Discovery of a pituitary adenoma following treatment with a gonadotropin-releasing hormone agonist in a patient with prostate cancer

We report the case of a T3 prostate cancer in a 70-year-old white man. Hormone therapy represents a prominent branch in the treatment of locally advanced and metastatic prostate cancer. Gonadotropin-releasing hormone agonists have been proven to have a double effect on androgen metabolism: an initially stimulating, followed by an inhibitory, effect on the pituitary gland. This phenomenon may be noxious in the case of gonadotroph adenoma, with subsequent symptoms of intracranial hypertension. Gonadotropin-releasing hormone antagonists (abarelix), by avoiding the flare-up reaction, might be used in such instances.     

The presence of a pituitary tumor in patients with prostate cancer is not a contraindication for leuprolide therapy

Purpose

Gonadotropin analogs like leuprolide play an important role in the management of prostate cancer. Pituitary apoplexy has been reported after leuprolide therapy. This report examines whether the presence of a pituitary tumor is a contraindication for leuprolide therapy in patients with prostate cancer.

Materials and methods

Two patients with prostate cancer and pituitary tumors were treated with leuprolide and radiation therapy. The first patient with a previously unknown pituitary adenoma had a leuprolide injection for prostate gland downsizing prior to brachytherapy. The second patient with a known pituitary microadenoma had a biochemical recurrence and was treated with leuprolide and radiation therapy.

Results

The first patient developed symptoms of apoplexy a few hours after the leuprolide injection. He underwent a transsphenoidal resection of the sellar mass with complete neurologic recovery. The second patient did not have any adverse events after leuprolide with follow-up MRI scans showing no growth of the microadenomas.

Conclusion

The presence of a pituitary tumor is not a contraindication for leuprolide therapy. While patients with a macroadenoma should have surgery first, those with a microadenoma may be considered for leuprolide therapy after careful evaluation by a multidisciplinary team.     

Effect of GnRH analogs on the expression of TrkA and p75 neurotrophin receptors in primary cell cultures from human prostate adenocarcinoma

BACKGROUND: GnRH analogs have antiproliferative and/or apoptotic effects on prostate cancer cells. Also, neurotrophin receptors TrkA and p75 have been reported in normal prostate suggesting a role in the gland growth control. In prostate cancer, TrkA receptors seem to be overexpressed and p75 receptors show a decreased expression. These changes in neurotrophin receptors may be related with unbalanced growth in malignant cells. In the present study we investigate the effects of GnRH analogs (leuprolide and cetrorelix) on the expression of TrkA and p75 neurotrophin receptors in primary cultures of human prostate cancer cells. METHODS: Tissue was obtained from radical prostatectomies due to prostate adenocarcinoma. Cells were isolated after sequential enzyme digestion and cultured in defined media. Nerve growth factor (NGF) receptors in untreated cultures were estimated by immunofluorescence. Cultures were treated with leuprolide (agonist) or cetrorelix (antagonist) and expression of TrkA and p75 receptors were evaluated by semi quantitative RT-PCR (polymerase chain reaction) and western blot. Cell proliferation was estimated by MTT method and apoptosis through COMET assay. RESULTS: Both leuprolide and cetrorelix induced a significant increase in p75 receptor gene and protein expression at a concentration that induce apoptosis and decrease proliferation. TrkA receptors showed no changes in presence of GnRH analogs. CONCLUSIONS: GnRH analogs, leuprolide, and cetrorelix, change the ratio between neurotrophin receptors TrkA and p75 by increasing gene and protein expression of p75 receptor. Considering that TrkA receptor is related with proliferation and p75 with apoptosis, we suggest that our findings may explain, in part, the effect of GnRH analogs on prostate cancer growth.     

Acute manic and psychotic symptoms following subcutaneous leuprolide acetate in a male patient without prior psychiatric history: A case report and literature review

Leuprolide acetate is usually used in the treatment of advanced prostate cancer. The adverse events associated with administration of leuprolide acetate include fatigue, hot flashes, loss of libido, impotence, and depression. These side effects can be treated conservatively. Acute manic and psychiatric symptoms following leuprolide acetate injection are very rare. Few case reports have been published documenting these symptoms. Here, we describe the case of a 62-year-old male with metastatic prostate cancer, who developed acute manic and psychiatric symptoms 2 months after subcutaneous leuprolide acetate injection. These symptoms were relieved after administration of neuroleptic drugs, such as risperidone. Administration of leuprolide acetate was eventually stopped. The exact mechanism causing the manic and psychiatric adverse events is unclear. Some experts have theorized that estrogen withdrawal following leuprolide acetate therapy may induce psychiatric symptoms. Manic episodes may arise from a deficit in central serotonergic neurotransmission. Based on these hypotheses, risperidone, lithium, and some anticonvulsants, such as divalproex sodium and carbamazepine, have been used effectively in the treatment and prophylaxis of manic episodes. Although psychiatric adverse events are rare following administration of leuprolide acetate, clinicians should be aware of the possibility.     

Serum prostate-antigen levels in patients with benign prostatic hypertrophy treated with leuprolide

We studied serum prostate-specific antigen levels in 12 men with benign prostatic hypertrophy treated with a long-acting GnRH analogue, leuprolide, 1 mg (0.2 mL) sc. daily for six months. The average decrease in prostate size measured by ultrasound was 45 percent after six months with concomitant improvement in the obstructive symptoms of prostatism. There was a steady decline in serum PSA levels which paralleled the decrease in prostate size. One patient who discontinued treatment after six months demonstrated both a regrowth of his prostate and a rise in serum PSA levels to pretreatment levels four months post-discontinuation of treatment. We conclude that treatment with a GnRH analogue caused reversible involution of prostatic epithelial cells with parallel effects on serum PSA levels. Consideration of the initial prostate size together with the serum PSA levels can help predict the response to medical castration in men with BPH.     

Abarelix and other gonadotrophin‐releasing hormone antagonists in prostate cancer

Hormonal therapy is the main recommended treatment for locally advanced and metastatic prostate cancer. Luteinizing hormone‐releasing hormone (LHRH) agonists, such as buserelin, goserelin, leuprorelin and triptorelin, stimulate the pituitary’s gonadotrophin‐releasing hormone (GnRH) receptor, ultimately leading to its de‐sensitization and subsequent reduction of LH and testosterone levels. However, this reduction is accompanied by a well described increase or ‘surge’ in LH and testosterone levels, necessitating the concomitant administration of an antiandrogen to combat the potential effects of transient acceleration in cancer activity. Two pure GnRH antagonists have been developed, abarelix and degarelix, that are devoid of any agonist effect on the GnRH receptor and consequently do not result in testosterone flare. Abarelix was the first GnRH antagonist to be developed and was approved by the USA Food and Drug Administration in 2004 for the initiation of hormonal castration in advanced or metastasizing hormone‐dependent prostate carcinoma, when rapid androgen suppression is necessary. Clinical data on both abarelix and degarelix show that they can produce rapid and sustained decreases in testosterone to castrate levels without the need for co‐administration of an antiandrogen, and with a very low complication rate in the short term.     

Changes in alkaline phosphatase levels in patients with prostate cancer receiving degarelix or leuprolide: results from a 12‐month,comparative, phase III study

Study Type – Therapy (RCT)
Level of Evidence 1b

OBJECTIVE

To compare the activity of degarelix, a new gonadotrophin‐releasing hormone (GnRH) blocker, with leuprolide depot 7.5 mg in the control of total serum alkaline phosphatase (S‐ALP) levels in patients with prostate cancer.

PATIENTS AND METHODS

In the randomized, phase III trial (CS21), patients with histologically confirmed prostate cancer (all stages), were randomized to one of three regimens: degarelix subcutaneous 240 mg for 1 month followed by monthly maintenance doses of 80 mg or 160 mg, or intramuscular leuprolide 7.5 mg/month. Patients receiving leuprolide could also receive antiandrogens for flare protection. We report exploratory S‐ALP analyses from CS21, focusing on the comparison of degarelix 240/80 mg with leuprolide 7.5 mg, in line with the recent approvals of this dose by the USA Food and Drug Administration and the European Medicines Agency.

RESULTS

Overall, 610 patients were included, with a median age of 73 years and median prostate‐specific antigen (PSA) level of 19.0 ng/mL. Baseline S‐ALP levels were high in metastatic patients and highest in patients with metastatic disease and a haemoglobin level of <13 g/dL. In metastatic disease, after initial peaks in both groups, S‐ALP levels were suppressed below baseline with degarelix but were maintained around baseline with leuprolide. The late rise in S‐ALP seen with leuprolide was not apparent with degarelix. The pattern of S‐ALP response was similar in patients with a baseline PSA level of ≥50 ng/mL. Between‐treatment differences in patients with metastatic disease and those with a PSA level of ≥50 ng/mL were significant at day 364 (P = 0.014 and 0.007, respectively).

CONCLUSION

Patients with metastatic disease or those with PSA levels of ≥50 ng/mL at baseline had greater reductions in S‐ALP levels with degarelix than with leuprolide. Patients in the degarelix group maintained S‐ALP suppression throughout the study, in contrast to those in the leuprolide group. This suggests that degarelix might offer better S‐ALP control than leuprolide and might prolong control of skeletal metastases, compared with GnRH agonists, over a 1‐year treatment period.     

New treatment paradigm for prostate cancer: abarelix initiation therapy for immediate testosterone suppression followed by a luteinizing hormone-releasing hormone agonist

Study Type – Therapy (prospective cohort) Level of Evidence 2a What's known on the subject? and What does the study add? The sequential administration of a GnRH antagonist followed by an LHRH agonist in the management of prostate cancer patients has not been studied, but such a program would provide a more physiologic method of achieving testosterone suppression and avoid the obligatory testosterone surge and need for concomitant antiandrogens that accompany LHRH agonist therapy. The current study which uses abarelix initiation therapy for 12 weeks followed by either leuprolide or goserelin demonstrates the ability to more rapidly achieve testosterone suppression, avoid the obligatory LHRH induced testosterone surge, avoid the necessity of antiandrogens, all of which were accomplished safely, without inducing either additional or novel safety issues.

OBJECTIVE

• ? To demonstrate the safety and endocrinological and biochemical efficacy of initiating treatment with the gonadotropin‐releasing hormone (GnRH) antagonist, abarelix, followed by administration of an luteinizing hormone‐releasing hormone (LHRH) agonist in patients with advanced and metastatic prostate cancer.

PATIENTS AND METHODS

• ? A multicentre, open‐label design study was conducted at 22 centres in the US involving patients with: localized, locally advanced or metastatic disease; with a rising prostate‐specific antigen (PSA) after definitive local treatment; patients undergoing neoadjuvant hormonal therapy before local therapy (radical prostatectomy, radiation therapy or cryosurgery); and patients in whom intermittent therapy was the planned treatment.
• ? All patients received abarelix for 12 weeks followed by an LHRH agonist (either leuprolide or goserelin) for 8 weeks
• ? The primary efficacy endpoint was achievement and maintenance of castration defined as testosterone <50 ng/dL from day 29 through to day 141 and whether abarelix initiation therapy could eliminate the testosterone surge after two consecutive doses of LHRH agonist therapy.
• ? PSA, LH and follicle‐stimulating hormone (FSH) levels were measured and adverse events were monitored.

RESULTS

• ? A total of 176 patients were enrolled into the present study, the majority of whom had localized prostate cancer (82%) and a PSA level <10 ng/mL (62%).
• ? At the end of the abarelix treatment period (day 85), 93.8% of patients achieved castrate levels; during the first week of switch over to the LHRH agonist therapy (days 85–92) the rate was 86.5% and during the week after the second LHRH agonist injection (days 114–12) it was 93.3%.
• ? A small, transient increase in testosterone occurred during the first injection of the LHRH agonist; mean (standard deviation [sd ]) values increased from 17 (17.8) ng/dL at day 85 to 37.3 (51.07) ng/dL at day 86.
• ? Mean (sd ) PSA levels decreased from 20.5 (56.6) ng/mL at baseline to 3.7 (23.5) ng/mL on day 85 and remained stable throughout the LHRH agonist treatment phase.
• ? Treatment‐related adverse events occurred in 84% of patients overall; a similar incidence was reported during the two treatment phases.

CONCLUSIONS

• ? Abarelix initiation therapy results in the desired effect of achieving rapid testosterone suppression; testosterone surges after subsequent LHRH agonist therapy are greatly abrogated or completely eliminated.
• ? This treatment paradigm (abarelix initiation followed by agonist maintenance) obviates the need for an antiandrogen.
• ? Abarelix was well tolerated and no clinically meaningful or novel adverse events were observed during abarelix treatment or in the transition to LHRH agonist maintenance therapy.

     

Hypophysectomy for prostate cancer: a revival of old knowledge?

The growth of prostate cancer is controlled by several hormones and growth factors. In cases of metastasized prostate cancer, antigonadotropic therapy is currently considered state-of-the-art treatment. Surgical therapies such as adrenalectomy and hypophysectomy are no longer in use. Nevertheless, hypophysectomy has proven efficacy for palliative pain treatment as well as increasing duration of survival. The authors present the case of a 63-year-old man with metastatic prostate cancer who presented with high serum prostate-specific antigen levels (1216 microg/L) and cavernous sinus syndrome. His disease was progressing despite leuprorelin and docetaxel therapy, and he had severe bone pain despite high-dose pain therapy. He was also anemic. Contrast-enhanced MR imaging showed a pituitary lesion as well as metastatic infiltration of the skull base including the cavernous sinus. The patient's serum level of prolactin was mildly elevated, testosterone was below the detection limit, and insulin-like growth factor-I (IGF-I) was in the upper range for a patient of his age (233 microg/L). Because of the elevated prolactin and high-normal IGF-I levels he was offered a hypophysectomy in addition to pituitary tumor removal. Histological examination of the resected lesion confirmed a nonsecreting pituitary adenoma with infiltration of prostate cancer cells. Postoperatively the patient's prostate-specific antigen levels dropped to 876 microg/L, his bone pain resolved, and the cavernous sinus syndrome improved. Nevertheless, he died of septicemia 4 months after surgery. Older publications as well as this case have shown the benefit of hypophysectomy for pain treatment. A reduction of IGF-I levels even in the final stage metastasized prostate cancer may play a major role. Respectively, clinical studies with somatostatin analogs are currently in progress, which may lead to a "new" way of treatment in these otherwise hopeless patients. On the basis of the pain relief seen after hypophysectomy in this case and similar benefits reported in older publications, the authors raise the question whether this treatment should be offered more frequently, and whether additional medical options of hormone treatment may be beneficial in similar cases.     

Idiopathic intracranial hypertension: A possible complication in the natural history of advanced prostate cancer

Idiopathic intracranial hypertension is a variety of intracranial hypertension that is extremely rare in men. Obesity and hypogonadism are the most important predictive factors. Etiological hypotheses include increased central venous pressure, and various hormonal and metabolic changes commonly found in obese patients. We described the case of an obese man with prostate cancer who showed a consistent bodyweight increase during treatment with taxanes and prednisone. He was hospitalized because of a severe loss of vision as a consequence of idiopathic intracranial hypertension. A complete symptom remission was obtained after 3 weeks of anti‐edema therapies (steroids, acetazolamide). Castration‐resistant prostate cancer is a risk factor for idiopathic intracranial hypertension. Long‐term androgen deprivation therapy, bodyweight increase, and fluid retention during chronic steroid administration and taxane chemotherapy might favor the disease onset. This severe complication has a good outcome, and should be suspected in the presence of symptoms and signs of intracranial hypertension.     

Inhibition of disease flare with diethylstilbestrol diphosphate and chlormadinone acetate administration for two weeks prior to slow-releasing leuprolide acetate in prostatic cancer patients

To determine whether administration of estrogen or gestagen prior to luteinizing hormone-releasing hormone (LH-RH) agonist prevents disease flare in prostate cancer patients, we pretreated the patients with either diethylstilbestrol diphosphate (DES-P) 300 mg daily (N = 17) or chlormadinone acetate (CMA) 100 mg daily (N = 16) or none (N = 16) for two weeks before the initial injection of leuprolide acetate (L). Blood samples for prostatic specific antigen (PSA), testosterone (T), and luteinizing hormone were collected before CMA and DES-P administration, before and at 2, 7, 14, 28, 56, and 84 days after the first administration of leuprolide. The treatment with DES-P and CMA prior to LH-RH agonist induced an early decline of PSA. The mean PSA level showed no significant secondary rise in those patients with pretreatment after L administration. In the patients pretreated with DES-P or CMA, the mean serum T level never exceeded the pretreatment baseline after L administration. On the other hand, in the patients without DES-P or CMA, both serum T and PSA levels increased after the first administration of L. These results clearly demonstrate that pretreatment with DES-P 300 mg daily or CMA 100 mg daily for 2 weeks is quite effective to prevent disease flare after the first administration of L in patients with prostatic cancer.     

The efficacy and safety of degarelix: a 12‐month,comparative, randomized,open‐label,parallel‐group phase III study in patients with prostate cancer

OBJECTIVE

To evaluate the efficacy and safety of degarelix, a new gonadotrophin‐releasing hormone (GnRH) antagonist (blocker), vs leuprolide for achieving and maintaining testosterone suppression in a 1‐year phase III trial involving patients with prostate cancer.

PATIENTS AND METHODS

In all, 610 patients with adenocarcinoma of the prostate (any stage; median age 72 years; median testosterone 3.93 ng/mL, median prostate‐specific antigen, PSA, level 19.0 ng/mL) were randomized and received study treatment. Androgen‐deprivation therapy was indicated (neoadjuvant hormonal treatment was excluded) according to the investigator’s assessment. Three dosing regimens were evaluated: a starting dose of 240 mg of degarelix subcutaneous (s.c.) for 1 month, followed by s.c. maintenance doses of 80 mg or 160 mg monthly, or intramuscular (i.m.) leuprolide doses of 7.5 mg monthly. Therapy was maintained for the 12‐month study. Both the intent‐to‐treat (ITT) and per protocol populations were analysed.

RESULTS

The primary endpoint of the trial was suppression of testosterone to ≤0.5 ng/mL at all monthly measurements from day 28 to day 364, thus defining the treatment response. This was achieved by 97.2%, 98.3% and 96.4% of patients in the degarelix 240/80 mg, degarelix 240/160 mg and leuprolide groups, respectively (ITT population). At 3 days after starting treatment, testosterone levels were ≤0.5 ng/mL in 96.1% and 95.5% of patients in the degarelix 240/80 mg and 240/160 mg groups, respectively, and in none in the leuprolide group. The median PSA levels at 14 and 28 days were significantly lower in the degarelix groups than in the leuprolide group (P < 0.001). The hormonal side‐effect profiles of the three treatment groups were similar to previously reported effects for androgen‐deprivation therapy. The s.c. degarelix injection was associated with a higher rate of injection‐site reactions than with the i.m. leuprolide injection (40% vs <1%; P < 0.001, respectively). There were additional differences between the degarelix and leuprolide groups for urinary tract infections (3% vs 9%. P < 0.01, respectively), arthralgia (4% vs 9%, P < 0.05, respectively) and chills (4% vs 0%, P < 0.01, respectively). There were no systemic allergic reactions.

CONCLUSIONS

Degarelix was not inferior to leuprolide at maintaining low testosterone levels over a 1‐year treatment period. Degarelix induced testosterone and PSA suppression significantly faster than leuprolide; PSA suppression was also maintained throughout the study. Degarelix represents an effective therapy for inducing and maintaining androgen deprivation for up to 1 year in patients with prostate cancer, and has a different mechanism of action from traditional GnRH agonists. Its immediate onset of action achieves a more rapid suppression of testosterone and PSA than leuprolide. Furthermore, there is no need for antiandrogen supplements to prevent the possibility of clinical ‘flare’.     

Determining dosing intervals for luteinizing hormone releasing hormone agonists based on serum testosterone levels: a prospective study

PURPOSE: Long acting luteinizing hormone releasing hormone agonists are the predominant form of androgen suppression in the treatment of prostate cancer with the goal of maintaining castrate levels of testosterone. Current dosing of luteinizing hormone releasing hormone agonists does not include monitoring the end organ response of serum testosterone. Recent evidence suggests standard dosing regimens fail to achieve castrate levels of testosterone in some patients while in other patients testosterone can remain at castrate levels longer than the manufacturer recommended dosing interval. We prospectively evaluated patients with prostate cancer receiving luteinizing hormone releasing hormone agonist hormonal therapy to determine the length of time that serum testosterone remains at or below castrate levels. MATERIALS AND METHODS: A 3-month dose of 22.5 mg leuprolide was administered to all patients as a first dose followed by a second dose 3 months later. Serum testosterone and prostate specific antigen were measured prospectively before starting hormonal therapy, after the first dose (12 weeks) and again following the second dose (24 weeks) to assess if castrate levels of testosterone (50 ng/dl or less) had been reached. At 24 weeks if patient serum testosterone was 50 ng/dl or less, then 22.5 mg leuprolide were not administered, and serum testosterone and prostate specific antigen were checked monthly. When serum testosterone was greater than 50 ng/dl a subsequent dose of 22.5 mg leuprolide was given. Serum testosterone and prostate specific antigen were then checked 3 months later and monthly thereafter until testosterone was greater than 50 ng/dl. Thus, the time that testosterone remained at castrate levels could be accurately established. RESULTS: From February 2003 to August 2005, 42 patients were treated in this manner with a median followup of 18 months (range 10 to 30). Average patient age was 77 years. Median Gleason grade was 7 (range 6 to 9). Median pretreatment prostate specific antigen was 15.1 ng/ml (range 0.6 to 433) and median posttreatment prostate specific antigen was 0.74 (less than 0.1 to 120). The median dosing interval was 6 months (range 5 to 12). Three patients had an increase in prostate specific antigen while receiving treatment despite castrate levels of testosterone. No patient required more frequent dosing than every 5 months. CONCLUSIONS: Testosterone based luteinizing hormone releasing hormone agonist therapy makes empirical sense. It represents continuous androgen ablation based on the patient physiological end point, namely testosterone. Early data suggest that using serum testosterone to guide luteinizing hormone releasing hormone dosing is safe, efficacious and cost-effective. By following end organ response, patients receive individualized care and more accurate androgen suppression therapy.     

Risk of clinical fractures after gonadotropin-releasing hormone agonist therapy for prostate cancer

PURPOSE: We assessed the relationship between GnRH agonists and the risk of clinical fractures in men with prostate cancer. MATERIALS AND METHODS: Using a database of medical claims from 16 large American companies we identified a study group of 3,779 men with prostate cancer who received treatment with a GnRH agonist and a control group of 8,341 with prostate cancer who were not treated with a GnRH agonist. Men with 1 or more medical claims for bone metastases were excluded. The rates of any clinical fracture, hip fracture and vertebral fracture were compared between the groups. RESULTS: The rate of any fracture was 7.91/100 vs 6.55/100 person-years at risk in men who received vs did not receive a GnRH agonist (relative risk 1.21, 95% CI 1.09 to 1.34). The rates of hip fracture (relative risk 1.76, 95% CI 1.33 to 2.33) and vertebral fracture (relative risk 1.18, 95% CI 0.94 to 1.48) were also higher in men who received a GnRH agonist. GnRH agonist treatment was independently associated with fracture risk on multivariate analyses. CONCLUSIONS: GnRH agonists increase the risk of clinical fracture in men with prostate cancer.     

A case of prolactinoma associated with craniopharyngioma

A surgical case of prolactinoma associated with craniopharyngioma is reported. A 47-year-old man was admitted to some neurosurgical clinic on October 12, 1982, because of visual disturbance, general fatigue and impotence. Laboratory study revealed hyperprolactinemia (360 ng/ml) and slight enlargement of sella turcica indicated the pituitary adenoma. Transsphenoidal surgery was performed to remove the tumor on November 20, 1982. Histopathological examination revealed chromophobe adenoma, and prolactin was stained in the tumor cells by means of immunoperoxidase staining. Though the clinical symptoms had been improved after surgery, visual disturbance became worse about one month later. At that time empty sella syndrome was suspected and the second operation (interhemispheric approach) was performed on January 21, 1983. No pathological changes were observed at all. On July 13, 1983, he was transferred to our clinic, because his visual acuity was deteriorating. At this time we reviewed the previous CT scan and noticed a suprasellar mass. It was supposed that the lesion had been overlooked and was the cause of the visual disturbance. On August 1, 1983, a bifrontal craniotomy was performed and the suprasellar tumor was removed. Pathological examination of the tumor revealed craniopharyngioma. So it was supposed that pituitary adenoma and craniopharyngioma had been coexisting since onset. Except for cases with von Recklinghausen's disease, multiple primary intracranial tumors of different cell types are relatively rare. A review of literature revealed 94 cases until 1986. The most frequent combination of multiple tumors was meningioma and glioma. But we could not find any case of pituitary adenoma associated with craniopharyngioma in the literature.(ABSTRACT TRUNCATED AT 250 WORDS)     

Gonadotropin‐releasing hormone: An update review of the antagonists versus agonists

Gonadotropin‐releasing hormone agonists and antagonists provide androgen‐deprivation therapy for prostate cancer. Unlike agonists, gonadotropin‐releasing hormone antagonists have a direct mode of action to block pituitary gonadotropin‐releasing hormone receptors. There are two licensed gonadotropin‐releasing hormone antagonists, degarelix and abarelix. Of these, degarelix is the more extensively studied and has been documented to be more effective than the well‐established, first‐line agonist, leuprolide, in terms of substantially faster onset of castration, faster suppression of prostate‐specific antigen, no risk for testosterone surge or clinical flare, and improved prostate‐specific antigen progression‐free survival, suggesting a delay in castration resistance. Other than minor injection‐site reactions, degarelix is generally well tolerated, without systemic allergic reactions and with most adverse events consistent with androgen suppression or the underlying condition. In conclusion, degarelix provides a rational, first‐line androgen‐deprivation therapy suitable for the treatment of prostate cancer, with faster onset of castration than with agonists, and no testosterone surge. Furthermore, data suggest that degarelix improves disease control compared with leuprolide, and might delay the onset of castration‐resistant disease. In view of these clinical benefits and the lack of need for concomitant anti‐androgen treatment, gonadotropin‐releasing hormone antagonists might replace gonadotropin‐releasing hormone agonists as first‐line androgen‐deprivation therapy in the future.     

The sustained release of LH X RH agonist from LH X RH agonist-polymer composite in patients with prostatic cancer

Luteinizing hormone-releasing hormone (LH X RH) agonist can be administered daily to patients with prostatic cancer with resulting clinical efficacy. A sustained drug release formulation of an LH X RH agonist, (D-Leu6)-des Gly-NH2(10)-LH X RH ethylamide (leuprolide)-vinyl polymer composite, was prepared by means of radiation-induced polymerization under a supercooled state. The sustained release of leuprolide from subcutaneously implanted leuprolide-vinyl polymer composite (14 mm in diameter and 4 mm in thickness) was obtained over a period of several months in five patients with prostatic cancer. Serum testosterone levels began to decrease on the tenth day, fell below 1 ng/ml after three weeks of implantation, and thereafter remained at the castration level until removal of the polymer composite. Clinical improvement was associated with serum hormonal changes, and support this as a novel and superior method of administration of LH X RH agonist.     

Equivalent and sufficient effects of leuprolide acetate and goserelin acetate to suppress serum testosterone levels in patients with prostate cancer

OBJECTIVE

To compare the effects of leuprolide acetate and goserelin acetate for suppressing serum testosterone levels in Japanese patients with prostate cancer, as several recent studies suggested that serum testosterone is not always suppressed below the upper limit of the castration range in patients using luteinizing hormone‐releasing hormone (LH‐RH) agonists, especially leuprolide acetate.

PATIENTS AND METHODS

In all, 232 patients with prostate cancer, whose serum testosterone levels were measured before and during treatment using a 1‐ or 3‐monthly formulation of leuprolide or goserelin, were enrolled in a retrospective study. The mean age of the patients was 69.8 years and the mean testosterone level before the LHRH treatment was 4.54 ng/mL. The patients had their testosterone levels assessed a mean (range) of 5.4 (1–35) times during the LHRH treatment. A castrate serum testosterone level was defined as ≤0.5 ng/mL.

RESULTS

The mean maximum testosterone level during 1‐monthly leuprolide (40 patients), 3‐monthly leuprolide (68), 1‐monthly goserelin (50), or 3‐monthly goserelin (74) treatment was 0.22, 0.20, 0.19 and 0.20 ng/mL, respectively (not significant). Four patients, including two treated with 1‐monthly leuprolide, one with 3‐monthly leuprolide and one with 3‐monthly goserelin, had serum testosterone above the castrate level, with a maximum of 0.5–0.65 ng/mL. Three of these patients had elevated testosterone only once or twice during the follow‐up, and the remaining patient had serum testosterone fluctuating at 0.4–0.6 ng/mL throughout the follow‐up.

CONCLUSIONS

One‐ and 3‐monthly formulations of leuprolide and goserelin have equivalent and sufficient effects to suppress serum testosterone levels in men with prostate cancer. There were testosterone levels just outside the castrate range in a few patients during treatment.     

Pure red cell aplasia in a prostate cancer patient treated with leuprolide acetate and chlormadinone acetate

Abstract  Pure red cell aplasia (PRCA) is characterized by anemia with reticulocytopenia but with normal leukocyte and platelet counts, and a bone marrow with a selective absence of erythroid precursor cells. Drug-induced PRCA is a rare secondary form of PRCA, and is usually acute and fully reversible by the withdrawal of the causative drugs. We report a rare case of PRCA in a prostate cancer patient treated with combined androgen blockade (CAB) consisted of leuprolide acetate as a luteinizing hormone-releasing hormone agonist and chlormadinone acetate as an antiandrogen. This case demonstrated that these drugs could be a cause of PRCA, and suggests that regular close monitoring for anemia is needed in prostate cancer patients treated with these drugs.