Periodontology 2000, Vol.

61, 2013, 232–251  2013 John Wiley & Sons A/S

Printed in Singapore. All rights reserved PERIODONTOLOGY 2000

Physiology, pathology and

pharmacology of the male
reproductive system
MICHAEL MAWHINNEY & ANGELO MARIOTTI

The function of the male reproductive system, com- roid and the hypothalamic–pituitary complex. In
prising the testicles, penis and accessory sex organs, men of >50 years of age, the free ⁄ nonprotein-
is to deposit viable semen in the female reproductive bound or biologically active fraction of the plasma
tract. Within the testes, seminiferous tubules produce hormone shows a decline of approximately 50%,
sperm, which subsequently mature in the epididy- owing, in part, to reduced Leydig cell sensitivity to
mus to develop both motility and the capability to interstitial cell-stimulating hormone and to the
fertilize the ovum. Upon ejaculation, sperm are pro- accrual of adipose tissue, which aromatizes testos-
pelled through the vas deferens into the urethra in terone to estradiol. In turn, estradiol increases the
conjunction with seminal fluid (plasma) from the concentration of sex hormone-binding globulin,
prostate gland and seminal vesicles, forming a sus- which has a relatively high affinity for plasma
pension of sperm (semen) for ejaculation through the androgens. Within most androgen-responsive cells,
penile urethra. Accessory sex organ secretions have plasma-derived testosterone is bio-activated by
unique components, including prostate-derived the enzyme 5a-reductase to dihydrotestosterone,
prostate-specific antigen and zinc. Prostate-specific which exhibits a preferential affinity for the intracel-
antigen has evolved to be a useful marker for the lular androgen receptor. Binding to the androgen
diagnosis and therapeutic monitoring of prostate receptor represents a requisite step in dihydrotes-
cancer. A deficiency of zinc in prostate fluid may be a tosterone-induced gene expression in androgen
key etiological factor predisposing some men to target tissues.
bacterial prostatitis. Genetic mutations leading to defective in utero
The reproductive system is regulated by both the dihydrotestosterone formation by the embryo selec-
endocrine system and the nervous system. Plasma tively prevent masculization of the urogenital sinus
testosterone, synthesized and secreted by the testic- and other common anlage. Termed testicular femi-
ular interstitial cells of Leydig, is the primary andro- nization II, such individuals are born with a blind
genic hormone responsible for the induction and vaginal pouch rather than a prostate gland, impaired
maintenance of all aspects of the male phenotype. phallic differentiation and undecended testes. Com-
Synthesis of testosterone by Leydig cells is stimulated ponents of the embryonic male reproductive system
by interstitial cell-stimulating hormone, a Ôgonado- that are not dependent on dihydrotestosterone for-
tropinÕ, which is secreted from the anterior pituitary mation, such as the Wolffian duct-derived epididy-
under the trophic influence of hypothalamic gona- mus, vas deferens and seminal vesicles, differentiate
dotropin-releasing hormone. The dramatic rise in normally in testicular feminization II. However,
testosterone at puberty occurs as a result of the dis- in utero mutation of the androgen receptor gene in
inhibition of gonadotrophin-releasing hormone by XY males results in complete feminization of all
higher centers in the central nervous system. Plasma androgen-dependent target tissues (testicular femi-
testosterone is maintained within a relatively narrow nization I). Phenotypically, such XY individuals ap-
concentration range owing to the presence of a pear as normal women, but lack a uterus and both
negative-feedback loop between the circulating ste- pubic and axial hair.

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 Factors affecting function of the male reproductive system

Endocrine therapy has been applied to both pros- Therapy of erectile dysfunction with drugs such as
tate cancer and benign prostatic hypertrophy. Exo- sildenafil is based on the enhanced vasodilator effect
genous administration of sex steroids, including of nitric oxide that is normally released from efferent
androgens, estrogens or progestins, reversibly intrapenile parasympathetic neurons in response to
suppresses gonadotrophin-releasing hormone and sensory sexual stimulation. Sildenafil enhances nitric
interstitial cell-stimulating hormone secretion, oxide-induced signal transduction by retarding the
resulting in the inhibition of testicular steroidogene- rate of intracellular cyclic guanosine monophosphate
sis. Therapy with estrogens provided symptomatic catabolism, which ultimately enhances vascular
benefit from disseminated prostate cancer by lower- smooth muscle relaxation and penile erection.
ing the plasma testosterone concentration and
eliminating the undesirable stimulatory effect on
androgen-sensitive tumor cells. More recently, syn- Androgens and the accessory sex
thetic gonadotrophin-releasing hormone Ôsuper- organs
agonistsÕ have been employed for the same purpose
(i.e. to lower interstitial cell-stimulating hormone and Male sexual differentiation
eliminate the stimulus for testosterone synthesis).
Overview
For relief of benign prostatic hypertrophy symptoms,
pharmacological therapy has included the use of 5a- The sexually undifferentiated embryo has the po-
reductase inhibitors in an attempt to reduce the mass tential to develop either a normal male or female
of androgen-sensitive tissue compressing the male reproductive system, regardless of genetic sex. Testes
urethra. or ovaries develop from the genital ridge. Both
Abuse of certain drugs has adverse effects on the Wolffian ducts and Müllerian ducts are present,
male reproductive system. Reversible testicular atro- which give rise to portions of the male and female
phy, secondary to inhibition of gonadotropins, is a reproductive tracts, respectively. The epididymus, vas
predictable effect in healthy young adults who abuse deferens and seminal vesicle differentiate from the
exogenous anabolic ⁄ androgenic steroids in an at- Wolffian duct, while the Müllerian duct forms the
tempt to increase muscle mass and physical perfor- oviduct, uterus and upper portion of the vagina.
mance. Narcotic use inhibits the release of gonado- Common anlage, such as the urogenital sinus, genital
trophin-releasing hormone, thereby lowering plasma tubercle and genital folds, form either the prostate
testosterone. Chronic ethanol abuse lowers plasma gland or vagina and the external genitalia of the male
testosterone as a result of gonadotropin inhibition, or the female embryo.
but intratesticular ethanol metabolites may also Embryonic differentiation of the male reproductive
cause irreversible testicular atrophy. Although several tract proceeds in a definitive temporal and regulated
studies in experimental animals concluded that cascade, beginning with the establishment of genetic
chronic cannabis (marihuana) administration re- sex at conception. Antecedent to Y chromosome-
duced plasma testosterone, the majority of findings dependent gonadal differentiation, testicular hor-
in humans and monkeys revealed no significant ef- mones induce male differentiation of both the
fects on the hypothalamic–pituitary–Leydig cell axis. Wolffian ducts and common anlage and affect
Cannabis can impair spermatogenesis, but the po- regression of the Müllerian ducts, culminating in the
tential impact on human male fertility has not been formation of the normal male reproductive tract. A
established. specific abnormality at any point in this hierarchy
Sympathetic adrenergic, and possibly cholinergic, ensures a disorder of all dependent components of
innervation of smooth muscle controls contractile this differentiation cascade.
processes in the smooth muscle of the vas deferens Embryogenesis of the normal XY male initially in-
and accessory sex organs, leading to the propulsion volves differentiation of the testicle from the genital
of sperm and to the extrusion of preformed seminal ridge with formation of the Sertoli cells, which are
plasma, respectively. Sympathetic cholinergic inner- encapsulated in the seminiferous tubules. Although
vation of the acinar epithelium of the accessory sex the primordial germ cells, precursors of the sperma-
organs regulates both the rates of formation and the togonia, migrate into the genital ridge from the yolk
extracellular secretion of seminal plasma. In addition, sac endoderm early in gonadal differentiation,
parasympathetic neurotransmission, particularly that primordial germ cells are not necessary for normal
mediated by nitric oxide, dilates the smooth muscle testicular differentiation. Sertoli cells secrete anti-
vasculature that results in penile erection. Müllerian hormone, which regresses the Müllerian

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ducts. Subsequent Leydig cell differentiation in the hormone by the Sertoli cells and those responsible
testis results in testosterone secretion, which stimu- for the synthesis of testosterone by the Leydig cells
lates differentiation of the Wollfian ducts and the (24, 84). Abnormalities in gonadal differentiation
male phenotype in the common anlage. Testosterone have been thoroughly characterized and the etiolo-
is the active intracellular hormone in the Wolffian gies have been increasingly linked to specific genetic
ducts, whereas dihydrotestosterone formation from mutations (88). Without exception, abnormalities in
testosterone within the common anlage induces gonadal differentiation have not been definitively
male-type morphogenesis. Both anti-Müllerian hor- linked to hormonal influences. However, the Free-
mone and androgens regulate morphogenesis via the martin (from the old English meaning Ôsterile beefÕ)
stroma or mesenchyme of the embryonic structure. was described by Lillie in 1917 as the female her-
Abnormalities in the sexual genotype perturb maphrodite (ovotestis) calf born twin to a male. The
gonadal differentiation and all subsequent steps Freemartin is actually a chimera, representing two
in hormone-dependent differentiation. A specific distinct genetic lineages in a given individual – not an
mutation in the androgen receptor results in testic- abnormal genotype within a cell. The Freemartin
ular feminization I, which is a female phenotype in develops from the admixture of the fetal circulations,
XY males. A deficiency in 5a-reductase, the enzyme exposing the female fetus to male hormones or cells.
responsible for dihydrotestosterone formation, re- Anti-Müllerian hormone produced by the embryonic
sults in testicular feminization II, which presents as testis at the time of ovarian differentiation causes sex
an ambiguous male ⁄ female phenotype in the exter- reversal in cultured XX gonads (85) and sex reversal in
nal genitalia and prostate gland in XY males. Failure transgenic female embryos overexpressing anti-
to express anti-Müllerian hormone leads to the per- Müllerian hormone (80).
sistent Müllerian duct syndrome (i.e. uterine tissue in
XY males). Accessory sex organs and external genitalia

The experimental evidence for the discrete actions of

Gonad
embryonic testicular anti-Müllerian hormone and
The human embryonic gonad differentiates at 6– testosterone on the differentiation of the male
7 weeks postconception from the genital ridge. Based reproductive tract is summarized in Fig. 1. In the male
on genetic sex, either the cortex of the genital ridge embryo, anti-Müllerian hormone normally induces
differentiates into an ovary or the medulla forms a regression of the Müllerian ducts at approximately
testis. Association of the Y chromosome with testic- day 60 postconception. Human XY male embryos that
ular differentiation was established by Ford and col- fail to express or respond to anti-Müllerian hormone
leagues in 1959, and approximately 30 years later, a in a normal manner present with the persistent
discrete site on the short arm of the Y chromosome Müllerian duct syndrome (i.e. retention of uterine
was identified as the putative sex-determining region tissue) (40). Approximately 10 days following the
(73). Subsequent studies revealed that expression of a normal secretion of anti-Müllerian hormone, the on-
specific gene (Sry) at this sex-determining region of set of testicular testosterone secretion (Fig. 2)
the Y chromosome correlated with testicular differ- activates morphogenesis of the Wolffian ducts and
entiation and that insertion of Sry into fertilized stimulates differentiation of common anlage, the
mouse eggs was capable of inducing the develop- prostate gland and external genitalia (40, 41). Unilat-
ment of normal testes and male reproductive tracts in eral removal of a testis revealed that morphogenic
XX embryos (45). Sry is initially expressed in pre- effects of anti-Müllerian hormone and testosterone
Sertoli cells on days 41–44 postconception, and the on the respective Müllerian and Wolffian ducts were
earliest definitive morphological progression from an localized to the ipsilateral side (41). Additional
undifferentiated gonad is the formation of Sertoli evidence, based on a distance gradient of abnormal
cells and testicular cords, which surround the pri- differentiation from the ipsilateral testis, also sup-
mordial germ cells at postconception days 45–50. ports the hypothesis that testosterone exerts differ-
Notably, the primordial germ cells, precursors of entiating effects on the Wolffian ducts through local
spermatogonia, are not required for testicular differ- diffusion or delivery through the ducts (41). For both
entiation. Under the direction of Sry, numerous genes the androgen, testosterone, and anti-Müllerian
are expressed in association with testicular differen- hormone, the morphogenic effects, which are most
tiation, including those responsible for the synthesis evident on the epithelium, are actually mediated by
of Müllerian duct regression factor or anti-Müllerian hormone action on the respective receptors that are

234
 Factors affecting function of the male reproductive system

Fig. 1. Experimental evidence supporting the organ-specific morphogenic effects of anti-Müllerian hormone and
testosterone from the embryonic testes. The figure was drawn based on the original experimental evidence and that by
Jost and colleagues (41). MD, Mullerian Duct; WD, Wolffian Duct.

reductase activity was present before the onset of

sexual differentiation while such enzymatic activity
was absent from the undifferentiated Wolffian duct
(94, 95). Accordingly, intracellular dihydrotestoster-
one was hypothesized to mediate testosterone-
dependent differentiation of the common anlage into
the prostate gland and external genitalia, while
intracellular testosterone mediated Wolffian duct
differentiation. Validation of this theory was realized
with the discovery of a disorder of sexual differenti-
ation in which XY males exhibited partial phallic
development with hypospadias and a blind vaginal
pouch (36). These individuals have an autosomal-
recessive defect in the expression of 5a-reductase
type II, which is normally expressed in both epithe-
lium and stroma of accessory sex organs. Experi-
Fig. 2. Dynamic changes in plasma testosterone in the mental attempts to further validate this mechanism
developing male. This figure was redrawn based on the have employed 5a-reductase II knockouts as well as
graphic depiction by Griffin & Wilson (22). treatment of pregnant animals with finasteride, a
relatively specific inhibitor of the enzyme. Both ap-
expressed in the underlying mesenchyme or embry- proaches revealed that while the Wolffian duct
onic stroma (12, 80). formed normal male structures with absent or
Genetic defects in the mechanism of androgen inhibited 5a-reductase, the urogenital sinus and
action are responsible for testicular feminization other common anlage differentiated into female
types I and II. Testicular feminization I represents structures. In contrast, isozyme I of 5a-reductase in
complete androgen insensitivity caused by a muta- the epithelium appears to have no role in urogenital
tion in the androgen receptor on the X chromosome. sinus differentiation (75).
Such XY individuals with normal testes mature with
Sexual behavior
no uterus and female external genitalia. Testicular
feminization II is caused by 5a-reductase isozyme II Male sexual behavior in rats is controlled by the
deficiency. Understanding this disorder was predi- hypothalamic medial pre-optic area, and is clearly
cated on the experimental observations that in androgen dependent. Definitive experimental evi-
common anlage, such as the urogenital sinus, 5a- dence supports the summation that plasma testos-

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Mawhinney & Mariotti

terone is metabolized within the hypothalamus to free (nonprotein bound) testosterone, despite no
both dihydrotestosterone and estradiol, which act in change in total plasma testosterone. With accumu-
concert to induce normal copulatory responses (55). lation of body fat, adipose tissue-derived estrogens
In humans, complete androgen resistance (testicular increase the concentration of plasma sex hormone-
feminization I) is associated with female behavior, binding globulin, which has a preferential affinity for
while individuals with partial androgen sensitivity androgens.
and phenotypic masculinization at puberty (testicu- A small percentage of plasma testosterone is de-
lar feminization II) often assume the male gender rived from the adrenal cortex, which synthesizes
role (93). As such, Ôandrogens are important deter- androgens as requisite precursors in cortisol synthe-
minants of gender role behaviorÕ (93), but the sis. As such, testosterone is secreted in constitutive
imperfect correlation between neonatal androgeni- association with adrenocorticotropic hormone-con-
zation in intersex states and male behavior supports trolled plasma cortisol. Drugs that are either agonists
additional mechanisms (20, 93). In contrast to or antagonists for testosterone-negative feedback
rodents, estrogen may not be important in the have no potential to affect adrenocorticotropic hor-
induction of human male sexual behavior in that mone and cortisol secretion.
genetic-based estrogen resistance in otherwise
normal human men does not de-masculinize sexual Testicular androgen synthesis
behavior (93).
All requisite organelles and enzymatic components
The etiology of male homosexual behavior in XY
exist within the Leydig cell for the de novo interstitial
individuals with a normal adult male phenotype is
cell-stimulating hormone-regulated synthesis of tes-
unresolved. Within this population, subsets have
tosterone (96). Interstitial cell-stimulating hormone
been scored as Ôhigh masculinityÕ or Ôhigh femininityÕ
stimulates both hypertrophy and hyperplasia of
(68). ÔGenetic clustersÕ exist, as do unsupported links
Leydig cells and induces testosterone synthesis from
to perturbations in male behavior with birth order
cholesterol, derived from either plasma or the
(20). Ultimately, the understanding of male homo-
intracellular cholesterol-laden droplets (Fig. 3).
sexuality must incorporate mechanisms in addition
Subsequent cholesterol side-chain cleavage to
to steroid hormone induction.
pregnenolone is the rate-limiting and key interstitial
cell-stimulating hormone-sensitive step in activation
of testosterone synthesis. Interacting with its plasma
Androgen synthesis and regulation of
membrane receptor, interstitial cell-stimulating
plasma testosterone
Overview

Testosterone is the biologically significant androgen

in male plasma. Approximately 90–95% of plasma
testosterone is derived from the Leydig cells, which
are immersed within the interstitial regions between
the seminiferous tubules of the testes. Leydig cells
occupy approximately 10% of the testicular volume.
Plasma testosterone is maintained through acute
stimulation of de novo steroid synthesis by the pitu-
itary gonadotropin, interstitial cell-stimulating hor-
mone, which, in turn, is under the control of
gonadotrophin-releasing hormone from the hypo-
thalamus. Insignificant concentrations of testoster-
one are stored within the Leydig cells. Regulation of
plasma testosterone concentrations is achieved
through negative feedback at the hypothalamic–
pituitary complex. In pubertal boys, the site of feed-
Fig. 3. Selective intratesticular localization and action of
back inhibition is at the hypothalamus, while in
follicle-stimulating hormone (FSH) and interstitial cell-
adults, testosterone acts primarily at the level of the stimulating hormone (ICSH). ABP, androgen-binding
pituitary. Postmaturational aging (beyond 50 years of protein. This figure was redrawn based on the work of
age) results in a decline, of approximately 50%, in Hansson and colleagues (28).

236
 Factors affecting function of the male reproductive system

hormone activates a cascade of signal transduction

through adenylate cyclase, culminating in an in-
creased rate of testosterone secretion within 3–6 min.
Within this time frame, interstitial cell-stimulating
hormone initiates synthesis of cyclic AMP, which
induces steroidogenic acute regulatory protein. In
turn, steroidogenic acute regulatory protein facili-
tates cholesterol transport across the mitochondrial
membrane and thus avails the cholesterol substrate
to the cyclic AMP-induced side-chain cleavage en-
zyme. Once formed, testosterone probably diffuses
with its concentration gradient into the vascular
space with distribution to the general circulation.
Leydig cells are ÔclusteredÕ in association with the
interstitial vascular supply, which is consistent with Fig. 4. Negative feedback regulation of plasma testoster-
the endocrine function of these cells. one. DHT, dihydrotestosterone; E2, estradiol (E2) hor-
mone; GnRH, gonadotropin-releasing hormone; ICSH,
Hypothalamus–pituitary and negative-feedback interstitial cell-stimulating hormone. This figure was re-
regulation drawn based on the graphic depiction in Mawhinney &
Neubauer (55).
Plasma testosterone concentrations are regulated by
interactive neural and humoral systems. In 1977,
Guillemin and Schally were awarded a share of the identical alpha subunit (92 amino acids) and a non-
Nobel Prize in part for their discovery of the deca- covalently linked beta subunit (115 amino acids),
peptide gondaotropin-releasing hormone. Brain cen- with a unique amino acid sequence that confers
ters innervating the hypothalamus impact the release biological specificity.
of gonadotrophin-releasing hormone, which stimu- Follicle-stimulating hormone supports spermato-
lates pituitary gonadotropin (follicle-stimulating genesis via a trophic effect on Sertoli cells, including
hormone and interstitial cell-stimulating hormone). the production of androgen-binding protein, which is
In turn, gonadotropins stimulate spermatogenesis secreted into the lumen of the seminiferous tubules.
and testicular testosterone production. Negative Modulation of follicle-stimulating hormone release
feedback signaling to the hypothalamic–pituitary involves a negative feedback through sex steroids
complex by testicular inhibin and testosterone serve and ⁄ or the Sertoli cell protein hormone, inhibin.
to regulate the trophic stimulation to the testes Being unprotected by the blood–brain barrier, pro-
(Fig. 4). Notably, endogenous opiates appear to teins such as inhibin have the potential to act on the
modulate the release of normal levels of gonadotro- pituitary gonadotrophs and modulate follicle-stimu-
phin-releasing hormone, as evidenced by the in- lating hormone release.
creased concentration of interstitial cell-stimulating Interstitial cell-stimulating hormone serves to reg-
hormone in men treated with the narcotic antagonist ulate the level of plasma testosterone through the
naloxone (19, 44, 82). Inversely, narcotic use is induction of Leydig cell testosterone synthesis. In
associated with suppression of gonadotropins and, turn, testosterone is the primary endogenous plasma
ultimately, in hypogonadism (11, 23, 34). Gonado- hormone that participates in the negative-feedback
trophin-releasing hormone, synthesized and released loop (Fig. 4), primarily at the hypothalamus in
from hypothalamic neurons, flows via the portal cir- pubertal boys and at the pituitary in adults (44).
culation to the anterior pituitary. Through binding to Within the hypothalamus of lower animals, forma-
membrane receptors on anterior pituitary gondao- tion of both dihydrotestosterone and estradiol from
trophs, gonadotrophin-releasing hormone rapidly testosterone is well documented, and the adminis-
activates the transcription and release of follicle- tration of either and anti-androgen or anti-estrogen
stimulating hormone and ⁄ or interstitial cell-stimu- to normal men will affect a supra-normal rise in
lating hormone, also termed luteinizing hormone, in interstitial cell-stimulating hormone. These findings,
women. Interstitial cell-stimulating hormone and along with additional supportive evidence, suggest
follicle-stimulating hormone are small proteins syn- that dihydrotestosterone and ⁄ or estradiol may
thesized within the same cell type (gonadotroph) in mediate the hypothalamic negative-feedback actions
the anterior pituitary and are each composed of an of testosterone (55). Steroid-mediated negative feed-

237
Mawhinney & Mariotti

back on the hypothalamic neurons may be manifest ulin may serve to protect the female embryo from
as suppression of both the amplitude and the fre- masculinization of the reproductive tract.
quency of gonadotrophin-releasing hormone release.
Selective negative-feedback modulation of follicle-
Postnatal imprinting and pubertal
stimulating hormone and interstitial cell-stimulating
development
hormone may occur through differential pulse fre-
quency of gonadotrophin-releasing hormone. Of Evidence obtained from experimental animals indi-
secondary significance, androgen and estrogens can cates that androgen imprints normal androgenic
inhibit gonadotropin release at the level of the pitu- sensitivity in target tissues such as the male accessory
itary through interacting with the respective steroid sex organs. In rats, androgen deprivation, either be-
receptors within the pituitary. Although testosterone tween days 2 and 5 of postnatal life or during the
is reduced to dihydrotestosterone, intrapituitary early onset of puberty, irreversibly blunts the normal
estrogen formation does not occur, owing to the lack development of the prostate as a result of partial
of aromatase. androgen resistance (63). Relative to humans, rats
In post-pubertal men, total plasma testosterone have a short gestation time, and whether such post-
ranges between 10 and 35 nM, the majority of which natal imprinting occurs in humans remains to be
is bound to plasma proteins. Only 2% of the total determined. However, the dynamics of plasma tes-
testosterone concentration circulates free of protein tosterone in human male development fosters the
complexes in a biologically diffusible or bioavailable speculation that imprinting of target organs may
form. Interestingly, salivary gland testosterone occur during the first few months of neonatal life.
concentrations closely parallel the free plasma That is, gonadotropin-releasing hormone and inter-
concentration. Ninety-eight per cent of testosterone stitial cell-stimulating hormone-dependent Leydig
circulates reversibly bound to either albumin or sex cell differentiation and plasma testosterone secretion
hormone-binding globulin and, as such, is theoreti- surge to a peak at 2 months of neonatal age (Fig. 2).
cally prevented from diffusing into cells. Approxi- This neonatal surge may also initiate the early post-
mately 54% of the total steroid is bound to albumin natal growth spurt (expressed as the percentage of
as a relatively low-affinity, nonspecific complex, total growth) that occurs during the first 2 years of
whereas 44% of testosterone is linked with much human life.
higher affinity to the steroid-specific sex hormone- Adrenarcy is defined as either the prepubertal in-
binding globulin. The rank order of sex hormone- crease in adrenal androgen synthesis ⁄ secretion or
binding globulin affinity for dihydrotestosterone, the adrenal component of pubertal development.
testosterone and estradiol is 3:1:0.5. Sex hormone- Approximately 2–4 years before the onset of gondar-
binding globulin is not found in all species, but in che (gonad-driven pubertal development), adrenal-
humans, the protein is of hepatic origin and is similar derived levels of androstenedione and testosterone
to the androgen-binding protein produced by Sertoli increase in prepubertal male and female children by
cells. As men age, the level of total plasma testos- unknown mechanisms that are independent of any
terone remains constant or slightly decreases during correlative changes in adrenocorticotropic hormone
the seventh or eighth decades of life, but free tes- or cortisol secretion. Speculated to be important for
tosterone may fall by as much as 50% after 50 years initiating prepubertal phenotypic sexual develop-
of age (55). Reduced interstitial cell-stimulating hor- ment, including long-bone growth and the appear-
mone-induced Leydig cell testosterone synthesis is a ance of axial ⁄ pubic hair, the phenomenon of
likely explanation (96). In addition, aged males gen- adrenarche actually appears to be unnecessary for
erally accrue adipose tissue, which is a site of aro- normal sexual maturation (25).
matization of testosterone to estradiol. Thus, the level Gonadarche is responsible for puberty, which has
of free testosterone may decrease in association with an average age of onset of 12 years for American
increased estrogen-sensitive hepatic synthesis of sex male individuals. Fertile ejaculates may appear
hormone-binding globulin. Any additional signifi- approximately 1 year after the initial onset of pub-
cance of androgen-bound sex hormone-binding erty. The earliest or initial phase of puberty is rep-
globulin in men remains speculative, but experi- resented by testicular growth, primarily as a result of
mental evidence does suggest that sex hormone- follicle-stimulating hormone-dependent seminifer-
binding globulin may enter androgen-sensitive cells ous tubule development. Leydig cells remain in a
and facilitate specific hormonal effects. During preg- rudimentary mesenchymal phenotype after the
nancy, estrogen-induced sex hormone-binding glob- neonatal surge in testosterone, and are stimulated by

238
 Factors affecting function of the male reproductive system

the pubertal rise in interstitial cell-stimulating Table 1. Androgen-dependent phenotypic pubertal male
hormone. Such gonadotropin-induced androgen development
synthesis ⁄ secretion is responsible for growth and
System ⁄ characteristic Change observed
differentiation to the adult male phenotype. Clearly,
Reproductive system Increased testicular size
the level of gonadotropins increases in response to
(‡2.5 cm)
the onset of the repetitive pulsatile release of Onset of spermatogenesis
gonadotrophin-releasing hormone, which, in early and androgen synthesis
pubertal development, occurs primarily during Growth of external
sleep. However, the mechanisms for the rise in genitalia; growth and
onset of secretion of the
gonadotrophin-releasing hormone, both in the early
accessory sex organs
neonatal period and at puberty, are not completely
resolved and may differ between humans and lower Somatic tissues Appearance of facial, axial
and pubic hair
animals. In primates, gonadotrophin-releasing hor-
Increased sebaceous gland
mone is chronically suppressed by the neurotrans- secretion and acne
mitter gamma-aminobutyric acid between the neo- Increased lean body mass
natal surge and the onset at puberty. The increased (50% greater than in age-
release of gonadotrophin-releasing hormone results matched women)
• reduction in subcuta-
from the reduction of this gamma-aminobutyric
neous fat
acid-ergic input by unknown, and possibly multi- • skeletal muscle cell
factorial, mechanisms (81). As an example, an hyperplasia and hyper-
epigenetic influence on the chronological age of trophy
puberty is energy balance and the accrual of adipose • Increased bone growth
and differentiation
tissue (69). Before 1940, the onset of puberty in the
• length of long bones
USA had occurred 2–3 months earlier per decade for • broadened shoulder
100 years (79), possibly because of the accrual of a shape
moderate percentage of body fat as a result of im- • relative growth of jaw
proved health and nutrition. Abnormally lean chil- and nose in face
• long-bone growth
dren exhibit delayed pubertal development, and loss
cessation as a result of
of normal body fat in post-pubertal females leads to closure of epiphyses
amenorrhea (89). Inversely, the stress–reward–eating Lowered voice tone as a
pattern of obesity is associated with infertility, and result of vocal cord
may be linked to the suppression of gonadotropins lengthening
through elevated levels of endogenous central ner- Behavior Increased libido, internal
vous system opiates (2). Body fat aromatizes turmoil, depression
androgens to estrogens and synthesizes hormones Vascular Increased systolic and
such as adiponectin and leptin, which impact insulin diastolic blood pressure
sensitivity and satiety or gonadotropin release. Increased erythropoietin
Adopikine receptors are expressed in the pituitary and hematocrit
Reduction in lymphoid
and either adiponectin or leptin can suppress
tissue
luteinizing hormone (64). Interestingly, adipose tis-
sue also synthesizes and secretes prolactin (6), and
hyperprolactinemia inhibits gonadal steroid synthe- prepubertal male subjects has the potential to stunt
sis. Currently lacking is a cohesive understanding of growth irreversibly.
the definitive processes by which adipose tissue and The classic experimental model system to bioassay
other systems normally and abnormally impact and study the mechanism of androgen action is a
gonadotrophin-releasing hormone release and the male accessory sex organ such as a prostate gland or
onset of puberty. a seminal vesicle. From such systems, several
Table 1 summarizes the spectrum of androgen- principles have been established. Growth and differ-
dependent changes that are evident during male entiation of the epithelium is dependent upon the
pubertal development. While most effects of andro- bioactivation of testosterone to dihydrotestosterone
gen are reversible, long-bone growth cessation and by the enzyme 5a-reductase, with dihydrotestoster-
changes in the vocal cords represent irreversible one-dependent growth mediated by interaction with
morphogenic events. As such, abuse of androgens by the androgen receptor (see later). Regardless of the

239
Mawhinney & Mariotti

duration of androgen deprivation, the cuboidal, de- terone, estradiol failed to affect the growth response
differentiated and nonfunctional epithelium retains (54). Endogenous estrogens do appear to be requisite
the potential to differentiate to a normal columnar mediators of androgen action on sexual behavior (55)
secretory epithelium with androgen repletion. That as well as pubertal bone growth and subsequent
is, under the tropic influence of androgen, dramatic terminal epiphyseal plate closure (83), at least in
increases are evident in the number of large colum- lower animals.
nar cells with the full spectrum of intracellular Although total plasma testosterone levels remain
organelles and secretory functions. Following the relatively constant between the second and eighth
initiation of androgen repletion, the initial responses decades of life, free testosterone declines by
in the epithelial cells are evident after 1–2 days and approximately 50% beyond 50 years of age (55, 66,
reflect cellular hypertrophy, including increases in 74). Free testosterone, representing the biologically
total RNA, total protein and the activities of specific active fraction, is determined in part by the con-
enzymes and their respective products. By day 3 of centration of sex hormone-binding globulin, which
androgen repletion, a definitive wave of DNA syn- binds testosterone with twice the affinity as estradiol.
thesis ensues and cell number accrues (78). Such As men age and accumulate aromatase containing
normal proliferation and differentiation of the epi- adipose tissue, the concentration of sex hormone-
thelial cells is dependent upon a coordinated syn- binding globulin rises in response to the elevated
thesis and deposition of the extracellular matrix, estrogen and reduces circulating free testosterone
particularly basement membrane or Type IV collagen (31).
(20). Inversely, withdrawal of the androgenic stimu-
lus results in an 80–90% loss of cell number as a
Mechanism of androgen action
result of apoptosis, with the remaining cells regress-
ing to a vestigial state. Since the late 1800s, technological developments
Accessory sex organ smooth muscle is an andro- have allowed a thorough characterization of the
gen-dependent tissue, expressing 5a-reductase and androgen-dependence of the morphology and
androgen receptors (3). In contrast to the classic metabolism of target tissues, such as the epithelium
reversible androgen-dependent growth of epithe- of the accessory sex organs. In the late 1960s, studies
lium, smooth muscle displays an initial mitogenic of the mechanism of hormone action were revolu-
response to androgen during puberty, which subse- tionized by the innovative endeavor to analyze the
quently progresses to an irreversible androgen-resis- fate of the hormone (38). Subcutaneously injected
tant amitotic state in the adult. Also, in contrast to radioactive estradiol was found to be accumulated
androgen action on the epithelium, this initial mito- and retained by the uterus in far greater concentra-
genic response is mediated by the androgen-depen- tions than in nontarget tissues such as skeletal
dent release of norepinephrine from the postgangli- muscle. Research revealed that the uterine accumu-
onic adrenergic nerve terminals innervating the lation of estradiol was caused by the target-tissue-
smooth muscle (43). The postmitotic smooth muscle specific and estrogen-specific binding protein, which
irreversibly differentiates to a state in which cell proved to be the hormone receptor. Subsequently, a
number is androgen resistant, yet parameters of cell like-minded pursuit of the fate of androgen in men
size remain androgen sensitive (52, 53). Male acces- generated no pattern of target-tissue-specific accu-
sory sex organ smooth muscle from a variety of mulation of radioactivity from injected testosterone.
species expresses a functional estrogen receptor and It was ultimately discovered that plasma testosterone
is sensitive to exogenous estrogen-induced growth served as a pro-hormone or substrate for the intra-
(55). However, based on estrogen receptor gene cellular formation of dihydrotestosterone, a requisite
knockouts, endogenous estrogens are not required step in the normal action of testosterone in most
for normal embryonic mesenchyme-driven prostate target tissues. In androgen-dependent cells, dihyd-
differentiation (15). Likewise, despite the high con- rotestosterone is selectively concentrated as a result
centration of a functional estrogen receptor in the of the tissue-specific expression of two functional
guinea pig seminal vesicle smooth muscle, its proteins: (i) 5a-reductase, the enzyme(s) that cata-
postpubertal development is not dependent on lyzes the formation of dihydrotestosterone; and (ii)
endogenous estrogens, the key evidence being that the androgen receptor (51). In addition, dihydrotes-
dihydrotestosterone, an inert substrate for estrogen tosterone exhibits a preferential affinity, relative to
formation, duplicated the stimulatory effects of tes- testosterone, for the intracellular androgen receptor
tosterone, and in combination with dihydrotestos- (94).

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 Factors affecting function of the male reproductive system

Two isozymes of 5a-reductase exist. Type I is found

in liver, in the nonbalding skin of men and in the
epithelial cells of the prostate (75, 94). The type I
isozyme appears to have little significance in men,
given that gene mutations or knockouts have no
detectable impact on the male phenotype or repro-
ductive function. However, in women, mutations in
the 5a-reductase type I gene reduce fertility and
block parturition. The type II isozyme is expressed in
balding skin and in both the epithelium and the fi-
bromuscular stroma of the prostate gland. Mutations
or experimental knockouts in this gene result in
androgen resistance of the dihydrotestosterone-
dependent organogenesis. Also, a pharmacological Fig. 5. Potential mechanism for organ-specific androgen-
treatment (finasteride ⁄ Proscar) of benign prostatic induced morphogenesis and gene expression. DHT, di-
hypertrophy is based on the inhibition of this enzyme hydrotestosterone. This figure was redrawn based on the
(47, 56). A relatively new drug for the treatment of original research and graphic summation by Coffey and
colleagues (34).
benign prostatic hypertrophy is the nonspecific
inhibitor (dutaseride ⁄ Avodart) of the 5a-reducta-
ses. Clinical efficacy relative to finasteride remains to
Androgen and other drugs of abuse
be established.
(narcotics, ethanol and cannabinoids)
The fate of the intracellular dihydrotestosterone–
impacting plasma testosterone
receptor complex has provided insight into the
mechanism of androgen-dependent gene transcrip- Contrary to popular opinion, the administration of
tion (19). Hormone binding to the receptor induces a androgens or so-called Ôanabolic steroidsÕ to healthy
change(s) in the protein complex that increases adult male humans does not consistently cause su-
binding affinity to specific DNA sequences and to pranormal skeletal muscle growth or strength. A
acceptor sites on the nuclear matrix (Fig. 5). Expres- major body of evidence indicates that in humans or
sion of these hormone receptor-acceptor sites are experimental animals with normal testicular func-
both tissue-specific and steroid hormone-specific. tion, exogenous androgens have only marginal, if not
Thus, binding between activated hormone receptors insignificant, effects on muscle mass and ⁄ or physi-
and these nuclear matrix sites may represent a cal performance (67, 92). From prospective analyses,
putative site for hormone-regulated gene transcrip- the maximum increases in human body weight from
tion. In fact, the irreversible hormone-dependent exogenous androgen administration were between 2
embryonic morphogenesis of organs such as the and 4 kg, possibly caused partly by fluid retention.
accessory sex glands is dependent on the organiza- Additional effects included increments in blood vol-
tion of DNA loops that have the potential to contact ume of 15%, a 1-mg ⁄ dl increase in hematocrit and a
the matrix and be susceptible to transcription. Such 20% increase in muscle creatine. Any initial retention
spatial concepts offer insight into the basis for the of urinary nitrogen, reflecting protein anabolism,
qualitative differences in the synthesis of secretions may be offset by subsequent autoregulation to a
among androgen-dependent organs, and may ulti- negative balance and then a return to normalcy, de-
mately lead to the understanding of the selective spite the continued administration of the steroid. On
sensitivity of the prostate to infection and neoplasia the other hand, some prospective studies have re-
(19). ported androgen-induced gains in lean body mass
In some organ systems, notably the brain and bone, and 5–20% increases in strength, as measured by
the normal expression of testosterone action is bench-press or squatting exercises (5, 30).
dependent on both reduction to dihydrotestosterone The widely held view that androgen abuse by men
and aromatization to estradiol (14, 42, 55). Human repeatedly and consistently induces supranormal
men with a dysfunctional mutation in aromatase have skeletal muscle growth appears to be perpetuated by
no detectable estrogen and are inordinately tall with the acceptance of reports or observations from
osteoporosis (39). On the other hand, skeletal muscle individuals willing to self-administer such com-
lacks a 5a-reductase, and testosterone represents the pounds. Hypotheses are that a subset of men suffers
active intracellular hormone in this system. from Ôreverse anorexiaÕ or ÔmegorexiaÕ, a possible

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Mawhinney & Mariotti

compulsive disorder, grounded in poor self-esteem

and perceived physical inadequacy. Such distortions
Pharmacological inhibition of
may manifest in a potentially self-destructive com- prostate gland growth: endocrine
mitment to dominance through development of therapy of prostate cancer and
imposing physical size and musculature. Self- benign prostatic hypertrophy
administration of androgens by such individuals,
either through a placebo effect or perturbations in Research into the pharmacological inhibition of
pain tolerance and aggressive behavior, may facili- normal prostate gland growth is driven by the goals
tate commitment to physical training. Retrospec- to treat prostate cancer and benign prostatic hyper-
tively, some steroid abusers do report increased pain trophy. For disseminated prostate cancer, the current
tolerance, irritability, aggressive behavior, episodes basis for pharmacological treatment is manipulation
of inappropriate rage (Ôroid rageÕ) and psychoses (30, of the negative-feedback loop to suppress plasma
92). However, with normal human subjects, experi- testosterone and thus reduce the endogenous stim-
mental findings did not consistently support either ulus of tumor cells. The Nobel Prize was awarded to
an androgen-induced aggression or other dysfunc- Charles Huggins in 1960 for estrogen-induced
tional behavior (86). symptomatic relief from prostate cancer. At a daily
Androgen abuse by pre-pubertal male subjects can dose of 5 mg ⁄ day of diethylstilbesterol, which had
prematurely and irreversibly stunt growth. In adults, no stimulatory effect on either normal or neoplastic
exogenous androgen administration suppresses prostate cells, the estrogen (acting via estrogen
spermatogenesis, but the effect is reversible with receptors in the hypothalamus and pituitary; Fig. 4)
cessation of use. Androgens also reduce the levels of suppressed plasma interstitial cell-stimulating hor-
high-density lipoprotein, a risk factor for atheroscle- mone (luteinizing hormone) and dramatically re-
rosis, but no increased incidence of cardiovascular duced plasma testosterone to levels equal to that of
disease has been linked to steroid abuse (30). orchiectomy. Diethylstilbesterol or orchiectomy pro-
As previously, discussed, narcotic abuse lowers the vided palliative relief from symptoms, such as bone
level of luteinizing hormone and plasma testosterone. pain, and prolonged the interval to disease progres-
In fact, endogenous opiates normally interact with sion. Significant reduction in cancer-based mortality
opioid receptors to suppress gonadotrophin-releasing was not achieved.
hormone. Inversely, the narcotic antagonist, nalox- Transition from estrogen therapy of metastatic
one, increases the level of interstitial cell-stimulating prostate carcinoma followed accumulating evidence
hormone (luteinizing hormone) and plasma testos- of diethylstilbesterol-induced cardiovascular toxicity,
terone in men. particularly thromboembolism (58). In addition,
Alcohol-related impotence and reduced libido are Ôtotal androgen ablative therapyÕ emerged using a
associated with reduced plasma testosterone, which combination of an anti-androgen with a long-acting
may result from either anti-gonadotropic or direct (1–4 months) subcutaneous depot of a synthetic
interactions of ethanol with steroidogenic enzymes. gonadotrophin-releasing hormone agonist (goserelin
In addition, impaired gonadotropin release not only or leuprolide). Based on clinical disease parameters,
contributes to steroidogenic deficiency, but may also androgen suppression with gonadotrophin-releasing
contribute to the infertility, testicular atrophy and hormone ⁄ anti-androgen therapy appears to be at
aspermia in alcoholism (26, 77). Testicular atrophy least as effective as diethylstilbesterol and less toxic.
from alcohol abuse is potentially irreversible, and Synthetic gonadotrophin-releasing hormone pep-
may stem from direct ethanol toxicity caused by the tides, substituted at positions 6 and 10, provide a
intra-testicular metabolism of ethanol to acetalde- longer half-life and greater receptor affinity, respec-
hyde (72). tively. However, the essential basis for reduction in
Studies with rodents indicated that cannabis plasma testosterone is down-regulation of interstitial
(marihuana) administration reduced plasma testos- cell-stimulating hormone secondary to chronic pitu-
terone (1, 29, 76). However, no significant effects of itary stimulation (Fig. 4). That is, after an initial (2-
chronic treatment were evident on the hypotha- week) period of gonadotrophin-releasing hormone
lamic–pituitary–Leydig cell axis in either male mon- induction of interstitial cell-stimulating hormone and
keys or men (1, 12, 65). Impaired spermatogenesis plasma testosterone, down-regulation of interstitial
has been reported with cannabis treatment (1, 29), cell-stimulating hormone ensues and the plasma
but the impact on human male fertility has not been testosterone concentration falls to levels achieved by
established. orchiectomy. Combination of an anti-androgen, such

242
 Factors affecting function of the male reproductive system

as flutamide, with gonadotrophin-releasing hormone pears to reliquefy clotted ejaculated semen by the
is employed to block any adverse tumor-promoting hydrolysis of semenogelin, the major coagulum
effects (Ôflare phenomenonÕ) secondary to the initial protein. The significance of reliquefaction in human
gonadotrophin-releasing hormone-induced rise in male fertility is not known, but may relate to the
testosterone. In addition, continued anti-androgen remobilization of sperm in the coagulum, and
therapy has the potential to block the tumor-pro- abnormalities in coagulation ⁄ liquefaction may lead
moting effects of residual androgens of adrenal ori- to impaired fertility (13, 61). However, in rodents,
gin, but the added financial cost and side effects the coagulation of ejaculated semen is irreversible
associated with sustained anti-androgen therapy of- and forms a vaginal plug that is ultimately shed
ten preclude this approach. intact. Beyond semen coagulation ⁄ reliquefaction,
Benign prostatic hypertrophy, unrelated to pros- current research hypothesizes that prostate-specific
tate cancer, is a benign adenoma originating from antigen may be involved in growth regulation of the
the innermost regions of the prostate gland and can prostate gland, as well as of metastases, through
compress the urethra. In contrast to the normal enzymatic activation of endogenous growth factors
gland, fibromuscular stroma predominates within or other proteins (91).
the adenoma (stroma ⁄ epithelium ratio = 5:1). The Following development of an immunoassay for
incidence of benign prostatic hypertrophy increases serum prostate-specific antigen in 1980 (46), rapidly
from 50% at 50 years of age to 80% at 80 years of progressing research established prostate-specific
age (4), but progression to symptomatic disease antigen as a tumor marker (9, 50). Serum prostate-
(urinary retention, outflow resistance and frequency specific antigen circulates as an enzymatically inac-
of urination) correlates with parameters such as tive protein, partly because of complexes with
smooth muscle density, inflammation and infarcts – endogenous inhibitors, but all forms are immunore-
not with adenoma size (17, 71). Only approximately active. Abnormally elevated serum prostate-specific
10% of men with benign prostatic hypertrophy will antigen is a noninvasive, relatively accurate marker
require surgical therapy (70). Not surprisingly, given for assisting in the diagnosis of early state prostate
the predominance of smooth muscle in benign cancer as well as monitoring the response to therapy
prostatic hypertrophy, a1-adrenoceptor antagonists and any subsequent relapse. Based on financial cost
consistently improved urinary tract symptoms (47, and frequency of disease detection, the use of pros-
57). Pharmacological therapy of symptomatic be- tate-specific antigen has been deemed unacceptable
nign prostatic hypertrophy with finasteride (a 5a- for screening the total male population for prostate
reductase type II inhibitor) either provided no cancer. Serum prostate-specific antigen values of
improvement (47) or only marginal improvement <4 ng ⁄ ml occur in 85–90% of men ‡50 years of age.
from baseline (57). In a study of 100 men with A prostate-specific antigen value of <4 ng ⁄ ml, cou-
symptomatic benign prostatic hypertrophy, 4 years pled with a normal result following digital rectal
of finasteride therapy was reported to reduce, by examination, has been considered consistent with a
55%, the need for prostatectomy. Wasson (90) cancer-free gland. However, more recent analyses
enlightened that this 55% reduction actually rep- have questioned whether data actually support an
resented sparing six men a transurethral prosta- upper limit value of a normal prostate-specific
tectomy at a total cost of finasteride of $280,000 in antigen, and current screening limits may represent
1998. false positives for malignancy (8, 32). Elevations
of serum prostate-specific antigen values up to
10 ng ⁄ ml may signal the presence of benign pros-
Prostate-specific antigen and benign and
tatic hypertrophy and ⁄ or carcinoma (8, 62). In
malignant tumors
approximately 20% of men, benign prostatic hyper-
Initially discovered in seminal plasma, prostate- trophy accounts for a serum prostate-specific anti-
specific antigen was identified in the prostate by gen level of between 4 and 10 ng ⁄ ml, but the rate of
Albin and colleagues and subsequently purified (87). increase in the level of prostate-specific antigen and
Along with as many as 10 other related proteases, the absolute level >10 ng ⁄ ml is significantly greater
prostate-specific antigen (molecular weight = for cancer than for benign prostatic hypertrophy
33,000) is a normal constituent of the seminal fluid, (48). Successful therapy for prostate cancer, and any
and is synthesized and secreted by prostate epithe- subsequent relapse, is reasonably well correlated
lial cells. Prostate-specific antigen has serine with the respective fall and rise in prostate-specific
protease and arginine esterase activities, and ap- antigen (48).

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Spermatogenesis, erection and

ejaculation
Overview
The ejaculate is comprised of sperm and the seminal
fluid. Spermatogenesis involves two basic processes,
spermatocytogenesis and spermiogenesis. Sperma-
tocytogenesis, the synthesis of sperm, occurs con-
tinually in the seminiferous tubules of the testes of
postpubertal male subjects under trophic influence
of follicle-stimulating hormone and testosterone. Fig. 6. Structural components of the human spermato-
Within the testis, follicle-stimulating hormone selec- zoon.
tively localizes to the seminiferous tubule basement
membrane, while interstitial cell-stimulating hor- dysfunction is predicated on the selective inhibition
mone is concentrated at the Leydig cell membrane of the enzymatic catabolism of neuronal nitric oxide-
(Fig. 3). Such selective localizations to the tubules induced cyclic guanosine monophosphate to en-
and interstitial cells are consistent with their hance dilation of the corpus cavernosum (Fig. 8).
respective functions of follicle-stimulating hormone-
induced spermatogenesis and interstitial cell-
stimulating hormone-induced steroidogenesis.
Semen formation
Spermiogenesis, the functional maturation of Spermatogenesis and hormonal regulation
anatomically mature sperm (Fig. 6), is an androgen-
Seminiferous tubules, spermatocytogenesis and sper-
dependent process occurring over time during
miogenesis. Spermatogenesis is a hormone-dependent
residence in both the seminiferous tubule and epid-
process involving the actions of Leydig cell-derived tes-
iymus. Spermiogenesis in the seminiferous tubules
tosterone and follicle-stimulating hormone on the
includes the final stages of anatomical differentia-
Sertoli cells and the germinal epithelium. Sperm
tion, such as condensation of the nuclear material
synthesis and a significant degree of differentiation
(loss of cytoplasm) and formation of both the fla-
take place within the seminiferous tubules. Num-
gellum and the acrosomal cap. Within the epididy-
bering approximately 1,000 ⁄ testis, such tubules oc-
mus, sperm acquire motility and the capability to
cupy approximately 80% of the testis volume and
fertilize. Vasectomy, which prevents ejaculation of
coalesce at the terminal ends into 6–12 ducts upon
sperm, does not impair spermatogenesis. Phagocy-
tosis within the epididymis clears residual sperm.
Seminal fluid is synthesized primarily by the prostate
gland and seminal vesicles. Synthesis per se is
androgen dependent, while secretion from the epi-
thelial cells into the acini of the accessory sex organs
is regulated by the cholinergic innervation. At the
time of sexual excitation, erection results from acti-
vation of the nitrergic innervation to dilate the penile
capillary network of the corpus cavernosum (Fig. 7).
Ejaculation is caused by the coordinated propulsion,
by smooth muscle, of sperm from the epididymus
through the vas deferens to the penile urethra in
association with seminal plasma. Activation of
adrenergic neurons stimulates smooth muscle
contractions of the vas deferens and accessory gland
acini, resulting in the propulsion of sperm and sem-
inal fluid beyond the penile meatus. Erectile dys-
function may be traced to deficiencies in the release
of neuronal and endothelial nitric oxide. Sildenafil Fig. 7. Anatomy of the human male accessory sex organs
(Viagra) and related drug therapy of erectile and external genitalia.

244
 Factors affecting function of the male reproductive system

64 days in humans. In rodents, and possibly in hu-

mans, this full spectrum of sperm proliferation and
differentiation from spermatogonia to spermatazoon
is represented along a longitudinal distance of a
seminiferous tubule. Thus, Ôwaves of spermatogene-
sisÕ appear within a length of a seminiferous tubule.
The functions of Sertoli cells are, for the most part,
the object of rational speculation. Tight junctions
between adjacent Sertoli cells form the Ôblood–testis
barrierÕ, which not only isolates the intraseminiferous
tubule space from bloodborne foreign compounds
but creates an immunologically privileged environ-
ment for spermatogenesis. By preventing leakage of
Fig. 8. Nitrergic neuron-dependent erection (dilation of sperm antigens into the vasculature, auto-sperm
the corpus cavernosum), and the mechanism of action of antibodies are rare in men with an unperturbed
sildenafil. cGMP, cyclic guanosine monophosphate; GMP, reproductive tract. Tight junctions additionally may
guanosine monophosphate; GTP, guanosine-5¢-triphos- allow formation of the unique biochemistry of the
phate; NO, nitric oxide; PDE-5, phosphodiesterase iso-
intraseminiferous tubular fluid, as well as the crea-
enzyme 5.
tion of microenvironments for developing sperm
cells in which both phagocytosis of debris and growth
entry into the epididymus. Attached to the seminif- regulation take place. Sertoli cells have steroidogenic
erous tubule basement membrane with orientation capability, including aromatization of testosterone to
to the external environment are both the germinal estadiol, and abnormally elevated levels of plasma
epithelium and Sertoli cells. Newly formed diploid estrogen may be present in individuals with Sertoli
spermatogonia from the germinal epithelium appear cell tumors. However, androgens derived from the
to have been ÔunderminedÕ by adjoining amitotic Leydig cell appear to be the primary source of
Sertoli cells and then sequentially encapsulated by androgen for the intratubular milieu, as evidenced by
the adjoining lateral surfaces of Sertoli cells during the fact that postvasectomy there is no reduction in
movement to the lumen. Coordinated with basal to the small concentration of steroids in seminal fluid.
luminal migration are both mitoses and differentia- Sertoli cell-derived androgen-binding protein func-
tion of diploid spermatogonia to haploid spermato- tions as an androgen reservoir within the seminifer-
cytes, which then undergo meiosis and further ous tubules (Fig. 3). Androgen-binding protein is
morphogenesis into haploid spermatids (16). These synthesized and secreted by the Sertoli cell under the
three ÔgenerationsÕ or stages of sperm cell develop- trophic influence of follicle-stimulating hormone
ment are all represented at a given time within (28). In turn, plasma follicle-stimulating hormone is
distinct microenvironments formed by the Sertoli regulated via a negative-feedback loop to the pitui-
cells. At the late stage of spermatid differentiation, tary by inhibin B, originating from components of the
tails are free in the tubular lumen, while the head spermatogenic cycle and the Sertoli cells (60). Sertoli
remains embedded within Sertoli cells. Before sper- cell-derived androgen-binding protein and liver-de-
matid release into the lumen and movement through rived sex hormone-binding globulin share the same
the lumen to the epididymys, the process of sper- amino acid sequence and preferential affinities for
miogenesis culminates in the formation of mature endogenous androgens, but differ in carbohydrate
spermatozoa. Spermiogenesis involves 19 definitive moieties (27).
steps or stages in the rat that lead to the formation of Essential for spermatogenesis is an intrascrotal
the tail or contractile flagellum with the highly con- temperature of 2–4C below that of the body core.
served microtubular structure (two central pairs and The temperature differential is established by coun-
nine surrounding pairs), helical organization of the ter-current heat exchange at the intrascrotal pampi-
packed mitochondria in the mid-piece, shedding of noform plexus, which is a network of closely
cytoplasm to concentrate nuclear material and for- approximated arterial and venous vasculature. As
mation of the acrosomal cap, which is a Golgi such, the warm descending arterial blood is cooled by
apparatus-derived, flattened secretory granule laden the venous return. With cryptorchidism (i.e. failed
with enzymes for penetration of the ovum (Fig. 5). androgen-dependent testicular descent through the
The entire process of spermatogenesis requires inguinal canal), infertility is the norm, along with an

245
Mawhinney & Mariotti

increased incidence of varicocele and testicular tu- The normal prostate gland produces a slightly acidic
mors. Normally, the human inguinal canal closes fluid containing citric acid, acid phosphatase,
irreversibly after birth, but in deer and in other sea- prostate-specific antigen and zinc. Interestingly,
sonal breeding wild animals, the testes are retraced coagulation-forming proteins (semenogellins) in
into the abdominal cavity through the patent inguinal ejaculated semen are derived from the seminal
canal during the winter or nonbreeding season. vesicles, while these gelatinous substrates are then
Despite the extensive knowledge of testicular func- cleaved ⁄ liquefied by prostate-derived prostate-spe-
tion, applied research into the induction of sper- cific antigen (39). The primary process for secretion
matogenesis in idiopathic male infertility has been from the accessory sex organs is exocytosis of secretory
unrewarding. Likewise, attempts to develop drugs as granules or merocrine secretion (33). Evidence does
male contraceptives have also not come to fruition. not support apocrine or holocrine secretion from these
organs. Notable species differences exist in the anat-
Epididymus and sperm maturation. Although sper- omy and function of the accessory organ complex. As
matozoa leaving the seminiferous tubules appear examples, dogs lack seminal vesicles and bulboure-
anatomically fully differentiated, residence within the thral glands. While the prostate gland in both men and
epididymus is required for the acquisition of both dogs is a spherical structure that completely surrounds
normal motility and the ability to fertilize ova. These the urethra at the base of the urinary bladder, four
two functions of the epididymus are androgen distinct prostate glands (anterior, dorsal, lateral and
dependent, and are probably mediated through the ventral) exist in mice and rats. Fructose is synthesized
classic scheme of receptor-mediated androgen action and secreted from the rat anterior and dorsal ⁄ lateral
through dihydrotestosterone formation (7). A defini- prostates, rather than from the seminal vesicles.
tive understanding of the biochemical changes in-
volved in the development of motility and fertilizing Androgen regulation of innervation and secretion.
capability is lacking. Accessory sex organ growth and differentiation,
including synthesis of the specific secretions, are
Seminal plasma and the male accessory sex organs
intimately dependent upon testicular androgens. In
Overview. Male accessory sex organs of humans fact, to paraphrase Williams-Ashman, no process or
include the bulbourethral glands (CowperÕs glands), parameter in the male accessory sex organs is alto-
peri-urethral glands (Littre glands), prostate gland gether androgen insensitive.
and seminal vesicles (Fig. 7). Approximately 90% of There is a notable paucity of insight into the hor-
the ejaculate is composed of seminal plasma, which is monal regulation of cholinergic inputs to the
derived primarily from secretion of the prostate gland epithelium and the mechanisms involved in the
(1.5 ml) and seminal vesicles (3.0 ml). CowperÕs glands hormonal ⁄ acetylcholine interactions that culminate
and glands of Littre contribute little of significance to in the induction of secretion. Functional adrenergic
this fluid. Relative to other fluids in the body, seminal neurotransmission in the smooth muscle is androgen
plasma contains uniquely high concentrations of ci- dependent. In the normal adult, nerve-induced con-
tric acid, fructose, prostaglandins, polyamines, phos- tractions are bimodal, with initial ATP-dependent
phorylcholine, acid phosphatase, prostate-specific and subsequent norepinephrine-dependent re-
antigen, growth factors ⁄ cytokines and zinc. Human sponses. Both transmitters may be released from the
seminal vesicles are paired, pouch-like structures, and same nerve terminal. In sexually immature animals,
each measures approximately 15 cm long and weighs the norepinephrine-dependent contractile response
4–5 g. Human seminal vesicles secrete a slightly to nerve stimulation is absent. Nerve-induced con-
alkaline fluid containing fructose and prostaglandins. tractions display only an ATP (purinergic)-mediated
The human prostate of adult men is a walnut-sized, response. The normal norepinephrine-mediated
tubulo-alveolar organ weighing approximately 20 g contractile responses only appear after sexual matu-
and completely surrounds the urethra at the base of ration or after treatment with exogenous androgen
the urinary bladder. Zones of the prostate have been (43, 49). Androgen appears to affect norepinephrine
characterized, based on either the histology of normal release per se, because smooth muscle from prepu-
glands (59) or exogenous estrogen-induced changes bertal animals contains a normal concentration of
in cellular differentiation (35). Internal or peri-ure- norepinephrine and normal postjunctional responses
thral portions of the human prostate give rise to to an exogenous alpha-agonist. Apart from effects on
benign prostatic hypertrophy, while prostate cancer neurotransmission, androgen also directly modulates
develops in the peripheral or posterior–lateral zones. smooth muscle contractility by suppressing sponta-

246
 Factors affecting function of the male reproductive system

neous contractions and the sensitivity to contractile genitalia (a penis and bilateral testes within the
stimuli (21, 49). In part, such effects may relate to scrotum) and the internal organs of reproduction (vas
androgen-induced hypertrophy of the smooth mus- deferens or ejaculatory ducts, prostate gland and
cle cells, thus causing a relative reduction in nerve seminal vesicles). While the seminiferous tubules of
density and norepinephrine concentration (21, 43). the testes produce structurally mature sperm (sper-
matocytogenesis), subsequent storage in the epi-
Estrogen regulation of innervation and secretion. didymus is required for two essential components of
Endogenous estrogens have little or no physiologi- sperm maturation (spermiogenesis): the acquisition
cally significant role in epithelial secretion or smooth of motility; and the ability to fertilize. Upon ejacula-
muscle contraction. Between species, as well as tion, sperm are propelled through the vas deferens
within a given species, the direct actions of estrogens into the prostatic urethra, at which point seminal
on the epithelium in androgen-depleted animals fluid (plasma) is expelled from the prostate gland and
range from little or no effect to squamous metaplasia. seminal vesicles, forming a suspension of sperm
In organ systems that are susceptible to estrogen-in- (semen) for ejaculation through the penile urethra.
duced squamous metaplasia, retinoids are anti- Artificial insemination of domestic livestock and hu-
estrogenic (52), suggesting that the metaplastic effects mans was made practical by the development of
of estrogen result from the perturbation of endoge- long-term storage of frozen semen.
nous retinoid action. With androgen repletion, estro- Functional viability of the male reproductive sys-
gens generally exhibit no anti-androgenic effects on tem is controlled by both the endocrine and nervous
the epithelium in a wide spectrum of accessory sex systems. Testosterone, the main male sex hormone in
organs (55). A noted exception is that estrogens are plasma, is produced by Leydig cells located within
selectively anti-androgenic on the fluid and electro- the interstices of the seminiferous tubules. Testos-
lyte components of the protein-rich secretion pro- terone synthesis is regulated at the level of a single
duced by the canine prostate gland (37). The canine steroidogenic enzyme by plasma interstitial cell-
prostate expresses high concentrations of the estro- stimulating hormone, which is secreted from
gen receptor(s), and to what extent endogenous the anterior pituitary under the trophic influence
estrogens modulate the process of secretion in this of hypothalamic gonadotropin-releasing hormone.
organ and other systems remains to be elucidated. Plasma testosterone is maintained within a relatively
The aromatization of testosterone to estradiol in the narrow concentration range owing to the presence of
hypothalamus and other parts of the central nervous a negative-feedback loop between the circulating
system is required, in some species, for the normal steroid and the hypothalamic–pituitary complex.
induction of male sexual behavior and differentiation Only free (nonprotein bound) testosterone diffuses
of the pattern of gonadotropin-releasing hormone into cells and amounts to approximately 2% of the
release by the hypothalamus (55). Such findings raise total steroid present. The protein-bound fraction
the possibility that androgen-induced norepineph- consists of both low-affinity complexes with albumin
rine release by the peripheral adrenergic innervation and high-affinity complexes with sex hormone-
of the smooth muscle may also be mediated by neu- binding globulin. During the fifth decade of life, free
ronal estrogen formation. However, aromatization of testosterone generally declines by approximately
testosterone to estradiol was undetectable in smooth 50%, despite no significant change in the total plas-
muscle and the nonaromatizable androgen, dihyd- ma concentration. The fall in free testosterone results
rotestosterone, duplicated the effects of testosterone from an increased concentration of sex hormone-
on catecholamine release (43). Relative to the epi- binding globulin, which, in turn, is induced by the
thelium, the smooth muscle contains very high con- elevated plasma estrogen from the accrued adipose
centrations of functional estrogen receptor (3), but tissue of aging men.
endogenous estrogens do not appear to influence the Through the regulation of gene expression, andro-
contractility of the smooth muscle. gens induce and ⁄ or maintain all aspects of the male
phenotype, including in utero differentiation,
growth ⁄ function of the external genitalia and
Summary accessory sex organs, steps in spermatogenesis,
sperm maturation, long-bone growth, peripheral fat
The male reproductive system functions to deposit distribution, skeletal muscle hypertrophy, body and
viable semen in the female reproductive tract. Ana- scalp hair growth ⁄ loss, voice tone and sexual
tomically, the male system consists of the external behavior. The spectrum of androgen actions have

247
Mawhinney & Mariotti

been subclassified into irreversible ⁄ morphogenic urinary tract as well as understanding drug side
and reversible ⁄ excitatory. Specific examples of effects in men. Arguably, the primary rationale for
morphogenic effects include the in utero differenti- basic research of human male reproductive physiol-
ation of the reproductive tract, the irreversible ces- ogy rests in the ultimate understanding of the
sation of long-bone growth and voice change etiology and treatment of benign and malignant
immediately postpuberty, as well as male-pattern prostate tumors. Exogenous administration of sex
baldness. The reversible excitatory ⁄ maintenance ef- steroids, including androgens, estrogens or proges-
fects of androgen are most evident in the epithelium tins, reversibly suppresses the secretion of both
of the accessory organs, which will repeatedly atro- gonadotrophin-releasing hormone and interstitial
phy and regenerate cell number, cellular morphology cell-stimulating hormone, resulting in the inhibition
and secretory functions in synchrony with the with- of testicular steroidogenesis. Capitalizing on this
drawal and repletion, respectively, of experimental principle of steroid-negative feedback, Charles Hug-
testosterone. Although testosterone represents the gins (Nobel Laureate in 1960) demonstrated that
biologically significant male sex steroid in plasma, estrogen therapy provided symptomatic benefit for
many androgen target tissues selectively express 5a- disseminated prostate cancer by lowering the plasma
reductase, which catalyzes the intracellular formation testosterone concentration and eliminating the
of dihydrotestosterone. Within such systems, dihyd- undesirable stimulatory effect on androgen-sensitive
rotestosterone formation represents the bioactivation tumor cells. More recently, synthetic gonadotrophin-
of testosterone, as evidenced by the preferential releasing hormone agonists have been employed for
affinity of dihydrotestosterone for the intracellular the same purpose. Gonadotrophin-releasing hor-
androgen receptor and the lack of testosterone action mone congeners act as super-agonists for interstitial
in the absence of normal dihydrotestosterone cell-stimulating hormone, initially affecting a rise
formation. For example, reduced expression of 5a- in interstitial cell-stimulating hormone and plasma
reductase expression in the male fetus results in a testosterone, and then eventually down-regulating
partially feminized male subject (testicular femini- interstitial cell-stimulating hormone and eliminating
zation II). Notably, the urogenital sinus differentiates the stimulus for testosterone synthesis. Drugs that
as a blind vaginal pouch, rather than as a prostate block the effect of androgen (i.e., anti-androgens) are
gland. Wolffian ducts of the embryonic testicular combined with gonadotrophin-releasing hormone
feminization II male embryo differentiate normally therapy to prevent the adverse (tumor-stimulating)
into the epididymus, vas deferens and seminal vesi- effects from the initial rise in plasma testosterone.
cles, because Wolffian duct differentiation is testos- The pharmacological therapy of benign prostatic
terone dependent. In utero mutation of the androgen hypertrophy includes the use of inhibitors of 5a-
receptor gene in XY male embryos results in com- reductase. Given the significant role of dihydrotes-
plete feminization of all testosterone and dihyd- tosterone in male sexual differentiation, pregnant
rotestosterone-dependent target tissues (testicular women are cautioned to avoid exposure to any drug
feminization I). Phenotypically, such XY individuals of this class. Testicular atrophy is a predictable effect
appear as normal women, but lack a uterus. in healthy young adults who abuse exogenous ana-
Sympathetic adrenergic, and possibly cholinergic, bolic ⁄ androgenic steroids in an attempt to increase
innervation of smooth muscle controls contractile muscle mass and physical performance. Narcotics
processes in the smooth muscle of the vas deferens inhibit the release of gonadotrophin-releasing hor-
and accessory sex organs, leading to the propulsion mone, thereby lowering the concentration of plasma
of sperm and the extrusion of preformed seminal testosterone. Chronic abuse of ethanol has the po-
plasma, respectively. Sympathetic cholinergic inner- tential to cause irreversible testicular atrophy. Etha-
vation of the acinar epithelium of the accessory sex nol abuse may also cause gynecomastia in men. Such
organs regulates both the rates of formation and the feminization results from an elevated plasma estro-
rates of extracellular secretion of seminal plasma. In gen ⁄ androgen ratio, caused by the inhibition of
addition, parasympathetic neurotransmission, par- testicular androgen synthesis coupled with a rela-
ticularly that mediated by nitric oxide, dilates the tively selective decline in hepatic estrogen metabo-
smooth muscle vasculature that results in penile lism. While aspirin and related drugs significantly
erection. lower the level of seminal fluid prostaglandins, fer-
The regulatory mechanisms in male reproductive tility does not appear to be impaired. Therapy of
physiology provide a rational basis for evolution of erectile dysfunction with drugs such as sildenafil is
pharmacological therapy of diseases of the genito- based on the enhanced vasodilator effect of nitric

248
 Factors affecting function of the male reproductive system

oxide that is normally released from efferent intrap- Section 7 Endocrinology. Washington DC: American Phys-
enile parasympathetic neurons in response to sen- iological Society, 1975: 21–56.
17. Franks LM. Gross and Microscopic Anatomy. In: Grayhack
sory sexual stimulation. Sildenafil enhances nitric
JT, Wilson JD, Scherbenske MJ; National Institute of
oxide-induced signal transduction by retarding the Arthritis M, Digestive D, editors. Benign prostatic hyper-
rate of intracellular cyclic guanosine monophosphate plasia : a workshop sponsored by the Kidney Disease and
catabolism, which ultimately enhances vascular Urology Program of the National Institute of Arthritis,
smooth-muscle relaxation and penile erection. Metabolism and Digestive Diseases, National Institutes of
Health, Bethesda, Maryland, February 20–21, 1975. Wash-
ington, DC.
18. Genazzani AR, Petraglia F. Opioid control of luteinizing
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