Anabolic-androgenic steroid effects on early morbid symptoms after open prostatectomy: A pilot study

Abstract

Objectives. Anabolic-androgenic steroids such as Nandrolone phenpropionate (NP) dramatically improve the tolerance to acute stress conditions, strength, and subsequently the quality of life in elderly men. We hypothesize that preoperative pulse-dose supraphysiological NP administration might improve the early morbid symptoms in older patients undergoing open prostatectomy.

Methods. From 2005 to 2006, 54 patients with a mean age of 70 years, diagnosed as benign prostatic hyperplasia and hospitalized for open prostatectomy were enrolled in the study. They were randomly selected to receive preoperative supraphysiological NP (100 mg, intramuscularly, pulse-dose) or sesame oil placebo, prospectively. Early postoperative morbid symptoms including subjective urinary symptoms (dysuria, bladder retention sensation), incision site pain and general satisfaction of their current urinary condition were assessed by a 6-point scale, self-administrated questionnaire at 24 and 48 h, postoperatively. The sex hormone binding globulin and the testosterone levels were also measured.

Results. The 24-h postoperative symptoms were significantly reduced in the NP group compared to the placebo (6.18 ± 2.81 versus 9.77 ± 2.15; P < 0.001). The postoperative symptoms were reported to have a decline in the 48 h following operation, though was calculated to be statistically insignificant (4.48 ± 2.32 versus 5.55 ± 1.84; P = 0.06). There was no complication attributed to NP therapy.

Conclusions. The data supported the hypothesis that the preoperative anabolic steroid supplements (such as NP) could result in a better postoperative endurance in elderly men undergoing open prostatectomy. Further studies, longer and repeated pulse injections in a larger number of older men are mandatory to prove the claim.

Keywords:

• Elderly men
• BPH
• open prostatectomy
• postoperative morbid symptoms
• anabolic-androgenic steroid

Introduction

Benign prostatic hyperplasia (BPH) is a common disease with an estimated prevalence of 25–50% in men of 40 to 79 years old; it is reported in more than 90% of men aged 80 years and more [1-3]. Open prostatectomy is a common therapeutic modality for patients suffering from BPH, particularly those with large glands; however, several minimally invasive techniques have also been developed [4-6]. Bladder outlet obstruction symptoms, commonly seen in such patients, are often accompanied with several problems, and affect the patients' quality of life subsequently [3-7].

A gradual and progressive decline in serum testosterone levels is stated in men due to aging; approximately 20% of men in their 60s and 50% of those aged 80 and more are reported to have low total testosterone levels [8]. Furthermore, several studies have demonstrated the impact of long-term use of certain medications (e.g. glucocorticoides, opiates, alcohol), chronic medical illnesses (e.g., renal failure, malignancy), and acute stress conditions (e.g. trauma, surgery) on decrement of the serum testosterone level in elderly men [9,10].

It is believed that elderly males with serum testosterone levels lower than the normal value have a poor performance in their daily activity. Generalized chronic body pain, lower pain threshold, loss of sense of well-being, decreased muscular mass, decreased strength, increased fat mass, mood disorders and sexual dysfunction are other frequent complaints of this group of patients [10-16].

Testosterone supplementation has been shown to improve rehabilitation outcomes in older men with low-normal serum testosterone levels during an inpatient rehabilitation stay [17]. Furthermore, it has recently been revealed that supraphysiological administration of testosterone improves the postoperative physical function and shortens the hospitalization period in elderly men undergoing major surgeries [18].

Short-term and medically adjusted doses of anabolic-androgenic steroids (AASs) are not reported to be accompanied with any major side effects [11],[19,20]. Nandrolone phenpropionate (NP), with the dose of 25–100 mg, is a short acting AAS. Its physiological effects occur after 12 h, and resolve within 24–36 h of injection (half life: 12–24 hours) [21,22].

The major indication of prostatectomy in BPH patients is to improve the quality of life [5,6]. Since the administration of testosterone dramatically improves the tolerance to acute stress conditions, strength, and subsequently the quality of life, we hypothesized that the administration of supraphysiological AASs might improve the immediate postoperative symptoms including the incision site pain, the subjective feeling of bladder retention (bladder fullness), dysuria and the general satisfaction level of the urinary symptoms. Therefore, we conducted a double-blind, placebo-controlled trial; in this study pulse-dose supraphysiological NP was administered in older men undergoing open prostatectomy and then the early postoperative morbid symptoms were compared with those who had received placebo.

Methods

Patients

Fifty-four open prostatectomy candidates, with a mean age of 70 years (range: 51–87) were screened and enrolled in our study. The study included patients older than 50 years who were candidates for open prostatectomy and willing to comply the study. All of them had been diagnosed to have BPH based on a standard international prostate symptom score (IPSS) questionnaire and an expert urologist decision (unaware of the study objectives). A complete history was taken from the subjects and they all underwent a thorough physical examination. The exclusion criteria included documented cancer of the prostate or any other organs, severe liver or kidney disease, severe psychiatric disorders, metabolic diseases such as diabetes mellitus, substance abuse, positive history of AASs use, long-term use of any drug known to interfere with the pharmacodynamics of AASs such as Nandrolone, advanced spinal cord lesion, or any other morbid and debilitating diseases (whether correlated with the genitourinary system or not).

Experimental design

The study was performed in the Urology Research Centre of Sina Hospital as a prospective, double-blinded, placebo-controlled clinical trial from March 2005 to March 2006. After obtaining the written informed consent, the 54 patients who met the inclusion criteria were allocated into two study groups, using a balanced blocked random number list. Patients in the treatment group (n = 27) received 100 mg NP (Iran Hormone, Tehran, Iran) intramuscularly 1 h before the surgery. The placebo group patients (n = 27) received 3 ml of sterile sesame oil, indistinguishable in appearance, at the same time the treatment group received the drug. An experienced nurse, unaware of the study objectives and the content of the syringes performed the injections. All subjects underwent suprapubic prostatectomy by the same surgery team, using the same anaesthetic procedure (spinal anaesthesia). Following open prostatectomy, a 3-way Foley catheter 24 (Wrap, Japan) was used in all patients; the catheter was removed 5–7 days post-operation. Cystostomy was removed 7–10 days after surgery. All patients received Ceftriaxone (1 g twice a day) plus Amikacin (500 mg twice a day) during the first 48 h post-prostatectomy; the regimen was then changed to Cefixime (400 mg daily) and continued for the next 5 days. Bladder irrigation was performed following surgery in the operating theatre and continued for 2 days. After the operation, they were all recovered in the general urology unit by the same urologic and nursing staff. All patients were mobilized the day after surgery. The study was performed in accordance with the Declaration of Helsinki and subsequent revisions, and was approved by the Research, Investigation and Ethics Committee of Sina Hospital and the Human Research Supervision Board of Tehran University of Medical Sciences.

Measurements

An investigator blind to the study procedures asked the patients to rate their dysuria, incisional site pain, urinary retention sensation and general satisfaction of their current urinary condition according to a 6-point visual scale. The highest scores were considered as discomfort, pain, fullness sensation and dissatisfaction, respectively. The scores were recorded 24 and 48 h after the operation. The maximum score was 20 (the worst condition) and the minimum was 0 (No complaints at all). The questionnaire was compiled by a group of urologists in the Urology Research Centre and approved by the Urology Board and Ethics Committee of Tehran University of Medical Sciences and Iranian Urological Association (IUA).

The patients' pain level was estimated subjectively (No pain = 0, Very mild pain = 1, Mild pain = 2, Moderate pain = 3, Severe pain = 4, and Awful pain = 5). No pain treatment was used when patients declared no, very mild or mild pain. In moderate pain, the well-trained nurses had the authority to use non-steroidal anti-inflammatory drugs (NSAIDs) (100 mg suppository Diclofenac sodium). In cases of severe pain, Tramadol (IV stat) was prescribed. If the patients complained of awful pain, they were examined by a surgeon and an expert nurse and suitable treatment was prescribed according to the patients' condition.

In each visit the patients underwent a complete physical examination and the vital signs were checked. In cases of dysuria, Phenazopyridine (100 mg per 8 h) was prescribed. In addition to routine laboratory tests (such as complete blood count with differentials, serum urea, creatinine, liver function tests, urinalysis and urine culture), prostate specific antigen (PSA, normal range: < 4 ng/ml), sex hormone binding globulin (SHBG) (normal range: 14.5–48.5 mmol/L) and serum total testosterone level (normal range: 225–800 mg/dl) were checked preoperatively in all patients. Serum total testosterone and SHBG were measured using electrochemiluminescence (Roche, Basel, Switzerland). The prostate volume was also estimated at the baseline using ultrasonography.

Statistical analysis

The analysis was performed using Statistical Package for Social Sciences (SPSS Inc., Chicago, IL). The results were compared in both groups using a non-parametric two-sample rank-sum test (Mann-Whitney) and a student t test. For all comparisons an α of 0.05 was considered significant.

Results

A total number of 54 patients entered the study, all of which completed the research. They were randomized to receive either AAS prior to the operation (NP group, n = 27) or placebo (placebo group, n = 27). Two patients in the placebo group needed blood transfusion. No perioperative mortality was reported. There were no significant differences in demographic and baseline characteristics of NP and placebo group (Table I). The IPSS questionnaire also indicated no significant differences in preoperative symptoms and the severity of BPH in the two studied groups (Table I).

Table I.  Baseline characteristics of the studied patients

Characteristic	NP^† group (n = 27)	Placebo group (n = 27)	P-value
Age (yrs)	70 ± 8.3	69 ± 7.7	0.91
Prostate volume (cm^3)	54.2 ± 17.6	58.7 ± 22.1	0.77
Serum prostate specific antigen (ng/ml)	5.2 ± 3.8	5.5 ± 5.4	0.82
Serum total testosterone (ng/dl)	491 ± 186.9	463 ± 141.6	0.96
Serum SHBG*(mmol/l)	31 ± 16.1	35.2 ± 9.2	0.24
IPSS^‡	17.04 ± 5.71	17.48 ± 6.28	0.78

Values are mean ± standard deviation (SD).

*SHBG, sex hormone binding globulin; ^†NP, nandrolone phenpropionate; ^‡IPSS, international prostate symptom score.

Compared with those who received placebo, the subjects in the NP group were more satisfied with their urinary condition in the first 24 hours following operation (mean score ± standard deviation = 1.67 ± 0.48 versus 2.48 ± 0.63; P < 0.001). This was also true for other variables including the incisional site pain (0.89 ± 0.89 versus 1.85 ± 0.9; P < 0.001), the urinary retention sensation (1.89 ± 1.01 versus 2.70 ± 0.86; P = 0.003) and dysuria (1.74 ± 0.90 versus 2.74 ± 0.71; P < 0.001) (Table II).

Table II.  Outcome of the studied patients based on their groups

Time	Outcome	NP^† group (n = 27)	Placebo group (n = 27)	P-value
First 24 h	If you were to spend the rest of your life with the current urinary condition, how would you feel?	1.67 ± 0.48	2.48 ± 0.63	<0.001
	How would you describe the pain of your incision site?	0.89 ± 0.89	1.85 ± 0.90	<0.001
	How would you describe your sensation of not emptying your bladder completely?	1.89 ± 1.01	2.7 ± 0.86	0.003
	How would you describe your burning sensation during urinating (dysuria)?	1.74 ± 0.90	2.74 ± 0.71	<0.001
Total score, mean ranks ± SD		6.18 ± 2.81	9.77 ± 2.15	<0.001
Second 24 h	If you were to spend the rest of your life with the current urinary condition, how would you feel?	1.41 ± 0.88	1.59 ± 0.74	0.41
	How would you describe the pain of your incision site?	0.37 ± 0.30	0.70 ± 0.70	0.07
	How would you describe your sensation of not emptying your bladder completely?	1.37 ± 0.92	1.63 ± 0.74	0.26
	How would you describe your burning sensation during urinating (dysuria)?	1.33 ± 1.10	1.63 ± 0.56	0.22
Total score, mean ranks ± SD		4.48 ± 2.32	5.55 ± 1.84	0.06

Values are mean ranks ± standard deviation (SD).

^†NP, nandrolone phenpropionate.

This statistically significant difference was not reported between NP and placebo groups, 48 h postoperatively (4.48 ± 2.32 versus 5.55 ± 1.84; P = 0.06).

The differences between the 24-h and the 48-h scale scores in NP (6.18 versus 4.48) and placebo group (9.77 versus 5.55) demonstrated a trend towards recovery in both groups. This rehabilitation was accompanied by lower morbid symptoms in the NP group compared with the placebo patients.

None of the subjects in the placebo group were reported to have a lower score in any of the variables compared to those in the NP group.

Discussion

To our knowledge, this is the first study to evaluate the impact of supraphysiological AAS on early morbid symptoms following open prostatectomy in elderly men with BPH. The results of our study demonstrated that the preoperative administration of supraphysiological AAS (NP) in elderly men undergoing open prostatectomy improves the immediate postoperative morbid symptoms. It is likely that the observed improvements were due to the anabolic effects of NP in enhancing the functional status; however, a beneficial effect of AASs on the perception of physical pain and the tolerance of acute physical stress, or mood might also be important [10-12].

Various effects of sex steroids and anabolic androgens on the patients' physical and psychological performance have been observed in several studies with controversial results. These observations have been directed towards body strength, functional performance, sexual functioning, libido, erectile function, mood, memory, exercise-induced coronary ischaemia, angina pectoralis, bone mineral density, self-perceived functional status, wound healing and quality of life [10-12],[17,18],[23-30]. For instance, Sih et al. in 1997 conducted a trial on 32 hypogonadal patients and administrated testosterone versus placebo. The testosterone group ended up in having a better muscle strength; however, no significant changes were observed in memory and PSA levels [23]. A similar study was performed by Schiavi and associates in 1997; they showed that androgen administration may activate sexual behaviours in their patients, while its effect on mood, memory and sexual satisfaction has not been promising [24]. Bakhshi et al. reported that exogenous testosterone administration improved sense of well-being and mood and also decreased anxiety [17]. These findings could subsequently indicate the decreased burning sensation observed in our patients.

Janowsky and colleagues in 2000 suggested that sex steroids could modulate working memory in men and act as modulators of cognition [25]. It has also been shown that even one dosage of supraphysiological AAS injection could cause euphoria in patients, which makes them feel less pain and also develops a proportional tolerance towards the new circumstances in the early post-operative phase, which is in line with our observation [12],[26,27].

In a 2-year prospective trial performed by Nair et al. in 2006, bone mineral density was shown to be improved due to the administration of Dehydroepiandrosterone (DHEA) and testosterone in men and women respectively. Although neither DHEA nor low-dose testosterone replacement in elderly people are proved to have physiologically relevant beneficial effects on body composition, physical performance, insulin sensitivity, or quality of life [28], nevertheless, Brill et al. have concluded that short-term testosterone administration improves certain measures of balance, physical performance and quality of life in elderly men [11]. Amory and associates have also emphasized the beneficial recovery outcome in postoperative phase following the short-term administration of testosterone in 25 patients who underwent knee replacement surgery [18].

Consistent with our study, Demling and Orgill reported that the use of a testosterone analogue, oxandrolone improves wound healing and subsequently incisional site pain without resulting in any significant side effects [29]. However, it has been reported that endogenous testosterone inhibits wound healing response in males and is associated with an enhanced inflammatory response [30].

The early postoperative conditions including dysuria, incisional site pain, bladder fullness sensation and general satisfaction of urinary system condition were significantly better in patients receiving NP compared with those receiving placebo; however, other variables should also be applied in order to evaluate the quality of life, completely.

These preliminary results deduced that the remarkable differences between 24 and 48-hour scale scores were attributed to NP's biological characteristics. As stated before, the initial physiological effect of NP begins after 12 h and is completed within 24–36 h of injection (half life: 12–24 h); this status endorsed our claim. Furthermore, no major complications were reported in our patients, neither shortly after the surgery nor in late follow-ups, which is compatible with other clinical trials [11],[28].

An additional benefit of preoperative androgen might be a decreased need for blood transfusions; androgen induces the erythropoietin production and results in an increased haematocrit prior to operation. A long-term androgen administration might even have more beneficial effects [10].

The decrease of rehabilitation period in the BPH patients undergoing open prostatectomy could be attributed to a faster ambulation after surgery; this was also important in reducing the risk of thrombotic complications [5-7].

In addition, as the focus of the present study was only on the immediate postoperative symptoms, the encouraging results warrant trials with a larger number of patients, longer preoperative drug administration, and longer follow-ups.

A larger study is also required to observe the effects on other perioperative parameters (such as transfusion rate). On the other hand, due to the trial limitations, we could not perform the regression analysis in order to identify the possible confounders. Even though the subjects were allocated randomly, the differences between the two groups could not be ruled out. The small sample size, the use of subjective questionnaire and short-term follow-up might also be considered as other limitations of this study.

In conclusion, open prostatectomy has improved quality of life in many older patients. The surgery is generally safe but there is a need for techniques to improve outcomes and speed recovery in older patients who undergo this procedure. Our pilot study showed that the pulse-dose AASs (such as NP) administered prior to open prostatectomy in elderly men can potentially improve the patients' tolerance and their quality of life within the first 24 hours.

Acknowledgements

The authors would like to thank the nursing, secretarial and administrative staff of the Urology Research Centre, Sina Hospital, especially Mrs L. Shekarpour for her excellent cooperation in the study, and also Dr P. Khashayar and Ms M. Tayebi for her helpful assistance in preparation of the manuscript.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.