treatment of idiopathic oligozoospermia and male factor subfertility
of Endocrinology, Elena Venizelou Hospital,
2 Venizelou Square,GR- 115 21
Athens, Hellas, Greece
Asian J Androl 2000 Mar; 2: 25-32
AbstractPharmaceutical 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.
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
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
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).
1. Specific and non-specific indications for medical treatment in oligozoospermia.
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
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.
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:
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
-Overactivation of androgen-dependent functions of the testes, epididymes,
prostate and seminal vesicles or,
-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.
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):
2. Sites of action and pharmaceutical agents used for treatment of idiopathic
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 although a significant
improvement was noted
in the case of TMX[5,6], which was not evident in earlier studies.
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. 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..
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.
Therefore, GnRH, hMG or hMG plus hCG can not be recommended as a therapeutic
approach in I.O..
High purity or recombioant FSH
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, testicular volume and spermatozoa
or a substantial pregnancy rate following IUI.
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.
Properly designed and controlled clinical studies are available only for two weak per os androgens, mesterolone and testosterone undecanoate.
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.
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).
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].
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).
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,
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.
Antiestrogens and androgens
3 Evidence in favor of pharmaceutical treatment
coming from properly designed studies have demonstrated a
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):
3. Significant post-treatment
improvement of primary end-points in I.O.
citrate and testosterone undecanoate
Increase of testicular volume as estimated by ultrasound after 3 months
of rec FSH treatment, this
being indicative of seminiferous tubules volume rise.
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
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.
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 and, therefore, better prognostic
indices for medical treatment.
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:
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. 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.
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:
4. Increment values of sperm parametres after 6 months of
rec-FSH treatment in relation to Sertoli cell reserves in I.O.
between (a) and (b): *P0.05,
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.
New pharmaceutical agents
Irvine DS. Epidemiology and aetiology of male infertility. Hum Reprod
1998; 13 suppl 1:
to: Prof. Dimitrios A. Adamopoulos.