Indian Journal of Urology
REVIEW ARTICLE
Year
: 2009  |  Volume : 25  |  Issue : 2  |  Page : 169--176

Adverse effects of androgen deprivation therapy in prostate cancer: Current management issues


Aditya Bagrodia, Christopher J DiBlasio, Robert W Wake, Ithaar H Derweesh 
 Department of Urology, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA

Correspondence Address:
Ithaar H Derweesh
Department of Urology, University of Tennessee Health Science Center, Chief of Urology, Regional Medical Center at Memphis, 910 Madison Avenue, Room 412, Memphis, TN 38163
USA

Abstract

Prostate cancer (CaP) is the most common visceral malignancy and a leading cause of cancer death in men. Androgen deprivation therapy (ADT) is an established treatment for locally advanced and metastatic CaP, and often used as primary therapy in select patients. As ADT has continued to assume an important role in the treatment of CaP, a greater appreciation of potential adverse effects has been acknowledged in men receiving this therapy. Given that all treatments for CaP are frequently associated with some degree of morbidity and can have a negative impact on health-related quality of life (HRQOL), the potential benefits of any treatment, including ADT, must outweigh the risks, particularly in patients with asymptomatic disease. Once the choice to proceed with ADT is complete, it is imperative for the urologist to possess comprehensive knowledge of the potential adverse effects of ADT. This permits the urologist to properly monitor for, perhaps diminish, and to treat any linked morbidities. Patient complaints related to ADT such as a decrease in HRQOL, cognitive and sexual dysfunction, hot flashes, endocrine abnormalities, cardiovascular disease, and alterations in skeletal and body composition are commonly reported throughout the literature. Herein, we review the principal adverse effects linked with ADT in CaP patients and suggest various universal strategies that may diminish these potential adverse consequences associated with this therapy.



How to cite this article:
Bagrodia A, DiBlasio CJ, Wake RW, Derweesh IH. Adverse effects of androgen deprivation therapy in prostate cancer: Current management issues.Indian J Urol 2009;25:169-176


How to cite this URL:
Bagrodia A, DiBlasio CJ, Wake RW, Derweesh IH. Adverse effects of androgen deprivation therapy in prostate cancer: Current management issues. Indian J Urol [serial online] 2009 [cited 2021 Apr 20 ];25:169-176
Available from: https://www.indianjurol.com/text.asp?2009/25/2/169/52907


Full Text

 Introduction



Prostate cancer (CaP) is the most common visceral malignancy in men, with an expected 218 890 new cases and 27 050 deaths estimated in 2007 in the United States alone. [1] Ever since the discovery of androgen-dependent CaP, androgen-deprivation therapy (ADT) has become an integral piece of the armamentarium for treating contemporary CaP. [2] The survival advantages have been documented with ADT when applied to patients as neoadjuvant or adjuvant therapy in combination with external-beam radiotherapy (EBRT), as well as when implemented as early adjuvant therapy in men diagnosed with lymph node metastases following radical prostatectomy. [2],[3] In addition to the applications of ADT in the settings of locally advanced or metastatic CaP, significant increases have been recognized in the use of primary ADT in select patients. [4] As the role of ADT in the treatment algorithm of CaP continues to evolve, there has been increasing attention towards identifying and preventing ADT-associated morbidities in recent literature. It is essential for urologists and oncologists to have a comprehensive understanding of the major adverse effects of ADT not only in order to properly counsel patients, but also to attempt to identify, alleviate, and treat these potential morbidities during therapy. Herein, we discuss the major ADT-associated morbidities, and provide methods for identifying and treating these complaints in men receiving ADT for CaP.

 Adverse Effects of ADT



Quality of life

The impact on health-related quality of life (HRQOL) following ADT induction has gained significant clinical attention. Several series have documented an association between ADT and declining HRQOL. [5],[6],[7],[8],[9],[10] Potosky et al. published a series of 661 men with localized CaP, comparing men receiving primary ADT (n = 245, 37%) to men selecting watchful waiting (WW, n = 416, 63%). Using the Medical Outcomes Study (MOS): 36-Item Health Survey, they compared HRQOL between these two groups. They found significantly higher rates of physical discomfort (P = 0.02) in men receiving primary ADT. Further, men receiving ADT reported more physical limitations and bother from CaP, though these were not statistically significant (P = 0.11 and P = 0.21, respectively). [5] Similarly, Dacal et al., compared HRQOL between men undergoing short-term ADT (6 months), and healthy controls. Again, using the MOS questionnaire, they found that men receiving any duration of ADT demonstrated significantly worsened HRQOL. In particular, ADT recipients demonstrated decreased scores in: Physical component health summary (P [6] Fowler et al. compared HRQOL between men treated with radical prostatectomy (n = 810) vs. radical prostatectomy in combination with adjuvant ADT (n = 220). [10] In this study, men receiving ADT demonstrated significantly decreased scores in all HRQOL domains studied. In particular, men receiving prostatectomy and ADT reported worse scores with respect to the effect of cancer and treatment on overall well-being (P [10] These findings have been supported by other studies demonstrating the negative impact of ADT on cognition, sexual function, social interaction, and role functioning, as well as an increase in the level of emotional distress. [8],[9] In addition to effects on overall HRQOL, recent data investigating the association between ADT and psychiatric illness has documented an almost two-fold increase in the risk of de novo psychiatric illness following ADT induction. [7]

As an increasing evidence base is collected regarding the negative psychosocial impacts of ADT, it is paramount that urologists discuss the potential adverse effects that ADT may pose to a patients' general mental and physical sense of well-being. Currently, no Level I evidence exists that clearly demonstrates association of ADT with a decreased HRQOL, and no consensus recommendations are published to minimize HRQOL-related adverse effects. As demonstrated in the above studies, though, a relationship between ADT use and decreased quality of life is beginning to surface in Level II/III evidence. Experts agree that patients must be advised that the potential for an overall or domain-specific decrease in HRQOL exists when the decision is made to initiate androgen suppression. A mental health history should be obtained prior to initiating androgen ablative treatment, and patients should be carefully followed for the onset of depressive symptoms during and after treatment. Further, since QOL is best thought of as the sum total of all adverse effects associated with ADT, culminating into how the patient actually perceives their existence, it is imperative that urologists and oncologists discuss this most important topic when deciding whether or not to begin ADT. The component parts to a potentially decreased HRQOL that are associated with ADT will now be discussed, and more specific recommendations to screen for, prevent, and minimize them will be provided.

Sexual dysfunction

Impotence and loss of libido were among the first described adverse effects of ADT. The relationship between androgen ablation and sexual function has been studied in several contemporary series. [2],[5],[10],[11],[12] Fowler et al., compared HRQOL outcomes in androgen-deprived (n = 298) and non-androgen-deprived men (n = 1095) following radical prostatectomy in a survey-based study using Medicare Provider and Analysis and Review (MedPAR) files. Overall, 166 men in the ADT group and 886 men in the non-ADT group responded to the survey questions regarding erectile dysfunction (ED). Patient receiving ADT reported higher rates of post-prostatectomy impotence (72 vs. 55%), but similar rates of impotence over the month prior to the survey (23 vs. 22%). Regarding the quality of erections, 3% (vs. 11%) of androgen-deprived men reported erections insufficient for intercourse, and only 2% (vs. 12%; P [10] In a Level I study, Potosky et al., analysed sexual and erectile outcomes in men receiving either orchiectomy (n = 132) or GnRH agonists (n = 299) as part of the Prostate Cancer Outcomes Study. Pretreatment, sexual function, and libido were similar between groups; however, patients undergoing orchiectomy reported slightly worse overall sexual function, though not statistically significant. Additionally, changes in sexual outcomes were similar between both ADT groups with reports of impotence increasing from 35.0 to 78.6% in the orchiectomy group, and from 37.9 to 73.3% in the GnRH analog group. Despite these similarities, 38.4% of men receiving GnRH agonist therapy reported a big/moderate problem in overall sexual function compared to only 25.6% in the orchiectomy group (P = 0.04). [13]

In another Level I evidence series, Potosky et al., compared men selecting WW (n = 416) with men selecting ADT (n = 245) during the first year following CaP diagnosis. [5] Patients completed sexual and QOL surveys at baseline, 6 months, and 12 months post-diagnosis. Among men reporting some sexual interest at baseline, 54% of the ADT group vs. 13% of the WW group reported no interest in sexual activity at approximately 12 months post-diagnosis (P [11],[12] Sexual dysfunction should actually be addressed prior to ADT initiation, so that physicians have a working idea of baseline sexual function and can then individually tailor treatments. Experts agree that patients should routinely be asked about changes in sexual function over the course of therapy. Level III evidence suggests that penile injections and phosphodiesterase-5 inhibitors (PDE-5 inhibitors) have demonstrated some success in treating the sexual side effects associated with ADT; however, diminished libido in men receiving ADT and the partial dependence of PDE-5 inhibitors on the presence of circulating androgens can attenuate their efficacy. [11] Nonetheless, reasonable treatment response outcomes have been reported. In a recent series of 395 men receiving ADT, DiBlasio et al., identified 57 men (14.4%) reporting post-ADT ED who went on to receive targeted therapy; 40 (70.2%) of which experienced new-onset ADT-associated ED. Overall, treatment success was reported in 33.3-47.4% of men receiving single-modality medical therapy, and 80% of men receiving combination medical therapy. [12] This Level III evidence suggests that combination medical therapy with PDE-5 inhibitors, prostaglandin E1 analogs, and vacuum erection devices, seem to provide a promising approach to treating ADT-induced ED, as they appear to have synchronistic properties that act through different biochemical and mechanical pathways. Higher level evidence is lacking largely due to difficulty in uniformly assessing baseline sexual dysfunction and treatment efficacy following initiation of targeted therapy. Randomized clinical trials are necessary to investigate which erectile dysfunction treatment or combination therapies are best suited for patients with ADT-induced ED.

Vasomotor symptoms

Vasomotor flushing, commonly referred to as 'hot flashes', are a well-described phenomenon in perimenopausal women manifesting as the sudden sensation of heat over the upper body, cutaneous flushing, and sometimes by drenching sweating or shivering at the conclusion of the event. These vasomotor symptoms are noted to occur at relatively high frequencies in men undergoing androgen ablation, and are one of the most frequently reported adverse consequences of ADT. [2],[14],[15] Spetz et al., performed a Level I prospective analysis comparing the incidence of hot flashes in men receiving complete androgen blockade (CAB) to men receiving estrogen therapy for treatment of CaP. [15] In their cohort of 915 patients with metastatic disease, 458 were treated with polyestradiol phosphate while 457 received CAB. Of men receiving CAB, 74.3% reported hot flashes compared to 30.1% in men receiving estrogen therapy (P [16] These interventions are largely based on anecdotal reports or small series but increasing resources are being dedicated to further research in this area. Megestrol acetate is the most extensively studied treatment for vasomotor symptoms. At doses between 20 and 40 mg/day, Level I evidence demonstrates that the drug can reduce hot flash symptoms by up to 85%. Chills, weight gain, and carpal tunnel-like pain are reported side effects of megestrol acetate. [16] Preliminary studies have shown that certain antidepressants including venlafaxine and paroxetine may relieve vasomotor symptoms in men receiving ADT. [14] Level I evidence is lacking since only placebo-controlled pilot studies have been conducted to this point; however, all show a decrease in vasomotor symptoms, and these drugs may be particularly effective in patients with hot flashes and symptoms of depression.

Endocrine dysfunction (ED)

Male hypogonadism is recognized as an independent risk factor for the development of endocrine dysfunction (ED). [17],[18],[19],[20],[21],[22] In particular, there is increasing evidence supporting an association between ADT and increased risk of the metabolic syndrome and its associated adverse endocrine and end-organ effects. [18] Metabolic syndrome is diagnosed when three of five criteria proposed by the Adult Treatment Panel III are met, including: Fasting plasma glucose >100 mg/dl, serum triglyceride level >150 mg/dl, serum high-density lipoprotein (HDL) 102 cm, and blood pressure >130/85. A recent cross-sectional study by Braga-Basaria et al., assessed differences in the overall prevalence of the metabolic syndrome in men receiving ADT, as well as various components constituting this syndrome.[18] In men receiving ADT, the authors noted a significantly higher overall prevalence of abdominal obesity (P = 0.007), hyperglycemia (P = 0.007), and hypertriglyceridemia (P = 0.06) - all factors that contribute to the diagnosis of metabolic syndrome. Further, the prevalence of the metabolic syndrome was found to be significantly higher in the men receiving ADT (55%) compared to both the non-ADT group (22%) and eugonadal controls (20%, P = 0.03).

Development of insulin resistance, a major constituent of the metabolic syndrome, has also been associated with the receipt of ADT. [17],[19],[20],[21],[22] In a Level II prospective 12-week study by Smith et al., 25 men with locally advanced or recurrent CaP and no evidence of metastasis or diabetes were studied for ADT-related effects on insulin resistance. Patients received a 12-week course of CAB (leuprolide depot and bicalutamide) and baseline, and follow-up comparisons were made between the following parameters: Plasma glucose, plasma insulin, hemoglobin A1c, lipid profiles, and percentage of fat body. Mean percent fat body mass increased 4.3 1.3% (P = 0.002) after three months, while percent lean body mass decreased 1.4 0.5% (P = 0.006). Further, ADT demonstrated significant effects on all of the lipid indices assessed, with rises in total cholesterol (9.4 2.4%, P [22]

Basaria et al., performed a cross-sectional study of 53 men: 18 with CaP who received more than 12 months of ADT, 17 age-matched patients with CaP treated with radical prostatectomy or external-beam radiotherapy (but no ADT), and 18 age-matched men with no history of CaP (control group). The authors identified significant increases in fasting serum glucose levels (P [17]

More recently, Keating et al., published a Level II large series of 73 196 men with local and regional CaP from the Surveillance, Epidemiology, and End Results (SEER) database. Of the 36.3% of patients in the cohort receiving medical castration, they identified a significant increase in the incidence of DM (P [20]

In another Level II retrospective cohort study, Derweesh et al. reported on 396 men receiving ADT for CaP. Overall, 319 were nondiabetics at ADT initiation and 36 (11.3%) were diagnosed with new-onset DM and received appropriate medical management. Additionally, the authors found that in the 77 patients with pre-existing diabetes, ADT was associated with a rise in serum HbA1c and fasting blood glucose levels of >10% in 15 (19.5%) and 22 (28.6%) patients, respectively. [19]

Thus, there is increasing evidence supporting a link between ED and ADT. Experts agree that patients who are to receive more than 6 months of ADT therapy should meet a nutritionist to discuss a healthy diet and weight-loss strategies. Further, exercise regimens should be planned, as Level II evidence suggests that exercise helps minimize insulin resistance, decrease weight gain, and improve fatigue and overall QOL. [16] No Level I recommendations to monitor for diabetes currently exist; however, Level III evidence promotes close monitoring of HbA1c and fasting blood glucose levels in patients with pre-existing diabetes and obese patients (BMI > 30 kg/m 2 ) without a history of diabetes. [19]

Cardiovascular phenomena

In addition to ADT-associated endocrinopathy, the association between hypogonadism and cardiovascular disease continues to be elucidated. Haffner et al., assessed the relationship between serum sex hormone levels and lipid indices in a cohort of 178 nondiabetic men. After adjustments for age, BMI, waist-to-hip ratios, and glucose and insulin concentrations, free serum testosterone levels were significantly correlated with lipid profiles, including triglyceride levels (r = 0.15) and HDL concentrations (r = 0.15). The authors concluded that a relatively hypogonadal state may confer increased risk of cardiovascular events as it is associated with a decrease in cardioprotective HDL cholesterol and an increase in serum triglyceride levels.[23] Khaw et al., demonstrated the relationship between serum testosterone and hypertension, another well-described cardiac risk factor, linking low endogenous serum testosterone levels to a higher incidence of hypertension. [24] This study also identified an inverse relationship between serum testosterone levels and both systolic (r = 0.17, P [24]

A more recent study by Dockery et al., identified arterial stiffness (an inverse of vascular compliance and cardiac risk factor) to be significantly increased in men receiving GnRH analogs. [25] This study compared central and peripheral arterial compliance in 16 men receiving ADT induction vs. 15 matched controls. Arterial compliance measures were recorded at baseline and again at 12-weeks post-ADT induction in this Level II study. A significant decrease in systemic arterial compliance, or increase in arterial stiffness, was observed in the ADT group but not in the controls (P = 0.03), with a potential for associated adverse cardiovascular effects.

In a Level II study by Malcolm et al., 395 men receiving ADT were reviewed for incidence of cerebrovascular accident or myocardial infarction. Logistic regression demonstrated a time-dependent relationship between risk of myocardial infarction [hazards ratio (HR) = 2.12, P = 0.03) and cerebrovascular accident (odds ratio = 3.22, P = 0.001) and increasing duration of ADT administration.[26] Further in another Level II study, Keating et al. identified a higher incidence of coronary heart disease (HR = 1.16, P [20]

Tsai et al., directly examined the relationship between ADT and cardiac-related death in an analysis of the Cancer of the Prostate Strategic Urologic Research Endeavor database (CaPSURE). [27] In this Level II study of 4892 patients with organ-confined CaP, 1015 received either neoadjuvant or adjuvant ADT, with median therapy duration of 4.1 months, in conjunction with local surgical or radiation treatment. Competing regression analyses that controlled for age, ADT administration, and a history of heart disease or diabetes mellitus at baseline, were used to compare cardiac-related mortality rates between men receiving ADT or treated without castration. [27] The authors found that in men treated with radical prostatectomy (n = 3262), age (HR = 1.07, P = 0.003) and ADT use (HR = 2.6, P = 0.002) were significantly associated with an increased risk of cardiac-related death. Moreover, 5-year cumulative incidence estimates of cardiac death were higher in men receiving ADT when stratified by age (P = 0.02 for 65). [27]

A relationship between ADT therapy and cardiovascular disease has only recently been described as increasing data suggests that ADT use increases the incidence of known risk factors for cardiovascular disease, including DM, hypertension, and dyslipidemia. There is a paucity of screening guidelines on this topic though numerous general health and prostate cancer-specific recommendations exist. As for all patients, men that are to receive ADT should be counseled against smoking, maintaining a healthy diet, and exercising regularly. Cardiovascular risk should be assessed before initiating ADT and then routinely, with blood pressure monitoring and analysis of serum lipid profiles. Currently no specific recommendations are made for patients with hypertension that are on ADT therapy and it can be assumed that goals should be systolic [16]

In addition to cardiac-related death, the relationship between all-cause mortality and ADT use has also been examined. [27] Tsai et al., utilized the CaPSURE database to study this survival endpoint. In this study, significant prognostic factors for all-cause mortality identified for men undergoing radical prostatectomy included: ADT administration (HR = 2.2, P [27] Again, this must be discussed globally with patients prior to initiating ADT therapy.

Skeletal composition and fractures

Osteoporosis in men has gained significant clinical attention over the last decade, and concerted efforts are underway to more completely delineate the disease process in males. T-score criteria for a diagnosis of osteoporosis and osteopenia are still evolving; however, it is estimated that using fractures as a clear endpoint for the disease in males have a 13-25% lifetime risk of developing osteoporosis. [28] Hypogonadism is well-described as one of the major causes of osteoporosis in men along with alcohol abuse, glucocorticoid excess, low-dietary calcium, vitamin D deficiency, and sedentary lifestyle. The increasing use of ADT in current practice patterns for the treatment of local and advanced CaP has made ADT one of the leading causes of hypogonadism, and thus osteoporosis in men. [29]

In a contemporary series of 395 men receiving ADT (Level II evidence), Malcolm et al., identified ADT as an independent risk factor for the development of osteoporosis and nonpathologic fractures. In this series, 23% of men receiving ADT developed osteoporosis, while 7% were diagnosed with nonpathologic fractures. Further, duration of ADT was identified to be an independent predictor for development of osteoporosis (P [30]

Recently, several large Level II series have reported evidence that GnRH agonists increase the risk of fractures in men receiving ADT when compared to controls. [31],[32],[33] Shahinian et al., analysed men with CaP from the SEER database to assess osteoporosis and fracture risk in the ADT population. For men surviving at least five years from CaP diagnosis, the incidence of fractures was 19.4% for patients treated with GnRH agonists vs. 12.6% for men treated with other modalities (P [31]

Smith et al., assessed the risk for fracture development in men with non-metastatic disease who were treated with ADT. [33] Nearly 4000 men with a history of ADT receipt were matched to men receiving no form of castration therapy (n = 7774). Their comparison study demonstrated a significantly higher clinical fracture risk in the GnRH agonist group (7.88/100 vs. 6.51/100 person-years at risk, P [33] These results were corroborated and demonstrated to be remarkably reproducible in another study by Smith et al., which utilized claims information from 16 large American insurance companies. This study identified a higher incidence of bony fractures in patients with non-metastatic CaP treated with GnRH agonists than in matched controls (7.91/100 vs. 6.5/100 person-years at risk, RR = 1.21, 95% CI 1.09-1.34). Again, ADT therapy was identified as an independent risk factor for fracture risk on multivariate analysis. [32]

The increased fracture rates in patients receiving hormonal therapy are multifactorial, including higher incidence of metastatic bony lesions, fragility from disease and disease-related treatment, and decreased bone mineral density (BMD) associated with ADT. [34] Several mechanisms linking decreased BMD with GnRH agonists have been proposed since it has been observed that ADT decreases BMD at a rate of approximately 4-5% per year, and increases urinary and serum concentrations, markers of osteoclastic and osteoblastic activity. [34] Leder et al., reported increased skeletal responsiveness to the bone-resorbing effects of parathyroid hormone (PTH) in men treated with ADT by comparing metabolic indicators of skeletal activity during PTH infusion prior to the initiation of ADT and after serum-confirmed GnRH-induced hypogonadism. [35] Further, 17b-estradiol levels, which have been shown to have a significantly positive relationship with BMD measurements, have also been demonstrated to with ADT. [36] A more thorough understanding of the mechanisms contributing to osteoporosis in men and specifically in males receiving ADT is driving clinical solutions.

Currently no consensus clinical guidelines exist for monitoring bone loss in chemically castrate patients. However, it has been proposed that these patients be monitored similarly to peri-and postmenopausal women, with a baseline dual energy X-ray absorptiometry (DEXA) scan or quantitative computerized tomography (qCT) scan and then at various intervals dictated by the baseline measurements. Patients already receiving ADT should receive a baseline scan and be routinely followed. Practically, DEXA scan may be better than the more sensitive qCT, as it is relatively cost effective and minimizes radiation exposure. [37] Recently, an expert panel (Level V evidence) has provided specific recommendations for this patient population. [38] The group proposed that men with CaP at increased risk for fracture (i.e. those receiving ADT or with a prior history of fractures) should have routine BMD screens every two years for T-score > 1 and every 6-12 months for T-score between 1.0 and 2.5. [38]

Treatment for increased fracture risk and osteoporosis in chemically castrate men starts with nonmedical therapy and overlapping strategies that are used in males without malignancies and postmenopausal females. Weight-bearing exercise regimens to preserve BMD, muscle mass, and total body weight should be implemented. Men with metastatic disease or established osteoporosis are to be counseled to refrain from heavy lifting. [37] All men at increased risk for fractures are advised to maintain a diet with adequate calcium (1200-1500 mg/day) and vitamin D intake (400-800 IU per day). [29] Bisphosphonate therapy is recommended for males with a diagnosis of osteoporosis or radiographically confirmed fractures following minimal trauma. [38] Pamidronate and zoledronic acid have both been shown to prevent bone loss in men receiving ADT in well-designed clinical trials (Level II evidence). [39],[40],[41] Optimal dosing regimens are still under investigation, but efficacy has been demonstrated with 60 mg pamidronate every 12 weeks, or a single 90 mg infusion every 6 months. [39],[41] Intravenous zoledronic acid, 4 mg every three months, has been shown not only to prevent bone loss, but actually to increase BMD in men receiving ADT. [40] Preliminary data suggests that other bisphosphonates may prevent osteoporosis and fractures in men on ADT; however, more data is requisite.

 Conclusion



Androgen deprived therapy remains a widely utilized therapy for treatment of both localized and advanced CaP. Evidence suggests that ADT is accompanied by a host of pervasive adverse effects-from diminished quality of life to decreased bone mineral density-that involve nearly all physiologic systems with varying incidences [Table 1]. Physicians must counsel and educate patients on the effects of ADT prior to initiating treatment and should continually screen for adverse outcomes over the course of therapy [Table 2]. Moreover, urologists must be aware of pharmacologic and non-pharmacologic interventions that are available to mitigate the undesirable effects of ADT. As demonstrated in this review, continued research into identifying, ameliorating, and treating the adverse effect of ADT are becoming increasingly important as the number of patients diagnosed with CaP continues to grow. Intermittent ADT and lifestyle alterations offer promising avenues for those more broadly ameliorating the effects of an androgen-deprived state.

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