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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
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.


-absolute or relative hormone excess or deficiency


-disturbances of extra-gonadal hormone secretion


-conditions affecting general health unfavorably


-long-term pharmaceutical treatment


-unfavorable influences on life-supporting systems


-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.


-pulsatile Gn-RH

pituitary complex

-anti-estrogens (clomiphene, tamoxifen)

Direct testicular

-hMG, hMG+hCG, hp/rec FSH



-weak androgens (per os)

Mainly accessory

-mesterolone (per os)

gland action

-testosterone undecanoate (per os)

gland action

-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 

Spermatogenesis and sperm maturation require the synergistic actions of both FSH and testosterone on Sertoli and germinal epithelium cells. In the case of I.O., some definite and demonstrable abnormalities of physiological function have been observed at one or more steps of hormone secretion and action, which eventually may compromise Sertoli cell function and androgen activity at the levels of seminiferous tubules, epididymes and accessory glands. In such conditions, sperm production and quality may be seriously impaired[22]. Therefore, enhancement of endogenous gonadotropin secretion by means of TMX administration and a co-treatment with a weak androgen as TU, to protect against potential disturbances in androgen synthesis, metabolism and/or transport, may exert a beneficial effect in I.O. patients. Indeed, a properly controlled trial has demonstrated that the combination of TMX 10 mg b.i.d. and TU 40 mg t.i.d. over a six month treatment period, increased significantly the functional sperm fraction as well as such indices of qualitative improvement as aniline and acrosine in patients[6]. In view of these results this type of combination has been employed as a first line treatment in selected patients with I.O. in our institution. Obviously, further trials on this combination are awaited with interest particularly with regard to its effect on pregnancy rates since this approach is practical, well tolerated and financially affordable.

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


rec FSH

testicular volume rise

seminiferous tubule effect

Kamischke et al. (1998)[15]



functional sperm fraction ** increase

testicular &  accessary gland effect

Adamopoulos et al. (1997)[6]


hp FSH

spermatic index and sperm number increase

effect on spermatogenesis

Foresta et al. (1998)[14]


rec FSH

sperm DNA condensation change

effect on sperm quality

Kamischke et al. (1998)[15]



sperm acrosine & aniline change

effect on sperm quality

Adamopoulos et al. (1997)[6]



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)


normal forms(%)

acrosine (g/mL)


rec-FSH6 months

(a) adequate response(50%) n:5






(b) inadequate response(50%) n:6







(c) normal response(50%) n:6






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

Development of task specific agents is the next challenge for I.O. therapeutics in the age of molecular pharmacology. Such an approach has been extensively researched and, in some cases, has been recently applied in such diverse conditions as growth hormone deficiency syndromes, osteoporosis, prostate-friendly androgens for substitutive treatment, etc. These types of agents may exert their action on specific steps of pituitary and testicular endocrine function, spermatogenesis and/or sperm maturation without interfering with the physiological processes. Obviously, this seems to be a distant prospect to be of clinical relevance at present as is the case with gene manipulations.

5 Summary

By and large, the prospects for effective pharmaceutical treatment in I.O. remain not very satisfactory at the moment. This part of Andrology requires urgent relevant basic research, better understanding of the physiological processes and more accurate and detailed investigative procedures. But, even with this information, it will take tremendous co-ordinated efforts to translate these basic research findings into clinically useful data whereas, as is inevitable, for a large population the damage will be irrevocable for want of a meaningful therapeutic approach. Studies comparing the effectiveness of medical treatment with that of A.R.T. must be undertaken to demonstrate eventually and decisively the relative merits of each modality. Failure to respond effectively to this challenge may eventually tempt those familiar with the cloning process into propagating its application in humans despite society's strong objections.


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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