Prostatitis syndrome is a frequent condition in men. It is not known in most patients if the prostate is the only organ involved. Therefore, the disease is characterized as chronic prostatitis–chronic pelvic pain syndrome (CP-CPPS). Although many studies have been performed in patients with CP-CPPS, current trial evidence is conflicting and therapeutic options are controversial. Given the need for long-term treatment in CP-CPPS patients, phytotherapeutics, such as pollen extract, are an option due to few side effects. Preclinical studies on pollen extract have shown effects on smooth muscles of the bladder and urethra, strong antiinflammatory effects, and antiproliferative effects.
The prostatitis syndrome is mainly characterized by genitourinary pain. Additional symptoms, such as lower urinary tract symptoms, psychosocial symptoms, neurologic symptoms, and sexual dysfunction, might be present in up to 65%. The prevalence of symptoms suggestive of prostatitis in the population ranges between 2.2% and 13.8% according to different studies. The classification of the prostatitis syndrome is best performed by the National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health (NIH) and is classically based on the clinical presentation of a patient, the presence or absence of white blood cells in the expressed prostatic secretion, and the presence or absence of bacteria in the expressed prostatic secretion. Chronic prostatitis–chronic pelvic pain syndrome (CP-CPPS) is the most frequent symptomatic subtype with a heterogenous and mainly unknown etiology. In the NIH classification, bacterial prostatitis (acute and chronic) is distinguished from inflammatory and noninflammatory CP-CPPS. Prostatitis is described as chronic when symptoms are present for at least 3 months. Recently, this classification was clinically amended by a phenotype directed description of patients’ symptoms and findings taking into account the various clinical presentations.
Etiologically, CP-CPPS may, at least in some patients, be defined by an initial injury to the genitourinary tract (such as infection, trauma, or dysfunctional voiding, in particular in the prostate) causing inflammation and/or neurogenic damage to the prostate, the muscles, fasciae, tendons, and/or nerves of the pelvis and/or perineum in anatomically or genetically predisposed men. This series of events may eventually result in both peripheral and central nervous system sensitization, with pain the common endpoint.
Evidence-based treatment of CP-CPPS has been difficult due to the heterogenous patient population associated with this syndrome. Although singular studies provide conflicting results, as in studies of α-blocker therapy, meta-analysis data show measurable effects for α-blocker and antiinflammatory therapies. Publication biases in those studies are often due to the common inclusion and exclusion criteria, which frequently did not stratify into phenotypic characteristics that might be targets for the studied agents. Modern therapeutic approaches incorporate considerations of the phenotypic patterns mirroring the possible cause.
Phytotherapeutic agents, such as pollen extract, quercetin, or saw palmetto, are widely used with variable success described in qualitatively heterogenous studies. The best evidence is currently available for pollen extract. Pollen extract, an herbal medicinal product, has been used for more than 40 years in the treatment of CP-CPPS as well as for benign prostatic hyperplasia. Pollen extract preparations are merchandised under several product names (Cernilton, Prostat/Poltit, and Pollstimol). Most preclinical studies have been conducted under the preparation name, Cernilton. Data from these studies are discussed in this article. Pollen extract is produced from machine-harvested pollen material from the species, Secale cereale L., Phleum pratense L., and Zea mays L. The proportions of mixture of the 3 species have been constant—30:1.5:1.
Pollen extract is a mixture of natural components, such as amino acids, carbohydrates, lipids, vitamins, and minerals. Phytosterols and secalosides are also believed important constituents in the extract. This highly complex total extract comprises 63 mg of the defined pollen extract fractions constituting 2 main components, the hydrophilic Cernitin T60 fraction and the hydrophobic Cernitin GBX fraction, both of which are devoid of allergenic properties. Inactive ingredients of pollen extract preparations are microcrystalline cellulose, silica, and magnesium stearate.
Pharmacology
The pharmacology of the total pollen extract and of the 2 pollen extract fractions, Cernitin T60 and Cernitin GBX, primarily, has been studied in different animal models using various modes of administration (oral, gastric intubation, and intraduodenal) and in different species, including mice, rats, and dogs, as well as isolated tissues and cells from different species. These studies revealed spasmogenic and/or spasmolytic effects, antiinflammatory effects, and antiproliferative effects of Cernitin T60 and Cernitin GBX.
Pharmacodynamics
Effects on smooth muscles
At concentrations of 10 −4 g/mL and higher, Cernitin GBX slightly enhanced the spontaneous movements in the smooth muscles of the intestine and uterus. A spastic action was not observed. In contrast, spasmogenic effects were observed with Cernitin T60. At a concentration of 10 −5 g/mL, Cernitin T60 led to a slight increase in spasms in the intestine and uterus, whereas at concentrations of 10 −4 g/mL and higher, there was a definite spastic action.
A synergistic inhibitory effect of Cernitin T60 and Cernitin GBX on noradrenaline-induced contraction of isolated rat urethral muscle was shown by Nakase and colleagues It has been suggested that Cernitin T60 acts on the α-adrenergic receptors whereas Cernitin GBX relaxes the external sphincter and Cernitin extract may relax both the internal and external sphincter muscle.
The total pollen extract contracted isolated detrusor muscles of rats, guinea pigs, and cats in a concentration-dependent manner. Increase of intravesical pressure was reduced completely by atropine and partly by phentolamine and guanethidine. This suggested that Cernitin total extract contracted the detrusor muscle via muscarinic receptor activation causing an increase of the intravesical pressure. Consecutive administration of Cernitin total extract increased the maximum pressure during urination to promote the urination reflex.
The clinical importance of these findings is uncertain, however, because the effects have been observed at relatively high concentrations in vitro.
Antiinflammatory effects
The inhibition of prostaglandin and leukotriene synthesis of pollen extracts has been studied in vitro. Cernitin T60 and Cernitin GBX were tested separately. The inhibition of 5-lipoxygenase activity (leukotriene biosynthesis) by Cernitin GBX was comparable to that of diclofenac and indomethacin, whereas the inhibition of the cyclooxygenase (prostaglandin biosynthesis) was comparable to that of diclofenac and approximately 10 times higher than that of aspirin. Cernitin T60 showed no effect in the test system used.
In an estradiol-17β –induced rat model of nonbacterial prostatitis, an approximately 2-fold to 3-fold increase of prostatic interleukin 6 and tumor necrosis factor α content and an acinar glandular inflammation and stromal proliferation were found in histologic examinations when compared with those of control rats. Pollen extract significantly decreased the increased interleukin 6 and tumor necrosis factor α values in a dose-dependent manner. The histopathologic changes were restored in rats treated with pollen extract as well as in rats treated with testosterone. These findings indicated that pollen extract might have an antiinflammatory effect within the prostate due to an inhibitory effect on the prostatic cytokine content. Further studies have shown that it is mainly Cernitin GBX, which protects the acinar epithelial cells, whereas Cernitin T60 inhibits stromal cell proliferation in association with enhanced apoptosis. In general, the antiinflammatory effect is most likely due to the inhibition of prostaglandin synthesis and prostatic cytokine content related mainly to the Cernitin GBX fraction, which has been shown to have about the same potency as established antiinflammatory agents, such as indomethacine and diclofenac in vitro.
Antiproliferative effects
Varying concentrations of Cernitin GBX were found to inhibit 5α-reductase activity in the epithelium and stroma of the prostate in vitro, inhibiting the formation of dihydrotestosterone from testosterone. Animal studies also found a possible effect on the prostate via the androgen metabolism.
Cernitin T60, furthermore, is a powerful mitogenic inhibitor of fibroblastic and epithelial proliferation. Although the exact mechanism is not understood, not only is there evidence that these responses are mediated via the androgenic pathways but also experimental data in nonbacterial prostatitis in rats showed that Cernitin GBX protects mainly acinar epithelial cells and inhibits stromal proliferation in association with an enhanced apoptosis mediated by Cernitin T-60. The cellular and molecular biology research on growth factors and receptor action indicates that Cernitin T60 and Cernitin GBX affect prostate growth, both with and without growth stimulation.
Pharmacokinetics
Pharmacokinetic studies on the absorption, distribution, metabolism, or excretion of the water-soluble fraction Cernitin T-60 or the lipid-soluble fraction Cernitin GBX have not been performed because it is not known which compounds are primarily responsible for clinical efficacy.
Clinical studies
In a cohort of 583 men with chronic prostatitis symptoms or benign prostatic hyperplasia accompanied by chronic prostatitis findings (eg, leukocytes in expressed prostatic secretions higher than 10 per high power field), the number of leukocytes was evaluated before and after a 12-week treatment with pollen extract (Cernilton). The number of leukocytes in expressed prostatic secretions improved to 59% in those patients. These initial findings on the antiinflammatory action of pollen extract led to further evaluate pollen extract in clinical studies investigating its effect on the symptoms of CP-CPPS patients.
Eight clinical studies since then have been performed in patients with CP-CPPS to evaluate the effect of pollen extract on symptoms. Two studies were performed in a randomized placebo-controlled design in 139 patients and 58 patients. In 6 noncomparative clinical studies, 90, 15, 24, 32, 25, and 106 patients with CP-CPPS were treated. Altogether 392 patients were treated in available studies with pollen extract preparations ( Table 1 ).
| Product Name | Study Type | Dosage | Duration | Patients (n) in Study | Patients (n) Treated with Pollen Extract | Clinical Response a | Refs. |
|---|---|---|---|---|---|---|---|
| Cernilton | Randomized controlled trial | 2 tid | 12 (24) Weeks b | 139 | 70 | 69% Pollen extract versus 49% placebo ( P = .015) >25% Improvement NIH-CPSI or 6-point decrease of NIH-CPSI a | |
| Prostat/Poltit | Randomized controlled trial | NI | 6 Months | 58 | 30 | 73% Pollen extract versus 36% placebo ( P <.05) Global subjective assessment a | |
| Cernilton N | Cohort study | 1 tid | 6 Months | 90 | 90 | 63% Global objective assessment a | |
| Cernilton | Cohort study | 2 bid | 1 to 8 Months | 15 | 15 | 87% Global subjective assessment a | |
| Cernilton | Cohort study | 3 tid | 4 to 6 Weeks | 24 | 24 | 63% >50% improvement NIH-CPSI a | |
| Cernilton | Cohort study | 2 tid | 12 Weeks | 32 | 32 | 66% Global objective assessment a | |
| Cernilton | Cohort study | 2 tid | 8 Weeks | 25 | 25 | 76% Global objective assessment a | |
| Prostat/Poltit | Cohort study | NI | 8 Weeks | 106 | 106 | NI |
a Responder criteria not uniform.
b Trial extension period 24 weeks, with all patients receiving pollen extract from week 12 on.
Randomized Placebo-Controlled Studies
The largest study, by Wagenlehner and colleagues, was a clinical phase 3 study in 34 German urological centers in 139 patients. Considering the predominantly antiinflammatory effect of pollen extract, this study was performed exclusively in patients with inflammatory CP-CPPS defined by the presence of 10 or more leukocytes in the voided bladder 3 (or post–prostatic massage urine). Patients were randomized to pollen extract or placebo for 12 weeks. In a subsequent open follow-up period of another 12 weeks, all patients received pollen extract. Patients were evaluated by Meares-Stamey 4-glass test and the NIH Chronic Prostatitis Symptom Index (NIH-CPSI) at baseline and after 12 and 24 weeks. Before starting study drugs, patients were pretreated with azithromycin for 1 day to eliminate atypical pathogens. After 1 week, inclusion criteria were rechecked, and patients were included in the treatment phase when both conditions, a pain domain of the NIH-CPSI greater than or equal to 7 and leukocytes greater than or equal to 10 in post-prostatic massage urine, were fulfilled. Patients were then allocated to receive either pollen extract or placebo in a randomized order.
The primary target of the study was symptomatic improvement in the pain domain of the NIH-CPSI. Secondary outcomes included symptomatic improvement of the NIH-CPSI total score and the micturition and quality of life domains of the NIH-CPSI questionnaire, responder assessment defined by improvement of NIH-CPSI summary score by greater than or equal to 25%, or improvement of NIH-CPSI summary score by at least 6 points as well as a decrease in the number of leukocytes in post-prostatic massage urine. Further explorative outcome criteria were changes in the International Prostate Symptom Score , the sexuality domain of a life satisfaction questionnaire, residual urine volume, and safety of the study drug. Only results of the intention-to-treat analysis are shown. After 12 weeks of treatment, the mean changes (±SE) from baseline in the pain domain of the NIH-CPSI were –4.50 ± 0.42 in the pollen extract group and –2.92 ± 0.42 in the placebo group ( P = .0086). The mean NIH-CPSI total score decreased form 19.18 to 11.72 in the pollen extract and from 20.31 to 14.94 in the placebo group ( P = .0126). Responder analysis showed a significantly greater percentage of patients in the pollen extract group who demonstrated 25% improvement or a 6-point decrease from baseline in the total score compared with the placebo group ( P = .0147 and P = .0256, respectively). The mean quality-of-life domain of the NIH-CPSI decreased from 6.44 to 4.26 in the pollen extract group and from 6.68 to 5.28 in the placebo group ( P = .0250). The mean changes from baseline in the number of leukocytes per field of vision were 5.0 in the pollen extract group and 3.0 in the placebo group ( P = .1243). The global assessment of the efficacy by the patient showed significantly higher rates of very good or good results in the pollen extract group (62.9%) compared with the placebo group (41.8%).
A total of 93 patients completed the follow-up period up to 24 weeks in which patients in the placebo arm crossed over to receive pollen extract. Thus 48 patients from the pollen extract arm continued to receive pollen extract up to week 24, and 45 patients in the placebo arm received pollen extract from weeks 12 to 24. The pain, quality-of-life domains, and the total NIH-CPSI score continued to improve at week 24 in both groups. The latter effects were more pronounced in patients with crossover from placebo to pollen extract from week 12 on. Urinary symptoms improved moderately, but not significantly, in both groups. Leukocytes in the post-prostatic massage urine improved significantly in both groups at week 12 and continued to improve at week 24 in both groups, with a more pronounced effect in the initial pollen extract arm. Adverse events were minor in all patients.
The conclusion of this study was that pollen extract compared with placebo significantly improved total symptoms, pain, and quality-of-life and reduced leukocytes in the post–massage urine in patients with inflammatory CP-CPPS without severe side effects up to 24 weeks. The beneficial effect continued to improve after 12 weeks’ treatment showing that pollen extract can be recommended for patients with inflammatory CP-CPPS for long-term treatment.
Randomized placebo-controlled study in patients with inflammatory or noninflammatory CP-CPPS
In a monocenter study by Elist, 58 patients with inflammatory or noninflammatory CP-CPPS were included. For inclusion in this study, no cutoff NIH-CPSI value was reported; case number calculations were also not reported. Patients were randomized to pollen extract or placebo for 6 months. Primary or secondary outcome variables were not discussed in the publication, but the analysis included data on pain and lower urinary tract symptoms, evaluated by a modified University of Washington symptom score, sexual dysfunction and an overall clinical response at baseline and after 24 weeks. Mean changes (±SE) from baseline in the pain symptom domain of the modified University of Washington symptom score were –6.70 ± 4.5 in the pollen extract group and –1.7 ± 3.2 in the placebo group, which were described as significant. Lower urinary tract symptoms also were reduced to a higher extent in the pollen extract arm compared with the placebo arm; sexual function was better in the pollen extract arm after 6 months’ treatment. The overall clinical response showed that 73% of patients were considered clinically improved or cured in the pollen extract arm, whereas in the placebo group only 36% of patients were considered improved. The investigators concluded that pollen extract administered for 6 months would ameliorate the symptoms associated with CP-CPPS effectively.
Nonrandomized studies in patients with CP-CPPS
In a study by Rugendorff and colleagues, 90 patients were prospectively treated with pollen extract (1 tablet 3 times a day for 6 months). Patients were assessed before and after 3 and 6 months’ treatment by physical examination, bacterial studies, leukocyte counts in urine, and measurement of complement C3/coeruloplasmin in the seminal fluid. For further analysis, the patients were divided into 2 groups: those without associated complicating factors (CFs) (n = 72) and those with CFs (ie, urethral strictures, prostatic calculi, and bladder neck sclerosis [n = 18]). In the group without CFs, 78% had a favorable response, 36% were cured, and 42% improved significantly. In the patients with CFs, only 1 patient showed a response. The investigators concluded that CFs should be considered in patients who fail to respond to treatment within 3 months.
In another open study by Buck and colleagues, 15 patients with CP-CPPS were treated with pollen extract (2 tablets twice a day for 1 to 18 months). In 13 patients there was either complete and lasting relief of symptoms or a marked improvement; 2 patients failed to respond. The investigators concluded that pollen extract was found effective in 87% of patients with CP-CPPS.
In a study by Monden and colleagues, 24 patients with CP-CPPS (16 patients with inflammatory CP-CPPS and 8 with noninflammatory CP-CPPS) were treated with pollen extract. Examination of changes in the NIH-CPSI scores revealed that scores of the items in all domains were significantly lower 4 to 6 weeks after the start of administration of Cernilton than those obtained before the drug administration in patients with CP-CPPS. In 62.5% of cases, the total NIH-CPSI score improved more than 50% compared with baseline. There was no difference between inflammatory and noninflammatory CP-CPPS patients.
A study by Li and colleagues was performed in 106 patients with CP-CPPS treated with pollen extract for 8 weeks and the mean NIH-CPSI score was significantly reduced from 24.1 at baseline to 12.2 at the end of treatment.
A study by Jodai and colleagues was another open study in 32 patients who received pollen extract for 12.6 weeks on the average. Improvement of subjective symptoms and objective findings was observed in 74.2% and 65.6% of the cases, respectively. The effective rate was reported to be 75.0%. No subjective symptoms or abnormal changes in laboratory data were observed in any case after pollen extract medication.
Another study was performed by Suzuki and colleagues in 25 patients with CP-CPPS treated with pollen extract for 8 weeks and longer. There was improvement of subjective symptoms and objective findings in 96.0% and 76.0%, respectively, of the cases. No side effects were observed.
In all studies, pollen extract was tolerated well by the patients over the extended periods of time.
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