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From the * Headquarters of Società Italiana
di Studi di Medicina della Riproduzione (SISMER), Bologna, Italy; and
Satellite Center of SISMER, Reproductive
Medicine Unit, Fermo (Ascoli Piceno), Italy.
| Correspondence to: Dr Giorgio Cavallini, via Mascheraio 46, 44100 Ferrara, Italy (e-mail: giorgiocavallini{at}libero.it). |
| Received for publication December 17, 2003; accepted for publication April 29, 2004. |
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Abstract |
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 Top Abstract Patients and MethodsResultsDiscussion and ConclusionsReferences |
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Key words: Male infertility, idiopathic oligoasthenospermia, varicocele, L-carnitine, acetyl-L-carnitine, cinnoxicam
A significant but clinically undetectable venous reflux (ie, subclinical varicocele) was found by scrotal echo-color Doppler at cord level in many OAT patients (Gattuccio et al, 2000). However, OAT associated with subclinical varicocele remains controversial: a moderate increase in sperm count was found after surgery (Yamamoto et al, 1996), but current evidence indicates that varicocele size does matter and that large varicoceles are more likely to improve with surgery. Appropriate medical treatment is warranted because surgery for subclinical varicoceles is not recommended (Jarow, 2001); however, no medical treatment could be successfully used until now.
Our team has demonstrated that intermittent administration of cinnoxicam (a nonsteroidal anti-inflammatory drug [NSAID]) suppositories improved sperm concentration, motility, and morphology in echo-color Doppler grade III varicoceles, but not in grades IV and V (Cavallini et al, 2003). In this study, we looked to see whether cinnoxicam improved the efficacy of carnitines in idiopathic and varicocele-associated OAT patients.
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Patients and Methods |
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TopAbstractPatients and MethodsResultsDiscussion and ConclusionsReferences |
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All OAT patients with deficiencies in all sperm patterns (sperm concentration < 20 000 000/mL, class A motility < 25%, typical forms < 30%) whose chief complaint was primary couple infertility longer than 12 months and regular intercourse (World Health Organization [WHO], 1999) were candidates for inclusion in the study. Eligible patients were those with normal sperm appearance, consistency, liquefaction, volume, and pH (WHO, 1999). A female partner free of any identifiable factor of infertility was required for eligibility. Female infertility factors were determined by the SISMER clinic with a medical history collection, an objective examination, a biphasic body temperature recording, a progesterone evaluation in luteal phase, an ultrasound of the uterus and of the ovaries, and a hysterosalpingogram to study tubal patency (Lenzi et al, 2003).
They were not admitted into the study if any of the following criteria were present: azoospermia (14 patients); seminal white blood cell concentration more than 1 000 000/mL, positive seminal cultural analysis, or positive urethral swab chlamydia test (27 patients); oligospermia less than 5 000 000/mL (11 patients); hormonal alterations (6 patients); age more than 40 years (10 patients); presence of anti-sperm antibodies (tested both in sera and bound to sperm surface, 12 patients; Lenzi et al, 2003); drug, tobacco, or alcohol abuse (18 patients); ongoing medical treatments (gonadotropins, anabolic steroids, cancer chemotherapy, NSAIDs; 6 patients); presence of hydrocele (4 patients); diabetes (2 patients); hypertension (4 patients); x-ray exposure in the previous 8 months (3 patients); peptic ulcer (1 patient); unexplained gastric pain (7 patients); previous hypersensitivity to NSAIDs or carnitines (0 patients); carnitine metabolism deficiency (0 patients); bilateral varicocele found with echo-color Doppler scanning or objective examination (29 patients); or prostate abnormalities found with digital rectal exploration or suprapubic ecography (19 cases). Prostate abnormalities were considered as volume more than 20 cm3, tenderness, modifications of consistency found with digital rectal exploration and modifications of echo-genicity found with suprapupic echoscan, or total serum prostatic-specific antigen higher than 4 µg/mL (Adamapoulos et al, 2003). Further exclusion criteria were previous or concurrent testicular pathology (torsion, undescended, orchi-epididymitis, surgery, trauma, or neoplasm) or testicle echographic abnormalities (intended as focal or diffuse change of testicle structure or of volume). Left testicular atrophy associated with clinical grade III or duplex grade IV and grade V varicoceles were not considered exclusion criteria (see Patient Sample section).
Patient Sample
This study considered 380 patients; our results include 325 patients (age
range 27–40, mean age 34 years) because 55 dropped out: 30 patients
refused to participate in a study where a placebo might be administered, 1
divorced, 1 reported a severe car crash, 6 preferred assisted reproduction
techniques, 5 naturally conceived, and 10 patients made mistakes in drug
consumption. All patients underwent a medical history collection, sexological
counseling session(s), an objective examination, an anti-sperm antibody
detection, a bilateral scrotal echo-color Doppler scanning and a testicular
volume calculation (cm3) with the 3-diameters technique
(Gattuccio et al, 2000), a
dosage of serum (PSA, FSH, luteinizing hormone [LH], prolactin, total and free
testosterone), and a suprapubic prostatic echoscan. Three samples of WHO 1999
sperm analysis were obtained from each patient
(WHO, 1999). Semen culture
analyses and chlamydia urethral swabs were performed on each patient.
Varicocele is intended as a venous reflux detectable with echo-color Doppler longer than 2 seconds at the level of the pampiniform plexus with or without the Valsalva maneuver. Varicocele was detected in 203 patients and classified by bilateral echo-color Doppler scanning according to the severity of venous reflux (Gattuccio et al, 2000): venous reflux with Valsalva maneuver limited to the cranial portion of the cord (grade 1), reflux with Valsalva until the upper pole of the testicle (grade 2), reflux with Valsalva until the lower pole of the testicle (grade 3), reflux in basal conditions increased by Valsalva (grade 4), reflux in basal conditions which does not increase with Valsalva (grade 5). Approximately duplex grades 1 and 2 correspond to subclinical varicoceles; duplex grades 3, 4, and 5 duplex varicoceles correspond to clinical grade 1, 2, and 3, respectively (Dubin and Amelar, 1970; Gattuccio et al, 2000). Distribution of patients according duplex and clinical classification is reported in Table 1.
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The testicular volume calculation revealed left testicular atrophy
(intended as testicular volume 
20% lower than the counterpart) in 67
varicoceles (Gattuccio et al,
2000).
Patients (123) were classified as idiopathic OAT because any known or demonstrable causes of dyspermia and of infertility could be found in the course of the above assessments (Foresta et al, 2002; Adamapoulos et al, 2003; Lenzi et al, 2003). Each varicocele grade or idiopathic OAT was considered 1 experimental unit.
Patient Randomization
The patients were asked to follow a standard diet (2000–2600 kcal in
3–5 meals: proteins 15%, sugars 52%, lipids 33%
[Gatti, 1980]) in order to
avoid the effects of variable carnitine intake. The patients were randomized
in 3 groups. Starch tablets (500 mg) and commercial glycerine suppositories
(Glicerolo supposte 2500 mg; Carlo Erba, Milano, Italy) were used as placebos.
Three groups of treatment were used. The first group used 1 x 500-mg
starch tablet twice daily and 1 glycerine suppository every 4 days. The second
group used oral L-carnitine 1 x 2 g/d (Carnitene, Sigma-Tau,
Pomezia, Italy) + oral acetyl-L-carnitine 500 x 2 mg/d
(L-carnitine/acetyl-L-carnitine, Zibren, Sigma-Tau,
Pomezia, Italy) + 1 glycerine suppository every 4 days. The third group used
L-carnitine/acetyl-L-carnitine + 1 x 30-mg
cinnoxicam suppository (Sinartrol, Società Produttrice Antibiotici,
Milano, Italy) every 4 days. The composition of the treatment groups is
presented in Table 1.
Active drug placebos identical in appearance could not be prepared. The
following procedures were adopted to ensure blindness
(Byington et al, 1985). Independent pharmacists prepared, anonymized, and certified starch tablets;
anonymized carnitine and cinnoxicam and glycerine suppository containers; and
filled and sealed anonymous color-coded boxes containing drugs, placebos, or
both; the code was transmitted to the Institutional Review Board (IRB) of
SISMER. The color code was disclosed to physicians by pharmacists and by IRB
at the end of the research. Written instructions to correctly consume box
contents were prepared by the physicians and enclosed by the pharmacists. The
pharmacists ensured and certified that patients had correctly consumed the
substances, and they informed the physicians without revealing whether the
substances were active drugs or placebos. Each box contained the quantity of
drugs, placebos, or both necessary for 3 months. The boxes were delivered
blindly by nurses on the basis of casual number tables
(Snedecor and Cochran, 1987).
Drugs were administered for 6 months. All study personnel and participants
were blinded to treatment assignment for the duration of the study. Only the
SISMER IRB saw unblinded data to alert physicians in the case of major side
effects, but this occurrence never happened and no one from the IRB had any
contact with study participants. Secretarial personnel not participating in
the trial asked nurses, physicians, and patients before periodic data
collection and drug delivery whether they were delivering or consuming group
1, group 2, or group 3 treatments. The blinding procedure was considered
successful if the percentage of correct answers did not significantly differ
in the chisquare test from the theoretical value of 33%. Medical doctors
answered correctly in 31% of the cases (
2 = 1.33, P
not significant), patients in 36.5% (2 = 2.030, P not
significant), and nurses in 35.7% (2 = 1.098, P not
significant).
Variables Examined
In this study, we tested the hypotheses that carnitines or carnitines +
cinnoxicam can improve sperm patterns and natural pregnancy achievement in
infertile couples because of idiopathic OAT or OAT associated with
varicocele.
The primary end points were side effects, bilateral testicular volume (cm3), sperm concentration (millions/cm3), percentage of WHO class A motile sperm and of incidence of typical forms and side effects. The data were collected before, during (at 3 and 6 months), and after (3 months after) therapy. Sperm patterns had been measured on 3 consecutive analyses (WHO, 1999).
The secondary end points were natural pregnancies achieved during the observation period of 9 months and their assumed time of spontaneous fertilization. The pregnancies were recorded monthly and estimated on the basis of the last ovulatory period of the female partner before the first ß-human chorionic globulin–positive result (Lenzi et al, 2003).
Data Analyses
Data analyses were carried out according to a pre-established plan.
Sperm patterns and testicular volume were analyzed as follows. Multiple
comparisons of paired series of data (ie, data comparison of each experimental
unit within an identical group of treatment) used randomized block (1 patient
= 1 block) analysis of variance (ANOVA), coupled paired comparisons used
randomized block orthogonal comparisons. Multiple comparisons of independent
series of data (ie, data comparison of each experimental unit between/among
different groups of treatment) used ANOVA, coupled independent comparisons
used orthogonal comparisons. When sperm patterns were submitted for analysis,
the tests were corrected for the number of replicated sperm analyses.
Testicular volume used natural data, sperm concentration used log-transformed
data, and motility and morphology used angular-transformed (sin-1
) data
(Snedecor and Cochran,
1987).
Percent incidence of side effects and of naturally achieved pregnancies were compared with the chi-square test among groups, between groups, or both (Snedecor and Cochran, 1987).
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Results |
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TopAbstractPatients and MethodsResultsDiscussion and ConclusionsReferences |
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Testicular volume data are listed in Table 3. No significant difference emerged among or within groups before, during, or after therapy.
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Cumulative percentage rates of naturally achieved pregnancies before,
during, and after treatment are presented in
Figure 1. At the end of the
follow-up, group 2 had a significantly higher pregnancy rate compared with
group 1 (2 = 20.795, P < .01), and group 3 had a
significantly increased pregnancy rate compared with group 2
(2 = 5.743; P < .05).
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Side effects were negligible and never resulted in therapy suspension. Two
patients from group 1, 2 patients from group 2, and 3 patients from group 3
reported mild euphoria, and 2 patients from group 1 and 2 patients from group
2 reported mild epigastralgia and nausea (2 < 1; P
not significant).
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Discussion and Conclusions |
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TopAbstractPatients and MethodsResultsDiscussion and ConclusionsReferences |
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The highest improvement in pregnancy rates occurred in group 3, and group 2 improved more than group 1. When drug administration was suspended, pregnancy rates did not increase any further in any group.
Only negligible side effects emerged, with no significant differences among the 3 groups. Patients (287/325) reported more abundant or easier defecation or both on the day in which suppositories were used, and they did not notice any appreciable discomfort; therefore, this occurrence was not reported as a side effect, and as a result, no significant difference emerged between cinnoxicam and glycerine. We used a suppository dosage much lower than the manufacturers' suggestions, which indicated a twice daily cinnoxicam dosage and a glycerine dosage not exceeding once per day (Federazione Nazionale Farmacisti, 2003).
Parametric tests have been preferred for the statistical analyses of sperm concentration, motility, and morphology, because nonparametric tests allocate the data in numbers of ranks that cause individual differences to go unnoticed and homogenize the treatment differences. A fundamental requirement of parametric tests is the equality of the standard deviations of the data series. Randomized block, paired data tests analyze the individual as a potential origin of variation. Significant differences were found in the course of active drugs and placebo administration. This means that there are individual responses to placebo and active drugs, corroborating on the one hand the knowledge that spontaneous variations in sperm patterns can occur (Lenzi et al, 2003) and, on the other hand, the hypothesis that idiopathic OAT might be a mosaic of infertilities (Bonanomi et al, 2002; Foresta et al, 2002). As a consequence, standard deviations of natural data of sperm concentration increased proportionally by their mean, and logarithmic transformation of the data was indicated. Motility and morphology natural data are percentages; their standard deviations tend toward zero for the extreme values (0% or 100%) and increase for the central values (50%): extreme low values of standard deviation were found in untreated patients, and more central values were found in the course of drug treatments. This means that angular transformation is appropriate. The Kolgorov-Smirnov and the Shapiro-Wilk tests indicated a nonnormal distribution of the natural data, but when these tests were applied to transformed data, they indicated a Gaussian distribution (Snedecor and Cochran, 1987).
Carnitine dosage was chosen according to previous literature. Lenzi et al (2003) used L-carnitine 1 x 2 g/d; Vicari and Calogero (2001) used acetyl-L-carnitine (1 g/d) + L-carnitine (1 x 2 g/d). Previous preparatory tests indicated that acetyl-L-carnitine/L-carnitine proved significantly more effective than L-carnitine alone and as effective as Cinnoxicam alone. Initially, we considered using oral and injected NSAID, but their affect on sperm count has proved lower than suppositories. No specific research on delivery has been conducted, but a more direct effect of suppositories on seminal plasma might be presumed because of rectal-prostatic lymphatic pathways (Gattuccio et al, 2000). To date, 4 NSAIDs are available in Italy as suppositories (diclofenac, nimesulide, piroxicam, and cinnoxicam). In previous tests, cinnoxicam was significantly more active than the other 3 in increasing sperm count, probably because it is lipophylic, which facilitates absorption (Berti et al, 1992; Bertè and Richelmi, 1998).
The cinnoxicam dosage was chosen from several possibilities (2 suppositories per day to 1 per week), and 1 every 4 days was the dosage that increased sperm count the most. Confirming this kind of "spot therapy," an experimental model showed that chronic treatment with NSAIDs at low doses improved sperm quality and fertility (Loescher et al, 1988), whereas in vitro experiments showed that a high cinnoxicam concentration inhibits sperm motility (Mangano et al, 2000).
Increased reactive oxygen species (ROS), subsequent lysosomal permeabilization, and apoptosis have been implicated as the final common pathway of most OAT cases. Increased ROS were found in tubular and seminal plasma of idiopathic OAT, OAT associated with varicocele, and male accessory gland inflammation. Increased ROS provoked membrane lipoperoxidation, leading to motility and morphology alterations and even to cell death (Sale and Agarwal, 2002). Spermatids and mature spermatozoa are deemed highly sensitive to ROS because their membranes are particularly rich in polyunsaturated lipids. Superoxide dismutase, catalase, glutathione-dependent peroxidase activity, reduced glutathione (GSH), tocopherol, and ascorbic acid concentrations were the highest of all the human fluids found in tubular and seminal plasma. A preventive measure against high ROS has been advised for tubuloseminal plasma for male gametes (Sale and Agarwal, 2002). A return to physiological ROS concentrations in the course of carnitine administration is associated with an improvement in sperm patterns in varicoceles (Gattuccio et al, 2000), idiopathic OATs (Lenzi et al, 2003), and postinflammatory OATs (Vicari and Calogero, 2001). Therefore, carnitines have been reputed as anti-ROS drugs (Gattuccio et al, 2000; Vicari and Calogero, 2001; Lenzi et al, 2003).
In humans and experimental models, carnitines have several activities that might be useful for the male gamete. Free radical production is reduced by depleting fatty acid peroxidation; carnitines restore the phospholipid composition of mitochondrial membranes; carnitines enhance cellular energetics in mitochondria, increasing cytoplasmic acetyl-coenzyme A concentration through the higher availability of acetyl groups, resulting in an increase of mitochondrial respiration and monoamine-oxidase activity and thus increasing the metabolism of histamine; and carnitines stabilize cell membrane fluidity by regulating phospholipid levels and reducing ceramide production and insulinlike growth factor 1. Carnitines prevent cellular death and apoptosis. Carnitines display most of their activity in the tubular microenvironment, rather than in epididymal functions (Gattuccio et al, 2000; Vicari and Calogero, 2001; Lenzi et al, 2003).
Carnitine administration increases E2 prostaglandin concentration (Vicari and Calogero, 2001), which affects sperm count (Ito et al, 1982; Fuse et al, 1984; Bendvold et al, 1987). Mast cell count increased in bioptic testicle specimens from idiopathic infertile males (Apa et al, 2002), and long-term administration of tranilast (a mastcell blocker) enhanced semen parameters in OAT patients (Hibi et al, 2002). NSAIDs might improve sperm count: polyzoospermia and OAT are associated with lowered and increased prostaglandin content of tubuloseminal plasma, respectively. In addition, NSAIDs stabilize lysosomal membranes, thereby partially preventing apoptosis (Ito et al, 1982; Fuse et al, 1984; Bendvold et al, 1987). These findings could explain cinnoxicam's complementary mechanism when it is administered in association with carnitines.
Conventional anti-ROS drugs (vitamin E, ascorbic acid, GSH, and essential fatty acids) failed to enhance sperm patterns in prospective controlled trials (Rolf et al, 1999; Comhaire et al, 2000; Bolle et al, 2002; Wong et al, 2002). Carnitines display a number of activities, and they restore the physiological concentration of ROS by acting on the Krebs cycle (Gattuccio et al, 2000; Vicari and Calogero, 2001; Lenzi et al, 2003). Conventional antioxidant drugs interact directly with the substrate (ROS) and decrease ROS regardless of their concentration (Comhaire et al, 2000; Bolle et al, 2002; Rolf et al, 2002). Whether this peculiar activity on ROS concentration is the only explanation of the different activities of carnitines and conventional anti-ROS drugs is only speculative. Either way, an increased ROS concentration is detrimental for male gametes, but a low ROS concentration down-regulates the capacitation and acrosomal reaction of male gametes (Bart Fauser, 2003).
In this study, pregnancy rates per couple month were 0.3% in group 1, 3.6% in group 2, and 6.3% in group 3. Group 1 and group 2 pregnancy rates per couple month fit with previous reports. The spontaneous pregnancy rate per couple month of placebo-treated patients in the prospective trials for idiopathic OAT ranges from 0% to 1.4% in the presence of an apparently fertile female partner (WHO, 1989, 1992; Rege et al, 1997; Kamischke et al, 1998; Rolf et al, 1999; Adamapoulos et al, 2003; Lenzi et al, 2003; Zawackzi et al, 2003). Pregnancy rate in couples waiting for assisted reproduction techniques (ART) because of male OAT was 0.13% per month (Matorras et al, 1996). Mean couple infertility duration ranged from 14 to 18 months in these studies. These rates were lower than the overall pregnancy rates of the couples waiting for ART (Bart Fauser, 2003). Male OAT decreases the monthly chance of conception in a dose-dependent manner, adding its effect to the duration of infertility (Jansen, 1993). As confirmation, an increase of sperm concentrations in OAT-infertile males has been associated with disproportionately higher fecundity (Adamapoulos et al, 2003). The studies of carnitines and male OAT used acetyl-L-carnitine or L-carnitine separately: only Vicari and Calogero (2001) used the association L-carnitine/actetylL-carnitine and obtained a 3.9% pregnancy rate per couple month.
Despite the size and duration of this trial, the population of patients with idiopathic dyspermia or with dyspermia associated with low-grade varicoceles is much larger: patients with sperm concentration lower than 5 000 000/mL or patients with isolated defects of motility or of morphology who have normal concentration have been excluded form this study because pretrial tests indicated that our therapy proved ineffective in them. Consequently, the results of this study cannot be extrapolated to all patients seen in general practice for dyspermia and infertility. A survey of the data of Adamapoulos et al (2003) and Wong et al (2002) indicated that their trials predominately treated patients with isolated alterations of motility, morphology, or both who have normal concentrations of sperm. Therefore, it might be interesting to look for a comparison of or an association between the different therapies.
This paper has addressed subclinical varicoceles, whose therapy is
controversial (Jarow, 2001)
and which cannot be extrapolated to the whole population of OAT associated
with varicoceles. Even though some authors still do not consider varicocele
surgical repair a treatment for male infertility
(Evers and Collins, 2003), there is agreement about the favorable effects of large varicocele repair,
which persists over time and could be easily performed as outpatient surgery
(Gattuccio et al, 2000;
Jarow, 2001; Cavallini et al, 2003). With
the continued presence of varicoceles, there is ongoing damage of seminiferous
tubules, which can be repaired by surgery
(Greenfield et al, 2002). It
is unknown whether it can be influenced by medical therapy. Atrophic
testicular volume has been shown to increase after surgery for high-grade
varicoceles (Gattuccio et al,
2000), and it has been regarded as a proof of increased
spermatogenesis. The volume of atrophic testicles with grade IV and V
varicoceles did not change significantly in the course of drug administration,
even though in grade IV/group 3 varicoceles with atrophic testicles the sperm
count increased, but to a lower extent than in lower varicocele grades. The
average cost for each naturally induced pregnancy in varicocele patients was
2133.60 and 1086.40 in idiopathic OATs. An overview of our data
indicated that the difference is due to the poor activity of the drugs in
high-grade (grades IV and V) varicoceles.
Sixty-four group 3 patients reached the WHO normal range of sperm analysis in the course of therapy, but only 41 conceived naturally. Because semen quality is positively related to ART outcomes (Bart Fauser, 2003), it should be interesting to assess the role of L-carnitine/acetyl-L-carnitine + cinnoxicam in those couples in which semen quality improved but who did not conceive naturally and ARTs were performed.
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