indicator of male fertility potential in the in vitro fertilization (IVF) situation, and aggregated data from several studies established the 5% and 14% normal morphology thresholds (strict criteria) associated with 82% and 75% pregnancy prediction, respectively. A subsequent review of 421 studies by Van Waart, Kruger, Lombard, and Ombelet (2001), which included a meta-analysis of six studies that used the strict morphology criteria, showed a significant improvement in pregnancy rate above the 4% threshold for strict criteria. This was also adopted in the World Health Organization (WHO) 2010 Laboratory Manual for Examination and Processing of Human Semen.

While these cut-off values have been based on outcomes during IVF, their application in vivo may be less clearly known, especially as it is known that within the female genital tract, sperm must negotiate different physical barriers that include ability to traverse the cervix, or the extent to which morphologically defective sperm are filtered during transit through the cervix.

Male Infertility, Sexual Health and Dysfunction, and Contraceptive Approaches

Male Infertility

Infertility affects 15% of couples, totaling 60 to 80 million couples worldwide (Avellino, Theva, & Oates, 2017; Bachir & Jarvi, 2014). Infertility is a failure of a couple to achieve a successful clinical pregnancy after one year of regular unprotected sexual intercourse (Zegers-Hochschild et al., 2017). Male factor is implicated in 40–50% of cases as the sole cause or contributory factor (Avellino et al., 2017; Bachir & Jarvi, 2014). Many conditions have been implicated as causes of male infertility including congenital malformations, exposure to environmental toxins, genetic and endocrine disorders, and infectious and inflammatory conditions (accounting for up to 15% of male infertility). Male reproductive organs including the prostate, testicles, and epididymis are susceptible to infection and inflammation, resulting in 15% of male infertility by affecting the functioning of these organs with altered spermatogenesis, sperm function, and transit (Bachir & Jarvi, 2014).

Diagnosis of infertility in a couple includes the evaluation of the female and male partner. In conjunction with the clinical picture of medical history and physical examination, the cornerstone of the male fertility evaluation commences with a semen analysis (Smith, Coward, & Lipshultz, 2014). Other tests have been developed to assess semen parameters but are not currently widely used. The WHO released valuable guidelines in interpreting and standardizing the results of semen analysis (see Table 1). This data was obtained from retrospective data of fertile men with partners who conceived within one year of stopping contraception (Oehninger & Ombelet, 2019; WHO, 2010).

Table 1. 2010 WHO Lower Reference Limits (5th Percentile) for Semen Analysis (WHO, 2010)

Parameter

Lower Reference Limit

Volume

1.5 ml

pH

≥7.2

Sperm concentration (106 per ml)

15

Total sperm number (106 per ml)

39

Total motility

40%

Progressive motility

32%

Strict morphology (normal forms)

4%

It should be noted that men whose semen parameters fall below the lower limits are not necessarily infertile and values within normal limits do not reflect normal fertility. No single parameter has been shown to be a powerful discriminator of fertility. In addition, these guidelines were not developed to predict the success of intrauterine insemination or ART (Oehninger & Ombelet, 2019; Smith et al., 2014).

Men with infertility may demonstrate oligozoospermia, azoospermia, or normal sperm counts. Oligozoospermia is a low mean sperm concentration in the ejaculate, while azoospermia is the absence of sperm in the ejaculate. About 8% of men presenting with infertility will have oligozoospermia, and serum FSH and testosterone to detect common endocrine disorders are recommended for men with less than 10 million sperm/ml. A varicocele may be commonly found with oligozoospermia. Men with severe oligozoospermia of less than 5 million/ml are at risk of a genetic abnormality, and a karyotype and Y-chromosome microdeletion analysis is recommended. Azoospermia is noted in 4% of men during an infertility evaluation. Nonobstructive azoospermia is a disorder of spermatogenesis, while obstructive azoospermia represents a normal spermatogenesis with ductal obstruction, detected by physical examination. Evaluation for endocrine disorders and genetic abnormalities is recommended. Therapy for isolated abnormalities is directed to correcting hormonal abnormalities and identifying genetic causes. If the cause is not determined, ART may be useful for procreation (Diagnostic evaluation of the infertile male: a committee opinion, 2015; Krausz, 2011; Smith et al., 2014).

Over 80% of infertile men have asthenozoospermia, low sperm concentration associated with decreased motility and normal morphology. Possible causes include prolonged abstinence, ejaculatory dysfunction, genital tract infection, and varicocele. If the cause is not treatable, ART may be used. A small percentage of infertile men have teratozoospermia, normal sperm concertation with a decreased motility and/or abnormal morphology (<4%). About 30% of men under evaluation for infertility present with oligoasthenoteratozoospermia, or with abnormalities in two or more semen parameters. Varicocele is the most common cause but may include fever, exposure to gonadotoxins, medications, and partial ejaculatory obstruction (Diagnostic evaluation of the infertile male: a committee opinion, 2015; Krausz, 2011; Smith et al., 2014).

Sexually transmitted infections represent major health, social, and economic issues worldwide and complications include infertility. The prevalence of male infertility secondary to genital tract infections is reportedly 20–25% and may be symptomatic or asymptomatic. Transient or permanent infertility may occur from impairment in testicular function and spermatogenesis, and/or orchitis, directly impairing sperm production and male accessory gland (epididymis, prostate, and seminal vesicles) function, and the urethral tract may be partially or completely obstructed, altering secretory function and release of inflammatory mediators (Garolla et al., 2013). Recent studies have shown that the presence of HIV, Hepatitis B, or Hepatitis C virus in semen impairs sperm parameters, DNA integrity, and forward motility (Cardona-Maya, Velilla, Montoya, Cadavid, & Rugeles, 2011; Lorusso et al., 2010). Little is known regarding the effects of human papillomavirus, herpes virus, cyclomegalovirus, and adeno-associated virus infection in semen but they have been shown to negatively affect semen parameters. These infections may also be transmitted to the female partner and fetus, as well as being implicated in fetal infection and pregnancy loss. Screening male partners for sexually transmitted infections is recommended. There are procedures to wash sperm to completely avoid transmission of infections and improve assisted or spontaneous fertility outcomes (Garolla et al., 2013).

Depending on the etiology of male infertility, management of male infertility involves an organized, evidence-based management approach. Fertility is multifactorial and relies on thresholds of sperm features, on coital frequency and sexual function, and on coexisting female factors (Oehninger & Ombelet, 2019). Etiologies of infertility in men vary worldwide. Whereas in a large proportion of men presenting with infertility, the underlying cause is unknown (idiopathic), etiologies involved include congenital and acquired factors, (see table 2)

Table 2. List of Etiological Factors Involved in Male Infertility

Congenital factors:

Anorchia

Cryptorchidism

Congenital absence of the Vas Deferens

Genetic abnormalities (karyotype anomalies including Klinefelter syndrome, Y-chromosome microdeletions, Kallmann syndrome, mutations in genes in the HPG axis, partial or mild androgen insensitivity syndrome)

Acquired factors:

Testicular trauma

Testicular torsion

Post-infection inflammatory forms (orchitis, epididymitis)

Obstruction, sub-obstruction of proximal and/or distal urogenital tract

Recurrent urogenital infections, prostatitis, prostatovesiculitis

Exogenous factors (medications, cytotoxic drugs, irradiation, heat, environmental factors etc.)

Systemic diseases (liver, renal, etc.)

Varicocele (depending on the grade)

Surgeries that damage vascularization of the testes

Sexual dysfunction

Acquired hypogonadotropic hypogonadism or endocrine disorders

Idiopathic forms:

Unknown etiology (about 50%)

Source: Krausz, 2011.

Promoting a healthy lifestyle in the male and female partner is the first intervention to improve fecundity (Krausz, 2011; Smith et al., 2014; Tournaye, Krausz, & Oates, 2017a). Pretesticular and post-testicular origins of male infertility may be amenable to specific therapies including lifestyle changes, or medical or urological interventions (Oehninger & Ombelet, 2019). Hormonal therapy has a limited role in specific infertile men. However, directed hormonal therapy is effective in azoospermic men with congenital hypogonadotropic hypogonadism. Surgical treatment to restore sperm flow in the ejaculate, to maximize sperm quality and quantity, or to harvest sperm from the epididymis or testis allows for natural conception or assisted conception with intrauterine insemination or in vitro fertilization with use of intracytoplasmic sperm injection (Tournaye et al., 2017a).

Male Sexual Health and Sexual Dysfunction

Normal development of a male sexual phenotype during embryogenesis requires androgens (Griswold, 1998; Neto et al., 2016). Aromatase converts androgens to estrogens and both are necessary for normal male physiology (Cooke, Nanjappa, Ko, Prins, & Hess, 2017). Androgens regulate GnRH and gonadotropin secretion by the HPG axis (Corradi et al., 2016). Androgens are also responsible for maintaining normal sexual function. At puberty, androgen-dependent phenotypic changes occur, as summarized in Table 3.

Table 3. Androgen-Dependent Phenotype Changes*

Characteristic

Change at puberty

Reproductive system

Increase in testicular size to ≥2.5 cm

Onset of androgen synthesis and spermatogenesis

Growth of external genitalia

Growth and onset of secretion of accessory sex organs

Somatic tissue

Appearance of facial, axial, and pubic hair

Increase in sebaceous gland secretion and acne

Lowered voice tone due to vocal cord lengthening

Increased lean body mass

Reduction in subcutaneous fat

Skeletal muscle hyperplasia and hypertrophy

Increase in bone growth and differentiation

Lengthening of long bones

Broadening of shoulders

Relative growth of jaw and nose

Long bone growth cessation as a result of closure of the epiphyses

Behavioral

Increased libido, internal turmoil, and depression

Vascular

Increased systolic and diastolic blood pressure

Increased erythropoietin and hematocrit

Reduction in lymphoid tissue

* Adapted from Mawhinney and Mariotti (2013, Table 1)

Normal sexual function involves closely knit interactions between vascular, neurologic, hormonal, and psychological systems (Krane, Goldstein, & Saenz de Tejada, 1989). The penis contains the corpora cavenosa, which communicates with the pendulous penis and corpus spongiosum that surrounds the urethra and forms the glans penis distally. The tunica albuginea encases these structures. Penile erections are triggered in three ways. Psychogenic erections, which are more common in early sexual years, are elicited by central or peripheral psychogenic stimuli. The central input is relayed by neurons in T11 to L2 of the spinal cord. The impulses then flow to the pelvic vascular bed and redirect blood into the corpora cavenosa. Reflex erections dominate in later life and are a result of physical stimulation of the penis or genital area. This results in an activation of a reflex arc originating at S2 to S4. Nonsexual nocturnal erections begin in early adolescence, may occur up to four times a night occurring with REM sleep, and are often not perceived. Increased blood flow in the corpora cavernosa and reduced venous return allow a man to acquire and maintain an erection. High levels of nitric oxide produced by the endothelium and nerve terminals is the primary neurotransmitter of penile erection. It maximizes blood flow and penile engorgement (Krane et al., 1989).

Sexual health is an integral part of overall health. Sexual dysfunction may have a major impact on quality of life, as well as psychological and emotional wellbeing. Sexual dysfunction is common in men and management takes a multidisciplinary approach (Montorsi et al., 2010). Four categories of sexual dysfunction include disorders of arousal, sexual desire/interest, orgasm, and sexual pain (Hatzimouratidis & Hatzichristou, 2007).

Erectile dysfunction is a disorder of sexual arousal. It may be neurogenic as a result of neurological disorders including multiple sclerosis, temporal lobe epilepsy, Parkinson’s disease, stroke, Alzheimer’s disease, and in patients with spinal cord injuries. Endocrinological erectile dysfunction occurs with testosterone deficiency in hypogonadotropic hypogonadism and hypergonadotropic hypogonadism with associated cardiovascular morbidity and mortality. Hyperprolactinemia and thyroid disorders also lead to sexual dysfunction. Psychogenic erectile dysfunction occurs when the brain inhibits an erection. This is usually as a result of performance anxiety, relationship conflict, sexual inhibition, conflict over sexual preference and gender, traumatic past experiences, major life events, or fear of pregnancy or sexually transmitted illnesses. Vasculogenic erectile dysfunction is seen with alterations in blood flow to and from the penis, most commonly as a result of arterial insufficiency. Etiologies include atherosclerosis, hypertension, hyperlipidemia, cigarette smoking, diabetes mellitus, perineal or pelvic trauma, and pelvic irradiation. Many medications have been implicated in drug-induced erectile dysfunction including antihypertensives, antidepressants, and antiandrogens as well as alcoholism and recreational drug use (e.g., marijuana and heroin use). Systemic illness including liver, renal, respiratory, and cardiovascular disease also result in erectile dysfunction. Reduced libido is estimated to occur in about 5–15% of men and increases with age, often associated with other sexual disorders. It may occur secondary to the disorders of erectile dysfunction discussed in this section, particularly psychogenic erectile dysfunction. Most of these conditions are treatable and it is essential to explore the etiology (Krane et al., 1989; Shamloul & Ghanem, 2013). However, further research is required to unravel the most effective treatment modalities for the various forms of male sexual dysfunction, and further defining the etiological factors.

Premature ejaculation is a rapid or early ejaculation that occurs always or nearly always prior to or within about one minute of penetration from the sexual experience or a clinically significant reduction in ejaculatory latency time. It is an inability to delay ejaculation on all or nearly all penetrations, with negative personal consequences including distress, bother, frustration, and/or avoidance of sexual intimacy. Premature ejaculation and erectile dysfunction may be comorbid conditions often mislabeled (Althof et al., 2014). Premature ejaculation may occur as a result of negative conditioning, penile hypersensitivity, or psychological and relationship issues. Management is dependent on the etiology and may include pharmacotherapy in men also suffering from erectile dysfunction. Behavioral therapy is effective for psychogenic and relationship issues (Montorsi et al., 2010; Rowland et al., 2010).

Ejaculatory dysfunction describes a spectrum of disorders in men, encompassing delayed ejaculation to inability to ejaculate or anejaculation, as well as retrograde ejaculation (Hatzimouratidis & Hatzichristou, 2007). Ejaculatory dysfunction may be associated with a decreased amount of seminal fluid and anejaculation. Its prevalence increases with increasing age, affecting 3% of men aged 50–54 years, and 35% of men aged 70–78 years. Anorgasmia, an inability to achieve orgasm, also increases steadily with age. Perceived ejaculation volume and force of ejaculation are reduced, and this also increases with age, being three times more common in men aged 60–70 years than in men under 40 years old (Avellino et al., 2017). The etiologies vary, including medical disorders, medications, or low testosterone levels. Retrograde ejaculation, which often occurs following surgery for benign prostatic hyperplasia, is managed with education, patient reassurance, pharmacotherapy, or bladder neck reconstruction. Delayed ejaculation and/or anorgasmia may have a variable etiology. Age-related penile hypoesthesia is managed with education, reassurance, and revised sexual techniques to maximize arousal (Rowland et al., 2010).

Paternal age at the time of conception is steadily increasing, with 25% of men fathering children over the age of 35 years old. This may be due to socioeconomic and cultural factors. Natural fertility depends on multiple interrelated physiological and psychological factors that include libido, erection, orgasm, ejaculation, and spermatogenesis. Alterations in these factors reduce fecundity when the goal of the sexual act is pregnancy (Avellino et al., 2017).

Medical comorbidities and an overall decline in physical health as age increases result in decrease in total sexual performance. Erectile dysfunction may occur at any age, however there is a high correlation with increasing age and coexisting cardiovascular disease. Without adequate vaginal penetration, the ejaculate may not be delivered appropriately during intercourse, decreasing the chance of spontaneous conception. Pregnancy may be achieved by correction of erectile dysfunction with oral phosphodiesterase type 5 (PDE5) inhibitor. Alternatively, the use of masturbated ejaculate for intrauterine insemination or in vitro fertilization may be employed (Avellino et al., 2017). As androgens also play a central role in spermatogenesis and infertility, their investigation may bring an abnormality to light. An infertility evaluation may be the only contact some men will have with medical professionals at a young age. This is an opportunity to assess for other comorbidities that may or may not be contributing to infertility or sexual dysfunction. Maintaining an overall healthy lifestyle is vital in optimizing and maintaining male sexual health.

Contraception in Men

Compared with female contraceptive options, male alternatives are relatively few and underused. Currently the only readily available methods of male contraception apart from abstinence and the withdrawal method (unintended pregnancy rate of 25–30% per year) include the male condom and bilateral surgical interruption of the vas deferens (vasectomy), accounting for over 10–14% of global contraceptive use (Amory, 2016; Kanakis & Goulis, 2015; Kogan & Wald, 2014; Roth, Page, & Bremner, 2016). Physical barriers, which prevent transport of sperm to the egg in the female reproductive tract, include the male condom, vasectomy, and experimental vas occlusion methods (Amory, 2016; Kanakis & Goulis, 2015).

The condom is the oldest form of contraception, with the advantages of being free of side effects and providing protection against sexually transmitted infections. However, its main disadvantage is high failure rates, mostly from improper or inconsistent use or breakage. Pregnancy rates in couples using only condoms for contraception are 15–20% per year. Some men report difficulty using condoms and diminished sexual pleasure. Allergic reactions to latex in either partner may occur. Polyurethane condoms are available if one of the partners has a latex allergy. However, they are slightly less effective than latex condoms with slippage due to their looser fit (Amory, 2016; Kanakis & Goulis, 2015). Vasectomy, one of the most effective male contraceptive methods, became popular in the 1960s and by the early 21st century was used by 2.7% of couples (10% in the United States), totaling over 40 million men worldwide (Kanakis & Goulis, 2015). However, vasectomy is not widely used globally, due to a general lack of knowledge and misconceptions (Shattuck, Perry, Packer, & Chin Quee, 2016). The advantages of vasectomy include the refinement of the procedure which has made it minimally invasive and highly effective, with failure rates less than 1% and low complication rates. The main disadvantage is 3–5% of men request reversal and some urologists recommend semen cryopreservation prior to the procedure. Vasectomy reversal (vasovasostomy) may restore fertility with pregnancy rates of 50–75% depending on various factors including length of time between procedures, granuloma formation, and age of the female partner (Amory, 2016; Kanakis & Goulis, 2015).

Other forms of contraception include methods that suppress spermatogenesis and methods that disrupt the maturation, function of sperm, or ability to bind and fertilize the egg after ejaculation (Amory, 2016; Kanakis & Goulis, 2015). The former includes hormonal contraception, with male and female options having a similar mechanism of action. Hypothalamic–pituitary–gonadal negative feedback suppresses spermatogenesis without resulting in hypogonadism (Roth et al., 2016). The latter method includes spermicides usually intended for intravaginal use by the female partner (Amory, 2016).

Male contraceptive methods that have been tested or are under investigation include hormonal contraception with androgen (testosterone) monotherapy and a combination of androgens with either GnRH analogues or progestins to further suppress FSH and LH from the pituitary, which may exert direct antisperm production in the testes (Amory, 2016; Gu et al., 2009; Liu, Swerdloff, Christenson, Handelsman, & Wang, 2006; WHO, 1996). The combination of an androgen with a progestin is analogous to the estrogen–progestin contraceptive approach in the female, and offers more complete sperm suppression than testosterone alone. Non-hormonal methods include pharmaceutical and mechanical methods of inhibition of spermatogenesis and methods disrupting sperm transport. Despite the social need and willingness of men to participate in family planning, there are no currently available male pharmaceutical contraceptive options for clinical use at this time (Amory, 2016; Kanakis & Goulis, 2015).

Male Fecundity

Male fecundity denotes the biological capacity of men to reproduce, although it is not measured directly in men. Clinically, fecundity is defined as the capacity to have a live birth (Zegers-Hochschild et al., 2017). For men, this requires appropriately timed deposition of an adequate number of morphologically normal motile sperm into the female reproductive tract. Formation of a mature sperm takes approximately 72 days from differentiation to spermiogenesis. The transport of sperm through the epididymis to the ejaculatory ducts takes another 12 to 21 days. Therefore, any impairment in spermatogenesis may take up to three months to be seen in the morphology of the sperm. Detailed biological factors that underlie male reproductive function, fertility, and infertility have been described previously (Introduction and Spermatogenesis sections). The processes are underpinned by hormonal regulation and adequate spermatogenesis, which normally occurs at a lower temperature in the testis (one to two degrees lower than the abdomen), and sperm transported to effect fertilization. A number of factors, in both men and women, can affect fecundity.

Specific to the male partner, many lifestyle factors have been associated with decreased sperm quality and reduced fecundity. Table 4 shows the most studied lifestyle factors and effect on semen or fertility. Although semen quality may be impaired, the negative effect on fecundity still remains controversial among studies of many factors. Overall, optimizing general health with diet, exercise, adequate sleep, and avoidance of toxins and illicit drugs may improve fecundity (Tournaye, Krausz, & Oates, 2017b).

Table 4. Lifestyle Factors and Semen Quality*

Factor

Effect on semen quality

Tobacco use

Reduces semen quality

No significant reduction in fertility in couples with a smoking male partner

Marijuana use

Reduces semen quality

Infrequent cocaine use

No significant effect

Coffee consumption

No significant effect with moderate daily consumption (<450mg/day)

Increases sperm aneuploidy

Alcohol

Low to moderate intake (<8 units/week) does not reduce semen quality

High intake (>20 units/week) adversely affects semen quality

Cola consumption

3 or more 550 ml bottles/week decreases semen volume

Obesity

Reduces semen quality

Reduces male fertility

Increases sperm aneuploidy

High-energy diets

Reduces semen quality

Fried food consumption

Reduced semen quality

Genital heat stress (e.g., tight-fitting underwear, sauna use)

Adverse effects on semen quality conflicting

Self-reported stress

Reduced semen quality

Mobile phone use

Adverse effects on semen quality conflicting

* Adapted from Panel 2 (Tournaye et al., 2017a)

Clinical factors that affect male fecundity include cancer treatment. Patients are surviving and living longer after cancer diagnoses because of advances in early detection and treatment. (Polland & Berookhim, 2016) With increasing survival, the treatment of cancer may affect fecundity temporarily or permanently. A multidisciplinary approach to cancer management will ensure men undergoing cancer treatment are counseled and offered options for fertility preservation.

Epidemiological methods and population-based studies have also been used to investigate male fecundity (Bonde et al., 1998; Olsen & Ramlau-Hansen, 2014). Studies have used time to pregnancy (TTP) to identify couple sub-fecundity, with TTP data correlated with sperm quality and quantity, to isolate the male component of fertility. Fertility markers in men, such as semen quality and hormonal or other andrological profiles, often reflect their biological capacity for reproduction or fecundity, irrespective of pregnancy intention. Suffice to say, in a significant proportion of men with semen anomalies, the etiology remains unclear, while the potential of contributory genetic, chemical, and environmental factors arising from modern lifestyle agents have been implicated (Oliva, Spira, & Multigner, 2001; Skakkebaek et al., 2016), with the latter, rather than genetic, being most important (Skakkebaek et al., 2016).

Conclusion

From the pulsatile GnRH secretion of the hypothalamus to the final stages of spermatozoa maturation in the Sertoli cells, the process of human male reproductive physiology is complex and still being unraveled. Further barriers to male reproductive function and fecundity lie with various etiologies of infertility, comorbidities, and lifestyle factors. The increasing recognition of sexual and reproductive health as entailing joint responsibility for both the female and male partner, including for contraceptive adoption and infertility investigation, requires a better understanding of male reproductive physiology and function at all levels, and concerted research on factors that enhance outcomes in both partners. Initial studies by the World Health Organization, and subsequently by industry, spurred multicenter research studies on reversible contraceptive methods that could be initiated by the male partner. This dual approach allows for shared responsibility for contraceptive use within the reproductive lifecycle of a fecund couple, while deriving additional data on sperm quality assessment that also applies in assisted reproductive technology. While demographic and health survey data includes rates of unmet need for family planning among women of reproductive age, future surveys may be able to provide insights on unmet need for family planning among men, as well as reproductive needs and choices that are met for both men and women. Factors that determine variable time to pregnancy and are associated with or affect male fecundity in multiple settings, also need to be further unraveled. While such data complements developments being made in the reproductive health of women, dual responsibility also subsumes the need for men to relate to and identify with the disproportionately high reproductive morbidity and mortality experienced in the female partner population, especially among low and middle income countries.

References