Mesterolone (Proviron) induces low sperm quality with reduction in sex hormone profile in adult male Sprague Dawley rats testis

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Abstract
Anabolic-androgenic steroid compounds are one of the most widely abused drugs by athletes and muscle builders with the goal of improving performance/muscle mass. However, increasing concern has been expressed because these compounds not only offer unappreciable benefits to infertile and subfertile males, but also might have deleterious effects on both human and animal physiology including sperm quality. In addition, there is the conflicting outcome of AAS usage in the clinical settings with its attendant reduced spermatogenesis and hypopituitarism in patient management. Hence, we aim to evaluate the effects of mestorolone, an anabolic-androgenic steroid, on the histomorphometry of seminiferous tubules with serum hormonal and seminal analyses in adult male Sprague-Dawley rat. Twenty adult male Sprague dawley rats divided into two groups of 10 each. The treated group received 0.06 mg/g body weight/ day of mesterolone (proviron) by oral gavage for six weeks while the control group received equal volume of 0.9% normal saline per day. SPSS analysis of data generated with P< 0.05 considered statistically significant. The result showed significant (P< 0.05) body weight gain in all the animals. However, both the raw testicular weight and relative testicular weight per 100 g bwt was significantly (P< 0.05) higher in control than treated. The mean sperm count significantly decreased by 28% (P< 0.05) and the motility reduced significantly by 56% (P< 0.05) in the treated compared to control. In addition, both FSH (follicle stimulating hormone) and T (testosterone) of the treated were significantly lowered by 73% (P< 0.05) and 63% (P< 0.05) respectively compared to the control. The use of mesterolone is with caution and short intermittent therapy is desirous for better semen quality and improved overall fertility.
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Scientific Research and Essay Vol. 4 (4), pp. 320-327, April, 2009
Available online at http://www.academicjournals.org/SRE
ISSN 1992-2248 © 2009 Academic Journals
Full Length Research Paper
Mesterolone (Proviron) induces low sperm quality with
reduction in sex hormone profile in adult male Sprague
Dawley rats testis
Shittu Lukeman A. J.1*, Shittu Remilekun K.2, Osinubi Abraham A. A.3 and Tayo Adetokunbo
A.4
1Department of Anatomical Sciences, University of Abuja, College of Health Sciences, Gwagwalada, Abuja, Nigeria.
2Medical Microbiology Unit, Bolomedics Laboratories, Egbeda, Lagos, Nigeria.
3Department of Anatomy, College of Medicine, University of Lagos, Idi-araba, Lagos, Nigeria.
4Department of Obstetrics and Gynecology, Lagos State University, College of Medicine, Ikeja, Lagos, Nigeria.
Accepted 16 February, 2009
Anabolic-androgenic steroid compounds are one of the most widely abused drugs by athletes and
muscle builders with the goal of improving performance/muscle mass. However, increasing concern
has been expressed because these compounds not only offer unappreciable benefits to infertile and
subfertile males, but also might have deleterious effects on both human and animal physiology
including sperm quality. In addition, there is the conflicting outcome of AAS usage in the clinical
settings with its attendant reduced spermatogenesis and hypopituitarism in patient management.
Hence, we aim to evaluate the effects of mestorolone, an anabolic-androgenic steroid, on the
histomorphometry of seminiferous tubules with serum hormonal and seminal analyses in adult male
Sprague-Dawley rat. Twenty adult male Sprague dawley rats divided into two groups of 10 each. The
treated group received 0.06 mg/g body weight/ day of mesterolone (proviron) by oral gavage for six
weeks while the control group received equal volume of 0.9% normal saline per day. SPSS analysis of
data generated with P< 0.05 considered statistically significant. The result showed significant (P< 0.05)
body weight gain in all the animals. However, both the raw testicular weight and relative testicular
weight per 100 g bwt was significantly (P< 0.05) higher in control than treated. The mean sperm count
significantly decreased by 28% (P< 0.05) and the motility reduced significantly by 56% (P< 0.05) in the
treated compared to control. In addition, both FSH (follicle stimulating hormone) and T (testosterone) of
the treated were significantly lowered by 73% (P< 0.05) and 63% (P< 0.05) respectively compared to the
control. The use of mesterolone is with caution and short intermittent therapy is desirous for better
semen quality and improved overall fertility.
Key words: Proviron, sperm parameters, germ cells, stereology, hormonal profiles, Sprague dawley rats.
INTRODUCTION
Increasing concern has been expressed recently about
the use and role of anabolic-androgenic steroid (AAS)
compounds, which are one of the most widely, abused
drugs by athletes and muscle builders with the sole pur-
pose of improving performance /ability, appearance or
muscle mass (Robert, 2000; Shittu et al., 2006).
*Corresponding author. E-mail: drlukemanjoseph@yahoo.com.
Tel: +234-804-7235 or +234-802-305-7810.
However, anabolic steroids usage though not legal in
many countries is on the rise worldwide. It can result in
many different types of side effects, which can be dele-
terious to ones health. Although, these side effects may
at times be reversible after drugs have been discontinued
in some cases.
Figure from the Canadian Centre for Drug Free Sport
estimated that in 1993, about 83,000 adolescent school
children between the ages of 11 - 18 had used androgenic
anabolic steroids in the preceding one year (Melia, 1994)
and this is bound to be on the increase.
Moreover, synthetic (exogenous) androgens have been
used in the treatment of male infertility or subfertility. This
is however based on the fact that the process of sperma-
togenesis is both androgenic and follicle stimulating hor-
mone (FSH) -dependent (Abel et al., 2008).
In addition, androgens stimulation as a whole is respon-
sible for the maintenance of spermatogenesis and secon-
dary sexual characteristics especially in the male. Thus,
the major androgen in the circulation of men and adult
males of most mammalian species including the rat
based on extensive literature search is testosterone (T)
that is produced by Leydig cells of the testis (Ren-Shan
and Mathew, 2006).
Nevertheless, the mechanism of actions of most andro-
gens are either through their direct stimulatory increase in
intratesticular testosterone level which in turn enhances
spermatogenesis and positively influences sperm trans-
port and maturation through its action on epididymis, duc-
tus deferens and seminal vesicles (Van-dekerckhove et
al., 2000). However, the other androgenic pathway of
action is via rebound effect (e.g. testosterone enanthate)
through the suppression of both spermatoge-nesis and
gonadotrophins (follicle stimulating hormone and lutei-
nizing hormone) secretion (Anonymous, 1990; Jocken-
hovel et al., 1999; Matsumoto, 1990; Van dekerckhove et
al., 2000). Thus, there is usually reversal of these
androgen-induced symptoms when such drugs are dis-
continued in some cases.
In addition, most AAS and high dose testosterone in-
take exert an inhibiting effect on the hypothalomo-
hypophysio-testicular axis with a resultant suppression in
the normal testicular function which may further lead to a
reduction in testosterone production, a decreased sper-
matogenesis, and a testicular atrophy. Although, this sup-
pression is dependent on the duration of the steroid
intake, the administered type of steroids and the dosage
of the steroid used (Bra¨mswig et al., 1984; Mauro, 1998;
Prader and Zachmann, 1978; Van dekerckhove et al.,
2000)
Generally, anabolic and androgenic activities of AAS
originate from their binding to and activation of the andro-
genic receptors (AR). However, the distinction between
these two biological activities depends on the organs and
target tissues involved. Thus, their anabolic impact con-
cerns certain organs such as muscles, bones, the heart
and kidneys with little 5-reductase activity. More-over,
the activity of AAS, especially testosterone will induce
protein synthesis, muscle fiber development, erythro-
poiesis, and stimulation of bone growth (Keenan et al.,
1993; Handelsman, 2000; Saudan et al., 2006; Urban et
al., 1995).
On the other hand, anabolic steroids are in essence
synthetic derivatives of testosterone, which are modified
to enhance its anabolic activities (that is, promotion of
protein synthesis and muscle growth) (Urban et al.,
1995).
Shittu et al. 321
In addition, anabolic steroids are known to displace glu-
cocorticoids from glucocorticoid receptors and inhibit
muscle protein catabolism, leading overall to an anabolic
or muscle building effect. Other mechanisms of direct and
indirect anabolic effects of AAS include increases in the
creatine phosphokinase activity in skeletal muscle, and
increases in both circulating insulin-like growth factor
(IGF)–1 (Arnold et al, 1996) as well as up-regulation of
IGF-1 receptors ( Urban et al., 1995).
Although, the abuse of AAS, especially dihydrotestos-
terone (DHT) analogues by athletes is on the increase
(Anthony, 2004). DHT has been found to contribute to
androgen action on the testis with support for some resi-
ual spermatogenesis in the rats` seminiferous tubules
(Shittu, 2006; Shittu et al., 2006). However, proviron
(mesterolone-DHT analogue, Schering, Germany) is also
thought to enhance spermatogenesis in oligospermic pa-
tients (Lee and Kim, 1985).
In addition, DHT androgenic activity is found more
potent than that of testosterone, by amplifying the activity
of T to as much as 10-folds. This is because DHT has a
higher relative binding affinity for and forms a more stable
complex with the AR that is not easily dissociable thereby
giving DHT a higher molar potency (Deslypere et al.,
1992; Grino et al., 1990).
DHT is formed from the irreversible conversion of tes-
tosterone by the action of 5-reductase enzymes, whose
activity is important in testicles, skin, prostate, intestines,
brain, bones, and adipose tissues etc. (Tenniswood et al.,
1982; Warren and Ahmad, 1978). Therefore, androgenic
effects of AAS predominate in these organs (Anthony,
2006; Proviron extract, 2006).
Moreover, DHT is shown to prevent the estrogen-de-
pendent augmentation of the progesterone cytosol recap-
tors (PRc) in human breast cancer cells. While, both DHT
and its metabolites also demonstrated a very high degree
of inhibition of estrogen in human breast cancer cells
(Hung and Gibbon, 1983). In addition, androgens are
capable of inhibiting both the estrogenic induction and the
ongoing stimulation of PRc receptor synthesis, but have
no apparent effect upon basal concentrations of this
receptor (MacIndoe and Etre, 1981).
Thus, DHT will certainly have beneficial effects on keep-
ing our estrogen in check, hence reason for its abuse by
sport machines. For example, with Proviron the athlete
obtains more muscle hardness since the androgen level
is increased and the estrogen concentration remains low.
This effect is usually appreciated to be positively en-
hanced when taken with diet during the preparation for a
competition. However, female athletes who naturally
have a higher estrogen level often take Proviron as their
steroid supplement resulting in increased muscle hard-
ness (Anthony, 2006).
However, the conflicting outcome of AAS usages in
clinical settings with their attendant reduction in sperma-
togenesis and induced hypopituitism usually observed in
male infertility management coupled with AAS abuse by
322 Sci. Res. Essays
sport machines during major sporting events have nece-
sitated the need for this study. We therefore aim to carry
out this study using the endocrine profile, histomorpho-
metric and seminal analysis of adult matured male Spra-
gue Dawley rats testis.
MATERIALS AND METHODS
Source of drugs
The proviron used for this study was bought from Agege phar-
maceuticals in Agege. Proviron SCHERING (PTY) LTD is a product
of Schering AG Germany/Allemagne, LOT # WEA6WX, manufac-
tured date (MFD) : 06, 04, expiry date (EXP): 06, 2009. Each oral
tablet contains 25 mg of mesterolone (17beta-hydroxy-1alpha-
methyl-5alpha-androstan-3-one) with 20 tablets in a bottle and the
preservatives methylparaben (0.02%) and propylparaben (0.01%).
Preparation of drug
A daily therapeutic dose of 20 mg of oral proviron tablet was used
in this study. However, we calculated the human dose based on the
physiological calculation for a 70 kg man, such that Proviron tablet
was dissolved in 100 mls of distilled water to make up to 0.06 mg/kg
bwt/day administered to the animal.
Animal
Twenty mature and healthy adult male Sprague Dawley rats weigh-
ing 120 to 200 g were procured from animal house of Lagos State
University, College of Medicine, Ikeja and housed in a well venti-
lated wire-wooden cages in the departmental animal house. They
were maintained under controlled light schedule (12 h Light: 12 h
Dark) at room temperature (28oC) and with constant humidity (40 -
50%). The animals acclimatized for a period of 7 days before the
start of treatment. During this period, they were fed with standard
rat chows/pellets supplied by Pfizer Nigeria Ltd and water ad-
libitum. Ear tag was used for individual identification of the entire
group animals.
Experimental procedure
The rats were randomly divided into two groups of ten rats each.
The control group received equal volume of 0.9% (w/v) normal
saline daily while the treated groups received 0.06 mg/kg body
weight /day of proviron solution via gastric gavage (oro-gastric
intubation) daily for a period of 6 weeks.
All procedures involving animals in this study conformed to the
guiding principles for research involving animals as recommended
by the Declaration of Helsinki and the Guiding Principles in the
Care and Use of Animals (World Medical Association and American
Physiological Society, 2002) and approved by the Departmental
Committee on the ethics and research.
Animal sacrifice
The rats were anaesthetized after post over night fasting using the
procedure described in our previous study (Shittu et al. , 2006).
Weekly weighing of the animals carried out all through the experi-
experimental period and prior to the sacrifice.
Organ harvest
The testes were was initially dissected out whole via midline abdo-
minal incision, cleared of fats and blotted dry. Their weights were
measured on a sensitive digital balance with volume measured by
water displacement using a 10 ml measuring cylinder. Later, the
sizes (length and width) were recorded by use of a sliding gauge (d
= 0.1) before eventually fixed in freshly prepared 10% formol saline
solution The two testes of each rat were measured and the average
value obtained for each of the two parameters was regarded as one
observation as described earlier in Shittu et al. (2006).
Tissue processing for light microscopy
Serial paraffin sections of 5 µm were obtained from fixed processed
testicular tissues blocks and stained with H & E stains as prepared
and previously described in our earlier studies (Shittu, 2006; Shittu
et al, 2007).
Cauda sperm forward motility
After anesthetizing the rat, epididymis was exposed by scrotal inci-
sion, and spermatozoa were expressed out by cutting the distal end
of the cauda epididymidal tubule. Spermatozoa with epididymal
fluid diluted with physiological saline was placed on a thin glass
slide and forward motility (rate and percentage) of 100 spermato-
zoa/mouse was observed under microscope at X 400 magnification
as previously described in Shittu et al. (2007, 2008).
However, the motility index was carried based on the method de-
scribed according to WHO (1999).
Sperm count
Spermatozoa were counted as per the method described in our
earlier studies (Shittu et al., 2007; 2008). Briefly, sperm suspension
drops were placed on both sides of Neubauer’s hemocytometer,
allowed to settle by in a humid chamber (wet) for 1 h. The numbers
of spermatozoa in the appropriate squares of the new improved
neuber haemocytometer were counted under the microscope at
X100 magnification as previously described by Shittu et al. (2007,
2008)
Hormonal assay
The estimation of serum Testosterone was carried out using the
procedure enclosed with the specific commercial kit purchased from
Amersham International Plc. (Bucking- hamshire, United Kingdom)
by ELISA method. While, FSH estimated by RIA techniques as
previously described in our studies (Shittu, 2006; Shittu et al., 2007,
2008).
Statistical analysis
The weight data were expressed in Mean ± S.D while other data
were expressed as Mean ± S.E.M. Comparison between groups
were done using the student t-test and non-parametric Mann-whit-
ney U test as the case may be. All the data input into SPSS 12 soft-
ware Microsoft computer (SPSS, Chicago, Illinois). Statistical
significance was considered at P0.05 (Shittu et al., 2006).
RESULTS
No obvious toxicity signs such as weakness, lethargy,
tremors, refusal of feeds, weight loss, hair-loss, coma
and death were seen in any of the animals. However,
most of the animals exhibited calmness; improve appetite
Shittu et al. 323
Table 1. Summary of body and organ weights of animals.
GROUP Pre-experimental
body weight (g)
(Mean + S.D)
Final body weight(g)
(Mean + S.D)
Raw Testicular weight.
(g) (Mean + S.E.M)
Testicular-body/body
weight (wt/100g bwt)
(Mean + S.E.M )
Control 27.3 ± 6.40 184.4 ±12.6 1.24 ± 0.01 0.67 ± 0.01
proviron 159.4 ± 5.16 185.2 ± 12.8* 0.89 ± 0.09* 0.55 ± 0.01*
N = 10 rats per group.
*P < 0.05 was considered significant statistically.
Table 2. Summary of mean sperm parameters.
Parameters group D Number of rats Proviron group Control group
Sperm Count (X 106 m/l) 10 58 ± 24.5* 80 ± 17.6
Sperm motility (%) 10 53 ± 10.2* 174 ± 46.9
Motility index 10 23 ± 4.9* 52 ± 9.7
Morphology ( % NORMAL) 10 83 ± 5.9* 88 ± 1.7
*P <0.05 is considered significant.
100 - % normal = % abnormal morphology.
Table 3. Summary of hormonal profile of the animals.
Hormone Types Number of animals Proviron group Control group
Testosterone (ng/ml) 10 0.3 ± 0.1* 0.8 ± 0.03
FSH ( I.U ) 10 3.0 ± 0.4* 11.0 ± 2.3
*P <0.05 is considered significant.
Table 4. Summary of % spermatogonial profile in
animals
Group Number of animals Mean ± SEM
Proviron 10 39.6 ± 6. 76
Control 10 62.6 ± 5.76
*P <0.05 is considered significant.
for food and water and general sense of well-being all
through the duration of the study.
Evidence of weight gained was observed in all the ani-
mals in both groups. Although, the mean average raw
body weight gained of animals in the proviron treated ani-
mals were lower in the control. However, the proviron
treated group weight was not significantly different from
that of the control, using ANOVA as shown in Table 1.
Moreover, both the raw testicular weight and relative
testicular weight decreased significantly (P < 0.05) in the
proviron treated group as compared to the control as
shown in Table 1.
Proviron group has the sperm count of about 1.4 times
significantly (P< 0.05) lower than the control. The sperm
motility of proviron is about 2.8 times significantly lower
than the control.
In addition, the percentage normal sperm morphology
in the proviron group was significantly lower than the
control as shown in Table 2.
Proviron has lower significant (P < 0.05) % spermatogo-
nial count than the control as shown in Table 4.
However, testosterone level in the proviron group was
about 2.7 folds significantly (P<0.01) lower than control.
While, the FSH level in proviron was 3.7 folds signifi-
cantly (P<0.05) lower than the control as shown in Table
3.
Histology of control rats’ testis (Figure 1a): Numerous
round tubules with a fewer elongated ones. Most of the
tubules are regularly shaped with evidence of active sper-
matogenic and spermiogenic activity seen.
Histology of the proviron treated animals testis
(Figure 1b): Regressive changes were seen in the tubu-
lar epithelia that affected both the germinal and sertoli
cells. Some evidence of spermatogenesis and spermio-
genesis were equally seen in some of the seminiferous
tubules with expanded intracellular spaces. Moreover,
there was a lot of liberation of germinal cells during deve-
lopment with abnormal luminal dilatation and gradual
reduction in epithelial heights of some of the tubules with
324 Sci. Res. Essays
Figure 1a. Photomicrographs of testicular histology of control animals.
There are numerous regularly round shaped seminiferous tubules with a fewer elongated ones
present within the testis. Moreover, most of the tubular lumens of the seminiferous tubules were
filled with spermatozoa and evidence of active spermatogenic and spermiogenic activity were
seen in both the X400 (right) and X100 (left) control animal slides.
Figure 1b. Photomocrographs testicular histology of the proviron treated animals.
Regressive changes were seen in the tubular epithelia that affected also both the germinal and sertoli
cells of the testis. Some evidence of spermatogenesis and spermiogenesis were equally seen in some
of the seminiferous tubules and most of them with fewer spermatozoa within their tubular lumens.
Moreover, there was a lot of liberation of germinal cells during development with abnormal luminal
dilatation and gradual reduction in epithelial heights of some of the tubules with thickened basement
membrane were observed in both the X400 (right) and X100 (left) proviron treated animal slides.
thickened basement membrane observed. However, imam-
ture germ cells with variable nuclear sizes and irregular
profiles associated with atrophic changes were seen in some
seminiferous tubules. In addition, localized accumulation of
leydig cells were seen around the atrophic tubular area.
Active hyperchromatic leydig cells with increased activity
were seen.
DISCUSSION
We now know that combination of well-characterized
animal models with stereological techniques always allow
for proper quantitative study of any hormonal impact on
male reproductive system (McLachlan et al., 1995; Shittu
et al., 2006).
In addition, rat appears to be a more suitable animal
model in studying the roles of the androgenic hormones
within the male reproductive system. Hence was used for
this study because, it operates on a two-way androgen
model (DHT and T) for its sexual differentiation. However,
unlike mouse model that is dependent on testosterone
action alone for the differentiation of its male urogenital
tract (George et al., 1989; Shittu et al., 2006; Tenniswood
et al., 1982).
The proviron treated group showed an insignificant (P>
0.05) gain in body weight, this is similar to the findings in
other studies where proviron is thought to enhance
weight gain from water retention in the body and de-
creased high-density lipoprotein among others (Anthony,
2006; Lee and Kim, 1985; Proviron extract, 2006).
The proviron group showed evidence of significant
reduction in both raw and relative testicular weights as
compared to control. However, these differential changes
in testicular weights observed were well correlated with
the seminiferous tubular profile/densities of the testis for
each group of animals as observed in our previous
studies (Shittu, 2006; Shittu et al., 2006).
These findings also implied that a major intratesticular
change is taking place during proviron therapy, which
accounted for the decrease in seminiferous tubule
size/diameters and testicular sizes (Barham and Berlin,
1974; Heller et al., 1950).
Both sperm motility and percentage normal sperm mor-
phology were significantly lowered in the proviron -treated
groups compared to the control. These were similar to
the findings in other studies where testosterone undeca-
noate and high dose of T-esters were used in rats and
human models (Bra¨mswig et al., 1984; Mauro, 1998;
Prader and Zachmann, 1978; Van-dekerckhove et al.,
2000; Yang et al., 2004). However, in another similar stu-
dy, a significant increased in sperm motility was observed
without any significant increased in sperm morphology in
proviron treated adult oligo-asthenozoospermic male
human subjects (Lee and Kim, 1985).
The low level of testosterone found in the treated group
in this present study must have been responsible for the
low sperm density and motility obtained as reflected in
Tables 2 and 3. However, a positive correlation exist
between T and sperm count including motility in other
studies (Doshi et al., 1994). In addition, the significant
reduction in sperm count in the proviron group was found
to be well correlated to the significant reduction in sper-
matogonia count and decreased in spermatocyte count
seen in testicular tissues histology as shown in Figure 1b,
Table 4 and in other similar study (Shittu, unpublished
data).
Moreover, the above finding may be as a result of the
reduction in proliferation of stem cells or spermiogenesis
as large masses of seminiferous tubules epithelium ap-
peared to be sloughing into the tubular lumen of the
proviron groups with associated evidence of testicular
atrophy as shown in Figure 1b.
Shittu et al. 325
However, on the contrary, Lee and Kim (1985) noticed a
rather significant, increased in the sperm count of their
proviron treated oligospermic-patients. Moreover, the
action of proviron on the AR in the testis is responsible
for the features stated above with a rebound effect and
may account for the reduced sperm count and quality
seen in the proviron treated group as observed in other
similar study ( Shittu et al, 2006).
In addition, studies have shown that the administration
of T-esters at high doses is associated with both
morphological/structural and cytological changes in adult
testes of rat and humans (Barham and Berlin, 1974;
Heller et al., 1950; Jezek et al., 1993). Such that, the
degenerative features like increased luminal dilatation (up
to 35%) and reduced epithelial height seen in other pre-
vious studies (Shittu, 2006; Shittu et al., 2006), were
amongst the other factors responsible for the testicular
atrophy (Oliveira et al., 2001) observed in some of the
seminiferous tubules of proviron treated groups in this
study.
Russell and co-workers (1993) had also speculated that
both FSH and T might co-operate and thus have a com-
mon post receptor pathway of action. Moreover, other
studies have shown that both FSH and androgen act in a
co-existing additive and synergistic manners in regulating
spermatogenesis and Sertoli cell activity (Abel et al.,
2008). However, the Sertoli cell still retain a significant
capacity for activity that is independent of direct hormonal
regulation (Abel et al, 2008).
Although, spermatogenesis in the adult male is a
complex hormonal interplay that is FSH and androgen
dependant (Shittu et al., 2006). However, ablation of
either hormone has deleterious effects on sertoli cell func-
tion and the progression of germ cells through sperma-
togenesis. Thus, a reduction of intratesticular androgen is
an essential factor needed for the inhibition of spermato-
genesis as reflected with the low sperm quality associa-
ted with a significantly low T as shown in Table 1 and 3.
However, DHT has the tendency to amplify the effects
of T with its binding on AR (Grino et al., 1996; Shittu et
al., 2006). This may also account for the reason why
some degree of residual spermatogenesis and spermio-
genesis took place within some of the seminiferous
tubules of the proviron treated groups in Figure 1b (Abel
et al., 2008; Grino et al.,1996; Shittu, 2006; Shittu et al.,
2006).
It is obvious that there is a complex hormonal interplay
existing at the level of the hypothalamic testicular axis
with negative feedback and rebound effects, which may
be the cause of the significant low FSH observed in the
present study as shown in Table 3. Moreover, we know
that FSH has a role in facilitating the transport and loca-
lization of testosterone within Sertoli cells involved in
spermatogenesis.
Other studies also showed that previously androgen-
treated tall men had significantly higher FSH levels com-
pared with controls normal subjects and further observed
326 Sci. Res. Essays
that there is a significant negative correlations between
plasma FSH levels and sperm concentration as well as
the age at start of therapy in the androgen treated men
(Stenvertl et al., 1998). On the contrary, in the present
study, we obtained a low FSH level in proviron treated
normal adult male rats compared with control and a
concomitant reduction in sperm quality. Thus, may imply
that there is a positive correlation between FSH and
sperm quality in the present study.
Moreover, other previous study has shown that, the
double inhibition of spermatogenesis, a phenomenon that
is usually active and effective in both monkey and hu-
mans after gonadotrophins withdrawal (a low FSH or low
LH as the case may) was found to be rather ineffective in
rats (Yang et al., 2004). This is because of its ineffective
inhibition effects on both the Leydig cell population and
intra-testicular testosterone level, thus may enhance
spermatogenesis in rats` testis (Yang et al., 2004).
In addition, we know that FSH is involved in increasing
spermatogonial number and maturation of spermatocytes
including meiosis process. However, spermatid matura-
tion is essentially T-dependent, a step, which cannot be,
completed in-spite of the presence of high doses of FSH
in the male reproductive system (Bartlett et al., 1989;
Cameron and Muffly, 1991). Thus, FSH and testosterone
act in synergism, which implied that a lower dose of
either of the two hormones is equally effective when the
other is available. Nevertheless, all these factors may
have accounted for the observed residual spermato-ge-
netic activity seen in some of the seminiferous tubules of
the proviron treated animals as shown in Figure 1b. In
addition, with associated evidence of mild significant
increaseed in tubular diameters compared to control rats
(Abel et al., 2008; Bartlett et al., 1989; Sinhan-Hikim and
Swerdloff, 1999; Shittu, 2006; Shittu et al., 2006; Sun et al.,
1989).
Moreover, Brown and Chakraborty (1988) have sug-
gested that clomiphene intake (antiestrogenic agent) de-
creased the synthesis and/or release of gonadotrophins
with decreased serum LH and testosterone concentration
in male rats. This was similar to the case with the provi-
ron (antiestrogenic- androgen) treatment in the present
study where chemical castration level was reached with
T< 0.5 ng/ml (T = 0.3 ng/ml) and with associated low FSH
level compared to control as shown in Table 3.
However, the significant low testosterone level observ-
ed in the proviron as shown in Table 3 was thought to be
due to selective conversion of testosterone to dihydrotes-
tosterone through increase in its 5a reductase enzymes
activity or reduction in DHT metabolism by enzymes.
Perhaps, this could also be because of the increased
competitive binding affinity of the exogenous DHT (provi-
ron) to the serum sex-steroid binding hormone (SHB) and
AR sites. Thereby displaying the testosterone with a re-
sultant reduction in T activity in the male reproductive
system or probably be due to reduction in the leydig cells
population or impact from the low FSH effect as the case
may be in this study. Therefore, the effect observed with
proviron (DHT) above may be purely receptor-based
action in nature.
In addition, several other studies have equally shown
that the negative impacts caused by the use of AAS are
likely to be reversible. This is because testicular volume
which was initially reduced following androgen usage in
adult men (Mauss et al, 1975) normalized after disconti-
nuation of therapy (Zachmann et al., 1976; Bra¨mswig et
al., 1984; Prader and Zachman, 1978; Mauss et al.,
1975). However, few studies proved otherwise that the
conditions are usually permanent with significantly small-
ler testicular sizes found in previously treated men (Willig
et al., 1991; Willig et al., 1992).
Therefore to maximize the positive effect of proviron at
the level of the hypothalamic-pituitary- testicular axis with
resultant improvement in semen quality, it would be
advised that intermittent rather than continuous treatment
for about 6 weeks maximum be initiated with a pre-and
post-hormonal check up as the case may be in any clini-
cal setting.
Thus, real battle and way forward is educating our youth
and athletes on the danger of taking AAS or other perfor-
mance enhancers and to re-focus their energy on taking
of adequate good diets and trainings.
Conclusion
The role of proviron in management of male infertility will
need to be reviewed based on results of present study. In
fact, proviron could probably serves as hormonal contra-
ceptive in the light of these present findings.
ACKNOWLEDGEMENT
The authors wish to appreciate the secretarial support of
Dorcas Adebayo and financial support of Jireh internatio-
nal foundation (JIF) towards the success of this study
(JIF-06-003).
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