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Medical
treatment of idiopathic oligozoospermia and male factor subfertility
Dimitrios
A. Adamopoulos
Department
of Endocrinology, Elena Venizelou Hospital,
2 Venizelou Square,GR- 115 21
Athens, Hellas, Greece
Asian J Androl 2000 Mar; 2: 25-32
Keywords:
idiopathic
oligospermia; prognosis; spermatogenesis; male fertility agents
Abstract
Pharmaceutical treatment for the so-called idiopathic oligozoospermia (I.O.) is possible and effective in a fair proportion of patients with the syndrome provided that appropriate investigative procedures may identify the major disorder or its level of disruption, this abnormality is reversible and appropriate prognostic indices for the treatment's success are devised and validated. According to the evidence available, minimal evaluation and prognostic indices for treatment eligibility in normogonadotropic men with I.O. include a routine work-up but, mainly, microscopical assessment of spermatogenesis and appraisal of Sertoli cell's functional capacity. Published data indicate that men with hypospermatogenesis without maturational arrest, respond favorably to agents stimulating Sertoli cells and germinal epithelium with increased sperm production. Furthermore, Sertoli cell activity as judged by cell-specific indices such as inhibin B secretion, may provide additional discriminating power to the microscopical picture of the testis. In this context, precise identification of the causative factor(s), together with the establishment of prognostic indices are the most important criteria on which the decision, for or against medical treatment in I.O., should be based. Obviously, further basic research and clinical trials are urgently needed in this particular field, and this should be a major task for clinical andrologists.1 Introduction
Medical
treatment for idiopathic oligozoospermia (I.O.) in recent years has been
the victim of totally inadequate investigative procedures, inappropriate
therapeutic attempts, replacement of therapeutic efforts by assisted reproduction
techniques (A.R.T.) and, worst of all, loss of interest and reluctance
of andrologists to work meticulously and patiently on this field. All
these shortcomings have led the community of reproductive medicine practitioners
away from pharmaceutical treatment and Andrology to the modern and relatively
rewarding terrain of A.R.T., for which the well defined and strict selection
criteria have been largely expanded in recent years. In this context,
almost any problem related to I.O. and male factor subfertility (M.F.S.)
has been assigned to the indications of A.R.T.'s and, as a consequence
of this, work and progress on medical treatment of
this syndrome has been totally neglected and ignored, although this condition
accounts for as much as 25%-33% of the cases[1,2]. This change
of interest has been so dramatic that in the last two Congresses of the
International Society of Andrology (Tokyo, 1993 and Salzburg, 1997) there
were no plenary lectures or symposia devoted to the medical management
of I.O.
As a result of this attitude, subpopulations of I.O. patients with a realistic chance of response to medical treatment, underprivileged people in developed countries and huge populations in emerging nations for which A.R.T.'s are not affordable or acceptable on financial, ethical or religious grounds have been deprived of the potential benefits of research and progress towards an effective, for some of them, medical treatment presently and in the future. This approach, although partly understandable by the self-conscious, medically advanced, economically affluent and sub-reproducing societies of Europe and North America, is not fully justified for the male patients at large for a number of valid reasons let alone the issue that a man and not his female partner should be treated for his problem and this should be a basic doctrine in the treatment of I.O.
In this review attention will be focussed on selected topics related to the types of empirical medical treatment for I.O. employed so far, the evidence justifying the effort for such a treatment, and, the prospects for medical treatment, as judged by current and/or future research.
2 Pharmaceutical treatment
The
therapeutic effort for absent, deficient or disturbed spermatogenesis
can be classified
into two major types, the aetiological and the empirical treatment. Moreover,
with the advent of A.R.T.'s, the therapeutic approach can be distinguished
in pharmaceutical treatment per se or medical treatment in the context
of an A.R.T. trial (Table 1).
Table
1. Specific and non-specific indications for medical treatment in oligozoospermia.
|
Aetiological- |
-absolute
or relative hormone excess or deficiency |
| specific |
-disturbances
of extra-gonadal hormone secretion |
| |
-conditions
affecting general health unfavorably |
| |
-long-term
pharmaceutical treatment |
| |
-unfavorable
influences on life-supporting systems |
| Empirical- |
-idiopathic
oligo-, astheno-, terato-zoospermia |
2.1
Aetiological approach
Aetiological
approach defines the type of treatment which aims to restore back to normalcy
a specific and well demonstrated deficiency, disturbance
or excess of factor(s) known to crucially affect the sperm production
and maturation in man. In such cases, appropriate investigative procedures have
identified specific abnormalities leading to dysspermia and, therefore,
the treatment prescribed affects favorably spermatogenesis and sperm maturation.
This approach has been employed with very satisfactory results in
patients with absent or disturbed sperm production and includes
conditions as:
(a) absent, deficient or disturbed production of hormones essential for
spermatogenesis, such as GnRH, gonadotropins and androgens,
(b) absent, deficient or excessive secretion of other endocrine factors
affecting secretion of GnRH, gonadotropins or androgens (e.g. prolactin,
GH, ACTH, TSH, thyroid hormones, etc.),
(c) conditions affecting unfavorably the general health state of an individual with
serious effects on reproductive function,
(d) side-effects of treatment with a variety of agents affecting the reproductive
system in concordance with the primary causative condition
(e.g. diabetes mellitus),
and
(e) unfavorable environmental influences such as working conditions, dietary
and living habits, use of intoxicating agents, exposure to testotoxic
factors, etc. In these
conditions, proper medical treatment and/or correction of the unfavorable
influences, have a very good chance to restore the disturbed sperm quantity
and quality. Unfortunately all these conditions account only for 15-20%
of the total number
of dysspermias, with endocrine causes accounting for only 1%[1].
2.2
Empirical approach
The
major problem facing the treatment of I.O. is the lack of a
definite diagnosis for each of the subgroups comprising this aetiologically
heterogenous and large group of dysspermia. For this reason, and the relative
paucity of specific treatment modalities, the therapeutic effectiveness
of empirical treatment has been found to be low and its usefulness has
been seriously questioned[3].
Empirical
treatment has been the earliest approach used so far in Andrology
and originally was
intended as a medical therapy per se or, recently, in the context of A.R.T.
trials for I.O. and M.F.S.. The rationale for this treatment is multifold
and its aims include:
(a) -activation of a quiescent or overactivation of a normal central regulatory
axis (hypothalamic-pituitary
axis) so that the gonadal stimulation could be amplified,
-restoration of altered pulsatile GnRH and/or
gonadotropin secretion in appropriate
conditions,
-substitution of relatively deficient or abnormal
molecular gonadotropin isoforms,
which are of inferior
biological activity.
These
tasks have been addressed so far by administration of anti-estrogens (tamoxifen
citrate, clomiphene citrate), pulsatile GnRH or human menopausal gonadotropin
(hMG) and intra-muscular or subcutaneous use of high purity (hp) or recombinant
(rec) FSH.
(b)
-Overactivation of androgen-dependent functions of the testes, epididymes,
prostate and seminal vesicles or,
-restoration of deficient androgen activity
caused by impaired
androgen synthesis,
metabolism and/or bioactivity, which is often observed in men with I.O.
For this purpose per os administration of weak androgens such as mesterolone
and testosterone undecanoate
have been employed empirically for a number of years.
(c)
-A combination of actions as those described in (a) and (b) has been recently
proposed by the introduction of simultaneous administration of tamoxifen
citrate (TMX) and testosterone undecanoate (TU). In this approach the
stimulatory effects of endogenously oversecreted FSH are combined with
that of TU so that both Sertoli and Leydig cells are overstimulated whereas
the androgens effect on spermatogenesis and sperm maturation is guaranteed.
In
this review evidence coming only from properly controlled studies, when
available, is presented and commented upon. The medications used so far
for empirical treatment
of I.O. include (Table 2):
Table
2. Sites of action and pharmaceutical agents used for treatment of idiopathic
oligozoospermia.
|
Hypothalamic- |
-pulsatile
Gn-RH |
| pituitary
complex |
-anti-estrogens
(clomiphene, tamoxifen) |
| Direct
testicular |
-hMG,
hMG+hCG, hp/rec FSH |
|
action |
-anti-estrogens |
| -weak
androgens (per os) |
|
| Mainly
accessory |
-mesterolone
(per os) |
| gland
action |
-testosterone
undecanoate (per os) |
| Extra-gonadal |
-regulators
of prolactin, GH, ACTH, TSH,cortisol, 17-OH-P, T3 and
T4 secretion |
2.2.1
Anti-estrogens
Administration
of antiestrogens has been a popular treatment in Europe for more than
two decades, with TMX citrate being the preferred agent. The mechanism
of their action has been established and it is mediated through an increase
in hypothalamic activity leading to an oversecretion of pituitary gonadotropins.
Moreover, direct action of TMX at testicular level has also been demonstrated
mainly in experimental
studies. Most of the properly designed clinical trials have demonstrated
no marked effect of
clomiphene citrate on sperm parameters[4] although a significant
improvement was noted
in the case of TMX[5,6], which was not evident in earlier studies[7].
Meta-analysis of published reports in terms of pregnancy rates gave an
odds ratio of 2.47 (confidence intervals 1.53-3.97), this being indicative
of a significant effectiveness[8]. However, after exclusion
of the cross-over trials the beneficial effect was not significant although
a proportion of patients had an effective response. It is important to
note that this meta-analysis was performed well before
the latest trials on TMX were published[5,6] and, therefore,
did not include studies
with clearly favorable results.
By and large, the evidence available indicates that this practical, well tolerated and inexpensive treatment has a good potential for a beneficial therapeutic effect in a subgroup of normogonadotropic men with I.O..
2.2.2
GnRH, hMG
Gonadotropin-releasing
hormone (GnRH) or human menopausal gonadotropin (hMG) administration in
a pulsative manner has been proposed as a means to correct slow-pulsing
oligozoospermia and induce testicular stimulation in a more physiological manner,
however, its clinical effectiveness has not been convincing[9,10].
On the other hand, hMG administration by intra-muscular route alone or
in combination with hCG in severe cases of I.O. does not seem to offer
any advantages over placebo treatment[11].
Therefore, GnRH, hMG or hMG plus hCG can not be recommended as a therapeutic
approach in I.O.[3].
2.2.3
High purity or recombioant FSH
Administration
of hp or rec FSH has been employed in recent years as a means to (a) overstimulate
Sertoli cells rendering them more supportive for disrupted spermatogenesis,
(b) modulate germinal-Sertoli cell junctions affecting the nucleus and
acrosome of spermatozoa and/or (c) affect directly or indirectly spermatogenesis
and sperm maturation[12,13]. This treatment appeared to be
very effective in most uncontrolled studies but could not demonstrate
any significant overall effect when tried in properly controlled protocols.
However, a rather recurring observation in all the studies performed so
far has been the finding of subsets of I.O. patients with a marked increase
of spermatozoa number[14], testicular volume and spermatozoa
DNA condensation[15]
or a substantial pregnancy rate following IUI[16].
Identification of these subgroups has not been possible with the
data presented, although in one study, testicular histology has been shown
to be a satisfactory prognostic index for FSH's treatment outcome[14].
2.2.4
Androgens
Properly designed and controlled clinical studies are available only for two weak per os androgens, mesterolone and testosterone undecanoate.
Mesterolone,
a 5- reduced, non-aromatizable, testosterone derivative, has been properly
tried in a few studies.
In all of them, no statistically significant improvement in sperm
parameters and pregnancy rates was noted[17].
However, in the large multi-center study, conducted by World Health
Organization administration of this androgen at the dose of 150 mg/day
produced a higher, although not significantly, pregnancy rate than placebo
cumulative life table pregnancy rate (196% vs 115%), with the
ratio of active to placebo pregnancy rates being 1.8 (0.7-4.4)[17].
Testosterone
undecanoate (TU) administration in men with I.O. has been tried in properly
controlled studies with some improvement particularly in sperm morphology
but not so much in spermatozoa concentration[18,19]. This effect
was achieved without
compromising the basal and/or stimulated pituitary gonadotropin or Leydig
cell secretory capacity[6,20].
A
meta-analytic study of trials employing treatment with androgens has shown
that their overall effect on pregnancy rates was not significantly better
than in placebo treated men, and the calculated odds ratio was approximately
1.30 (confidence intervals approximately 0.8-2.0)[8].
By
and large, one may conclude that per os weak androgens do not significantly
improve any of the sperm characteristics in men with I.O. except, possibly,
their morphology[21].
However, it is possible that a beneficial effect may be exerted in a subgroup
of thus treated patients,
but this subset could not be identified with the evidence available.
2.2.5
Antiestrogens and androgens
3 Evidence in favor of pharmaceutical treatment
Observations
coming from properly designed studies have demonstrated a
beneficial effect
of medical treatment resulting to a degree of sperm improvement in men
with I.O.. In particular, significant changes indicative of improvement
have been observed for a number of individual sperm parameters, these
including (Table 3):
Table
3. Significant post-treatment
improvement of primary end-points in I.O.
|
Type
of treatment |
Primary
end-point |
Biological
significnace |
Controlled
study |
|
|
1. |
rec
FSH |
testicular
volume rise |
seminiferous
tubule effect |
Kamischke
et al. (1998)[15] |
|
2. |
TMX+TU* |
functional
sperm fraction ** increase |
testicular
& accessary
gland effect |
Adamopoulos
et al. (1997)[6] |
|
3. |
hp
FSH |
spermatic
index and sperm number increase |
effect
on spermatogenesis |
Foresta
et al. (1998)[14] |
|
4. |
rec
FSH |
sperm
DNA condensation change |
effect
on sperm quality |
Kamischke
et al. (1998)[15] |
|
5. |
TMX+TU |
sperm
acrosine & aniline change |
effect
on sperm quality |
Adamopoulos
et al. (1997)[6] |
|
6. |
uFSH |
sperm
ultramicroscopy |
effect
on fertilization |
Ben-Rafael
et al.(2000)[16] |
*tamoxifen
citrate and testosterone undecanoate
**a product of volume, number, good motility (%), normal morphology
(%)/104
(1)
Increase of testicular volume as estimated by ultrasound after 3 months
of rec FSH treatment, this
being indicative of seminiferous tubules volume rise[15].
(2) Higher post-treatment
sperm functional fraction, a product independent of the changes of specific
parameters such as volume, number, motility an d morphology[6].
(3) A marked improvement of histological indices such as Sertoli and spermatic
histologic indices and doubling of total sperm count in 33% of I.O. patients
treated with hp FSH.
This finding was indicative of a positive hormone effect on spermatogenesis
and sperm maturation[14].
(4) A significant change of sperm DNA condensation following rec FSH treatment[15]
or a marked decrease of spermatozoa aniline staining after combined TMX
and TU therapy[6],
both being indicative of better spermatozoa quality.
(5) A marked increase of sperm acrosine in I.O. men treated with a combination of TMX
and TU, an observation implying a better spermatozoa fertilizing capacity
in the active treatment group[6].
(6) A significant increase of fertilization rate following treatment with
urinary FSH (uFSH) as a result of subcellular organelle improvement.
From the evidence presented it appears that medical treatment, mainly through an increase of FSH activity, has been related to significant improvements in sperm parameters. Moreover, it appears that these changes have been brought about independent of the source of FSH excess (endogenous or exogenous). Finally, androgen supplementation seems to potentiate these beneficial effects.
4 Prospects of pharmaceutical therapy
The
cornerstone for the future medical therapy in I.O., lies on (1) development
of precise investigative procedures allowing for a better aetiological
diagnosis and better understanding of testicular paracrinology, (2) better
selection of cases for medical treatment based on precise diagnosis and
application of properly evaluated prognostic indices, and (3) development
of task-specific pharmaceutical agents for correction or improvement of
disturbed processes in sperm production and maturation.
4.1
Investigative procedures
Ideally,
understanding of the cross-talk between testicular cell populations in
interstitial space and seminiferous tubules together with a clear knowledge
of the biology of spermatogenesis may unravel the mystery of some physiological
processes in detail. This knowledge may lead to more appropriate investigative
procedures in future[23] and, therefore, better prognostic
indices for medical treatment.
At
present, a proper evaluation of dysspermia should include morphometric,
exocrine (sperm), endocrine, and molecular investigations. In particular,
a complete work-up should include the following battery of investigations:
(a) complete sperm evaluation with tests of fertilizing capacity, presence
of autoantibodies, indices of accessory gland function, duct potency,
and gene mutation related abnormalities[29],
(b) microscopic or ultramicroscopic
evaluation of germinal epithelium and spermatozoa as well as assessment
of hormone receptors' functional integrity, and
(c) study of GnRH and gonadotropin pulsatility, secretion and molecular
structure under basal and/or stimulated conditions and assessment of Leydig
and Sertoli cell secretory ability.
Some
of the findings from this ideal work-up, may totally exclude empirical
pharmaceutical treatment as an option in some men with I.O. (e.g. receptor
inactivating mutations, azoospermia factor related mutations, severe Sertoli
cell and germinal epithelium damage, extra-testicular oligo-/azoospermia,
etc). On the other hand,
other results may define potentially responsive subgroups (e.g. altered
gonadotropin molecular structure, pulsatility, and secretion, disturbed
androgen synthesis and/or metabolism, abnormal epididymal and accessory
gland function, sperm autoimmunity, etc) and in such cases specific medical
treatment may hold a good chance of being effective. Finally, some findings
may classify a patient in the
gray zone of equivocal possibilities and it is in such cases appropriate
indices should be devised to distinguish between patients unresponsive
to medical treatment from men with a realistic chance of response. In
the former situation, A.R.T. should be advised as the only option. In
clinical practice, a very limited number of investigations are usually
carried out following an algorithm which is not universally applied but
varies according to the sophistication, abilities, and research orientation
of the laboratory, the experience of the clinicians, the financial conditions
and the clinical setting of each unit[25]. Usually, the average
evaluation of a subfertile man is limited to two spermogramms and a determination
of basal FSH concentration, with morphometric or histologic assessment
only in selected cases. As a result of this incomplete
investigation an inconclusive classification ensues and, very often, the
clinician is unable to make up his mind on whether or not a medical treatment
stands a chance of success.
4.2
Prognostic indices
The
devise of prognostic indices to select proper cases for pharmaceutical
treatment is an essential part of the work-up in men with I.O. and include,
presently, two possibilities:
(a) Histological assessment of seminiferous tubules: As as been recently
demonstrated, I.O. patients with hypospermatogenesis but without maturational
disturbances display a significantly good response to hp FSH treatment
with more than doubling of their basal sperm concentration[14].
Based on this evidence,
one may postulate that FSH secretagogues, such as TMX, may also have the
same effect on patients with similar histology.
(b) Functional Sertoli cell evaluation: This cell behaves as an endocrine
gland and, therefore, its function may be assessed under basal and/or
stimulated conditions[26]. Since its proper secretory activity
is of paramount importance for spermatogenesis, evaluation of its functional
capacity may be a proper way to distinguish men with normal Sertoli cell
function from those with compromised Sertoli cell function. This has been
demonstrated using cell-specific indices as inhibin B secretion, a marker
of Sertoli cell activity[27-30]. Evaluation of Sertoli cell's
responsiveness to stimulation by rec FSH has been explored as a prognostic
index for therapeutic administration of this hormone in patients with
I.O. An average inhibin B
increase of more than 50% after 150 i.u. rec FSH and 1500 i.u. hCG in
normogonadotropic normozoospermic men was considered as normal[31].
In a pilot study of rec FSH
administration (150 i.u.3 week for a six month period) to men with I.O., the
response to treatment was markedly better in patients with satisfactory
basal and stimulated inhibin B concentration in comparison to subjects
with sub-normal response[12]. This difference was noted not
only in quantitative but also
in functional sperm
parametres (Table 4). One may hypothesize that anti-estrogens, such
as TMX, may also conform to this way of action on their effect on spermatogenesis.
Further evidence from a larger series of patients is being awaited.
Table
4. Increment values of sperm parametres after 6 months of
rec-FSH treatment in relation to Sertoli cell reserves in I.O.
men.
|
Inhibin
B |
total
no.(106) |
motility(%) |
normal
forms(%) |
acrosine
(g/mL) |
aniline(%) |
| rec-FSH6
months |
|||||
| (a)
adequate response(50%) n:5 |
12.16.1*++ |
13.25.1++ |
9.43.1+ |
7.13.5+ |
15.95.1**++ |
| (b)
inadequate response(50%) n:6 |
5.03.0* |
8.34.2+ |
6.72.1 |
4.22.3 |
7.13.2**x |
| control |
|||||
| (c)
normal response(50%) n:6 |
4.74.1 |
4.12.1 |
4.93.1 |
3.31.9 |
3.22.0 |
differences
between (a) and (b): *P0.05,
**P0.01.
differences between (a), (b) and (c): xP0.05, +P0.01,
++P0.001.
(c)
A combination of germinal epithelium histological assessment with an evaluation
of Sertoli cell functional capacity may offer an even better, practical
and realistic investigative and prognostic approach for medical treatment
in men with I.O. Indeed, by employing this type of assessment one may
reliably identify and distinguish I.O. patients
likely to respond to treatment from those with no chances of success.
Apparently, meticulous work is required to substantiate or refute this
hypothesis which, if proven correct, may be used as a prognostic index
in routine practice.
(d) Molecular studies for detection of cases with I.O. due to microdeletions
of the azoospermia factor gene on the Y-chromosome are expected to become
a necessary procedure in the investigation of severe I.O.[32,33].
Positive findings will enable the clinician to exclude such candidates
and spare them from unnecessary treatment and counsel them on the opportunities
and implications of A.R.T.
4.3
New pharmaceutical agents
5
Summary
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Correspondence
to: Prof. Dimitrios A. Adamopoulos.
Tel: +30-1-640 2261 Fax: +30-1-641 1156
E-mail:
hel-soc-andro@ath.forthnet.gr
Received
2000-01-25 Accepted 2000-02-25
