Function of seminal vesicles and their role on male fertility

Gustavo F. Gonzales

Department of Physiological Sciences, Faculty of Sciences and Philosophy and Instituto de Investigaciones de la Altura, Universidad Peruana Cayetano Heredia,Lima, Peru

Asian J Androl  2001 Dec; 3: 251-258

Keywords:    seminal vesicles; male fertility; male infertility; true corrected fructose

Abstract

The present review has been designed to update the recent developments on the function of seminal vesicles and their role on male fertility. It is indicated that the true corrected fructose level is a simple method for the assessment of the seminal vesicular function. Measurement of seminal fructose used universally as a marker of the seminal vesicle function is not an appropriate approach due to its inverse relationship with the sperm count. The true corrected fructose defined as log. motile sperm concentration multiplied by seminal fructose concentration has been shown to be a better marker of the seminal vesicle function.

Seminal vesicular secretion is important for semen coagulation, sperm motility, and stability of sperm chromatin and suppression of the immune activity in the female reproductive tract.

In conclusion, the function of seminal vesicle is important for fertility. Parameters as sperm motility, sperm chromatin stability, and immuno-protection may be changed in case of its hypofunction.

1 Introduction

The seminal vesicles are composed of tubular alveoli and the mucosa is thrown into an intricate system of folds with the epithelium overlaying the lamina propria^[1] . The seminal vesicles join the ampulla of the deferens to form the beginning of ejaculatory ducts. Secretion of the seminal vesicles constitutes the main (50%) and the last fraction of the ejaculates.

The sex differentiation and the growth of seminal vesicles are highly dependent on androgen^[2,3]. Endogenous increase of serum testosterone increased the secretory activity of the seminal vesicles in men^[4]. In rats, any increase in serum testosterone or treatment with androgens were associated with increased secretory activity of the seminal vesicles^[2,5,6] and increased seminal vesicle weight^[7]. The seminal vesicles possess 5 alpha-reductase activity, which converts testosterone to dihydrotestosterone, the active hormone. More recently, it has been demonstrated that seminal vesicles contain LH/hCG receptors, thus making this accessory reproductive organ a potential target of direct regulation by LH^[8].

The secretory activity of the seminal vesicle is also regulated by the nervous system and both the cholinergic and adrenergic neurons affect its function^[9]. Muscarinic stimulus (cholinergic) increases nitric oxide production. Seminal vesicle is a source of nitric oxide synthase in men^[10]. An increase in nitric oxide may improve the secretion of fructose by the gland^[11] .

The seminal vesicles and prostate share the same blood supply with a comparable chance of exposure to carcinogens. Despite these similarities, fewer than 60 adenocarcinomas of the seminal vesicles have been described so far, whereas prostate cancer is the most common cancer in men^[12]. The reason underlying this difference in cancer incidence is not clear.

Seminal vesicles secrete a great variety of products^[1] . The importance of these secretions in male fertility needs to be elucidated. This review attempts to demonstrate the role of seminal vesicles on male fertility.

2 Assessment of the seminal vesicle function

Measurement of seminal fructose has been used in almost all laboratories of the world as a marker of the seminal vesicular function. The WHO includes the measurement of this sugar to assess the function of these glands^[13]. Several studies have demonstrated an inverse relationship between sperm count and seminal fructose concentration. To our knowledge, sperm count should not be related to seminal vesicular function. This association seems to be associated with any event occurring after ejaculation.

After ejaculation, fructose is consumed by the spermatozoa in a process named fructolysis. At higher sperm counts, the process will be stronger resulting in a low seminal fructose concentration. That is the reason that seminal fructose is higher in azoospermic and oligozoospermic than in normozoospermic or polyzoospermic men. It can thus be concluded that it is impossible to assess the function of the seminal vesicle simply from seminal fructose determination^[14-16]. In addition, there is no correlation between fructose and sperm motility^[15,16] despite that a lot of evidences suggest that seminal vesicles are important for sperm motility^[1]. Seminal fructose concentration is inversely correlated with the motile sperm concentration, suggesting that only the motile sperm consume fructose after ejaculation^[17].

This can be seen that the value of seminal fructose concentration is not appropriate as a marker of the secretory activity of the seminal vesicles, unless the influence of sperm count on the fructose concentration can be excluded. This is done by multiplying the seminal fructose by the logarithm of the sperm concentration (corrected fructose) or the motile sperm count (true corrected fructose)^[16,18,19]. Lower levels of corrected seminal fructose were observed in men with either low serum testosterone levels^[1,16] or with an obstructive process at the seminal vesicles^[19].

Seminal levels of the specific protein of the seminal vesicles (MHS-5)^[20] and the protein C inhibitor (PCI), a plasma serine protease inhibitor of activated protein C^[21], have also been used to assess the seminal vesicle function. Other methods to assess seminal vesicles function include transrectal ultrasonography (TRUS)^[22,23] and magnetic resonance imaging^[24].

3 True corrected seminal fructose

The corrected seminal fructose calculated as log. sperm concentration multiplied by seminal fructose concentration has been shown to be a better marker of seminal vesicle function than simple measurement of the seminal fructose concentration^{[1,16,19,25-28]}. Low levels of corrected seminal fructose have been observed in men with hypofunction of the seminal vesicles^[26,28] and this has been related to male infertility. Subjects with hypofunction of the seminal vesicles have low sperm motility, which itself may cause infertility^[16,19].

Corrected fructose is correlated with the sperm motility in men with normal sperm motility whereas seminal fructose is not^[16]. However, in asthenozoospermic samples, we were unable to observe a relationship between the sperm motility and the corrected fructose value^[28]. Thus the corrected fructose value is not a good  marker of the seminal vesicle function in infertile men.

We have described a new approach to assess the seminal vesicle function based on fructose measurement and motile sperm concentration. The value obtained has been named true corrected fructose^[18]. With this correction, we have shown a prevalence of 47.6% with hypofunction of the seminal vesicle in men attending our infertility service. Moreover, from 18 cases of asthenozoospermia, 12 was associated with seminal vesicle dysfunction. The finding is important from the point of view of the diagnosis and treatment of male infertility. The demonstration that several cases of asthenozoospermia were due to a low seminal vesicle function will direct to appropriate treatment aiming at the improvement of the function of these glands.

4 Test for androgen activity

Seminal vesicles are androgen-dependent and this property may be used as biological marker of androgenic activity. Gonzales^[4] has developed a method to assess the androgen activity at the reproductive tract level based on both the serum testosterone level and the corrected seminal fructose level under the basal and the post-clomiphene stimulation. Men received 100 mg clomiphene citrate daily for 5 days. The second blood and semen samples were obtained one day after the last administration of clomiphene. Levels of serum testosterone were more related to the  corrected seminal fructose than to seminal fructose concentration^[4]. Seventy-one percent of subjects with low serum testosterone levels had low levels of corrected seminal fructose, whereas only 28% of the same subjects had low levels of seminal fructose (uncorrected fructose). The results suggest that corrected seminal fructose may be used as a biological marker of androgen activity in the reproductive tract^[4].

More recent study has demonstrated that the true corrected seminal fructose was a better marker of seminal vesicle function^[18]. The combined measurement of the serum testosterone level and the level of corrected seminal fructose allows the diagnosis of hypoandrogenism and/or obstructive process at the reproductive tract^[25]. An increase in the serum testosterone after clomiphene stimulation without increase in the corrected or true corrected seminal fructose suggests an obstructive process at the reproductive tract level, whereas absence of increase in serum testosterone and corrected/true corrected seminal fructose levels may indicate hypogonadism^[18].

Normal levels of serum testosterone and low values of seminal fructose have been found in men with azoospermia due to obstruction of the ejaculatory ducts^[4,25,29]. One third of azoospermia and severe oligozoospermia have an obstruction of the ejaculatory duct^[30].

About 10% of azoospermic patients have congenital absence of the seminal vesicles and vas deferens. Low seminal volume (<0.5 mL), low pH and low concentration of seminal fructose with normal serum FSH levels are diagnostic criteria for this condition^[31]. Diagnosis is also possible through measuring the seminal level of the specific protein of the seminal vesicle (MHS-5). This protein is absent in agenesis of the seminal vesicle^[20]. PCI is present at high concentrations in the seminal plasma of normal subjects and is decreased in some infertile patients[21]. PCI was significantly lower in the seminal plasma of patients with seminal vesicle and/or vasal agenesis. This is another useful marker for agenesis of seminal vesicles and/or the vas deferens^[21].

5 Physiology and physiopathology of human seminal vesicles

The seminal vesicle secretion appears in the later fractions of ejaculation. Coagulation occurs immediately after ejaculation. This step is important to allow all spermatozoa to be in contact with the ingredients in the semen. Thus, seminal vesicle secretion may promote sperm motility, increase stability of sperm chromatin, and suppress the immune activity in the female reproductive tract to avoid rejection of spermatozoa and embryo (in case of fertilization) that have antigens foreign to women.

5.1 Coagulation

At ejaculation, semen is a liquid and after contacting with the seminal vesicular secretion, it coagulates^[33]. The major component of this coagulum is semenogelin I, a 52-kDa protein expressed exclusively in the seminal vesicles^[34,35]. The protein is rapidly cleaved after ejaculation by the chymotrypsin-like prostatic protease, prostate-specific antigen (PSA) to generate peptides of various biological activities that were found on and inside spermatozoa. Coagulation fails to occur in ejaculates with decreased seminal vesicle activity^[36]. Poor coagulation was also related to poor sperm motility^[37]. 

5.2 Semen consistency

The consistency of semen seems to be also related to seminal vesicle function^[27]. The normal semen consistency is viscous. If the viscosity is abnormally increased, it may be associated with infertility. High seminal viscosity has been associated with hypofunction of the seminal vesicles^[27,38]. Semen with high viscosity has low sperm motility. Male pseudo-hermaphrodites with 5 alpha-reductase-2 deficiency have diminished values of dihydrotestosterone. In these cases, low semen volume and high seminal viscosity were also observed^[39].

5.3 Sperm motility enhancers

Several products of the seminal vesicles are stimulators of sperm motility. These are potassium^[40], bicarbonate^[41,42], magnesium^[43], 19-OH-prostaglandin^[44], and prolactin^[45,46]. Bicarbonate stimulates sperm motility through an action on the adenylate cyclase system by increasing the production of cAMP^[41,42]. Human semen contains large amounts of prostaglandins produced mainly in the seminal vesicles^[47]. Vasectomy does not affect semen prostaglandin concentration^[48]. Sperm motility seems to be related to PGE, PGF, 19-OH-PGE and 19-OH-PGF^[49,50]. Prolactin is found in seminal plasma of fertile and infertile men^[46]. Prolactin in semen is secreted preferentially by the seminal vesicles^[47,51] and is related to sperm motility^[45,46].

5.4 Sperm motility inhibitor

Human seminal plasma contains a sperm motility inhibitor (SPMI) that originates from the seminal vesicle in a precursor form. This precursor is degraded into smaller peptides by prostatic proteases shortly after ejaculation. The SPMI precursor was found to be almost identical to semenogelin^[52]. The SPMI precursor was found to inhibit sperm motility in a concentration-dependent manner. The motility of SPMI-immobilized spermatozoa was partially recovered after washing off^[52].

5.5 Antioxidant function of the seminal vesicles

As many as 25% of semen samples from infertile men produce high levels of reactive oxygen species (ROS)^[53]. The higher levels of ROS produced by damaged spermatozoa have been believed to be associated with loss of motility and decreased sperm-oocyte fusion capacity^[54]. Leucocytes produce more ROS than spermatozoa^[55]. Although ROS has been known to be an essential prerequisite for the normal functioning of many cells, excessive exposure may be harmful to spermatozoa^[56]. In addition, oxidative stress occurs even in patients with very low leucocyte counts and may therefore impair fertility^[57].

Normally, the antioxidant-rich seminal plasma protects sperm from ROS. Seminal pxdlasma has ROS scavengers, such as superoxide dismutase, catalase^[58], glutathione peroxidase/reductase pair^[59], ascorbic acid, uric acid, and thiols^[60].

Ascorbic acid is secreted by the seminal vesicles^[60,61] and plays a significant role, in association with antioxidant defenses that preserve the functional competence of spermatozoa exposed to an oxidative attack^[56]. Ascorbic acid may be oxidized by cooper, thus diminishing the protective activity. This is important, since there are situations where cooper is increased as in some pathological situations or in smokers.

Another product of the seminal vesicle, semenogelin and its degradation products, may be natural regulators of sperm capacitation. They prevent capacitation process from occurring prematurely. The action may involve an interference with the superoxide anion generation^[62].

5.6 Immunology

Seminal vesicles secrete antigens that seem to prevent female immune response against spermatozoa^[63] and embryo^[64]. The seminal vesicles secrete antigens of IgG-Fc receptor III that could protect spermatozoa from IgG-mediated destruction and from antibody-mediated cellular cytotoxicity^[63]. The seminal vesicles are also the source of seminal plasma trophoblast lymphocyte cross-reactive (TLX) antigen^[64]. TLX antigen is absent from seminal plasma in congenital agenesis of seminal vesicles^[65].  This is supportive for the origin of the seminal plasma TLX antigens from the seminal vesicles.

The maternal recognition of allotypic TLX antigens is proposed to be involved in the immunologic acceptance of the allogenic fetus. The presence of TLX antigens in seminal plasma suggests that sensitization can occur before fertilization and implantation^[64]. The release of TLX antigens by seminal vesicles could represent a mechanism of priming mother's immune function for normal implantation and pregnancy^[65,66]. Maternal Fc-gamma receptor blocking antibodies have been linked to pregnancy success. Idiotype-antiidiotype regulated maternal responses to TLX are proposed to be necessary for successful pregnancy. Conformational site induced by C3b (iC3) binding to MCP (membrane cofactor protein) may be responsible for TLX allotypy^[67].

Three sperm-coat antigens have also been identified to be originated from the human seminal vesicles: MHS-5 antigen^[68], lactoferrin (80 KDa)^[69], and ferriplan (15 KDa)^[70,71]. Although the iron-chelating protein lactoferrin is secreted by the seminal vesicles, the precise role of lactoferrin in semen is unclear. Lactoferrin was increased in oligozoospermia^[72].

5.7 Sperm chromatin stability

DNA packing during the transformation of round spermatids into spermatozoa involves the replacement of somatic-type histones with basic proteins, which are rich in arginin and cystein, and are termed protamines. During epididymal transit the formation of S-S cross bridges between the protamin-cystein residue occurs, assuring a stable condensation of the nucleoprotein complex. Nuclear condensation of sperm is stabilized further by zinc, which interchelates between the free amino groups of arginin and the free thiol groups of cystein^[74]. This further stabilization occurs after ejaculation.

Zinc bound to metallothionein, which is secreted mainly from the prostate gland, is one factor that contributes to the chromatin stabilizing effect of human prostatic fluid^[75]. This effect occurs after ejaculation. The amount of zinc present in the prostatic fluid that is taken by spermatozoa needs to be regulated. Regulation occurs through the seminal vesicle secretion. In fact, the stability of sperm chromatin was decreased in seminal plasma dominated by vesicular fluid^[76]. In addition, chromatin zinc was related inversely to markers of seminal vesicular secretion^[77]. In conclusion, prostatic fluid ensures appropriate zinc and stability of sperm chromatin, whereas vesicular fluid regulates chromatin stability by reducing chromatin zinc content. Content of zinc in sperm chromatin is regulated by the action of zinc ligands of seminal vesicular origin^[77].

Spermatozoa assessed 1 min after ejaculation underwent decondensation of DNA with sodium dodecyl sulphate treatment (SDS). Spermatozoa assessed 45 min after ejaculation did not undergo decondensation with SDS treatment^[78]. This suggests products in semen during process of coagulationliquefaction act on spermatozoa to allow nuclear stability of human spermatozoa. 

5.8 Other substances secreted by the seminal vesicles

Insulin or an insulin-like peptide found in human seminal plasma was secreted mainly by the seminal vesicles^[80,81]. The insulin levels were higher in the seminal plasma than in the serum^[82]. The functional significance of insulin in the seminal plasma is unknown.

6 Treatment of hypofunction of the seminal vesicles

Hypofunction of the seminal vesicles may be medically^[85] or surgically^[30] treated. Medical treatment may be effective in cases of partial obstruction and/or mild hypoandrogenism^[85]. Medical treatment includes human chorionic gonadotropin (hCG), low dose of testosterone, or clomiphene citrate^[85]. Antibiotic treatment in prostato-vesiculitis led to positive effects on sperm output and spontaneous pregnancy rate (40%) by removing pro-oxidant noxae (microbial and/or white blood cell-related reactive oxygen species)^[55].

Surgical treatment has been used for ejaculatory duct obstruction. Ejaculatory duct obstruction was considered in patients with low to normal ejaculate volume, azoospermia or oligospermia, decreased motility, normal serum gonadotropin and testosterone levels, absent or low fructose in the ejaculate and evidence of obstruction on transrectal ultrasonography. Transurethral resection of ejaculatory ducts resulted in improvement of ejaculate volume, sperm count and sperm motility as early as 3 months after treatment. The pregnancy rate is still low, which could be related to the hazardous effects of urinary reflux into the ejaculatory ducts or functional abnormalities of the seminal vesicle^[86].

Depending on the localization of the obstruction site, either a microsurgical reconstruction (tubulovasostomy, vasovasostomy) or a transurethral resection of the ejaculatory ducts can be done^[87].  Ejaculatory duct obstruction due to cysts appears to respond best to surgical treatment. Such treatment may also decrease the need for IVF/ICSI in many cases and allow IVF/ICSI to be performed with ejaculated rather than surgically retrieved sperm^[24].

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Correspondence to: Prof. Dr. G.F. Gonzales, Instituto de Investigaciones de la Altura, Universidad Peruana Cayetano Heredia, Postal Office 1843, Lima, Peru.
E-mail: iiad@upch.edu.pe
Received 2001-10-06    Accepted 2001-11-21