ADT for Prostate Cancer: A Comprehensive Overview

Androgen deprivation therapy (ADT) is a cornerstone of treatment for advanced prostate cancer, aiming to reduce androgen levels that fuel tumor growth. While effective in slowing disease progression, ADT also introduces physiological and psychological effects that impact patients’ quality of life.

Understanding how this therapy works, its different forms, and its consequences can help patients and healthcare providers make informed decisions.

Hormonal Pathways In Prostate Cells

Prostate cells rely on androgens, primarily testosterone and its potent derivative dihydrotestosterone (DHT), for growth and function. These hormones bind to the androgen receptor (AR), a nuclear transcription factor that regulates gene expression. Testosterone, produced mainly by the testes and in smaller amounts by the adrenal glands, enters prostate cells and is converted into DHT by the enzyme 5α-reductase. DHT binds to the AR with higher affinity, and the hormone-receptor complex then activates genes involved in cell proliferation and survival.

In prostate cancer, this pathway becomes dysregulated, leading to uncontrolled growth. Mutations in the AR gene, increased AR expression, or alterations in co-regulatory proteins enhance receptor sensitivity, enabling cancer cells to thrive even in low-androgen environments. Some tumors can synthesize their own androgens from adrenal precursors or cholesterol, bypassing systemic androgen deprivation. This intratumoral androgen production contributes to the progression to castration-resistant prostate cancer (CRPC), where the disease advances despite reduced circulating testosterone levels.

Initially, ADT induces apoptosis or growth arrest in prostate cancer cells by disrupting AR signaling. However, over time, adaptive mechanisms emerge, including AR splice variants that remain active without ligand binding, increased expression of steroidogenic enzymes, and activation of alternative growth pathways like PI3K/AKT/mTOR and MAPK. These adaptations contribute to therapeutic resistance, necessitating next-generation AR-targeting agents and combination treatments.

Classes Of Androgen Deprivation Agents

ADT employs pharmacological agents to suppress androgen signaling and limit prostate cancer progression. These agents fall into three primary categories: gonadotropin-releasing hormone (GnRH) agonists, GnRH antagonists, and antiandrogens. Each class operates through distinct mechanisms to reduce testosterone levels or block AR activation.

GnRH Agonists

GnRH agonists, also known as luteinizing hormone-releasing hormone (LHRH) agonists, initially stimulate the pituitary gland to release luteinizing hormone (LH), causing a temporary testosterone surge. Continuous stimulation, however, desensitizes the receptor, suppressing LH secretion and reducing testosterone to castrate levels. Common agents include leuprolide, goserelin, and triptorelin, administered via subcutaneous or intramuscular injections at intervals of one to six months.

A key drawback of GnRH agonists is the initial testosterone surge, or “flare” effect, which can temporarily worsen symptoms in metastatic patients. Antiandrogens are often co-administered during the first few weeks to mitigate this. Long-term use is associated with osteoporosis, metabolic changes, and cardiovascular risks, requiring careful monitoring.

GnRH Antagonists

GnRH antagonists, such as degarelix and the oral agent relugolix, directly inhibit GnRH receptors in the pituitary gland, leading to immediate LH and testosterone suppression without a surge. This rapid reduction makes them particularly beneficial for patients with symptomatic metastatic disease.

Degarelix is administered monthly via subcutaneous injection, while relugolix offers a daily oral option, improving convenience. Clinical trials like the HERO study (2020) showed relugolix achieved sustained testosterone suppression with a lower incidence of major cardiovascular events compared to leuprolide. Despite these advantages, GnRH antagonists may cause injection-site reactions (for degarelix) or gastrointestinal side effects (for relugolix), requiring individualized treatment considerations.

Antiandrogens

Antiandrogens block the AR, preventing testosterone and DHT from activating cancer-promoting signaling pathways. They are classified into first-generation (e.g., bicalutamide, flutamide, nilutamide) and second-generation (e.g., enzalutamide, apalutamide, darolutamide) agents. First-generation drugs are often combined with GnRH agonists to counteract testosterone flare, while second-generation agents are more potent and can be used as monotherapy in some cases.

Second-generation antiandrogens have shown superior efficacy in delaying disease progression, particularly in non-metastatic castration-resistant prostate cancer (nmCRPC) and metastatic hormone-sensitive prostate cancer (mHSPC). Trials like PROSPER (2018) and SPARTAN (2018) demonstrated that enzalutamide and apalutamide significantly prolonged metastasis-free survival in nmCRPC patients. However, these agents can cause fatigue, hypertension, and an increased risk of seizures (notably with enzalutamide), necessitating careful patient selection and monitoring.

How The Therapy Affects Tumor Cells

ADT disrupts the AR signaling axis, a key driver of tumor growth, by suppressing testosterone and DHT. Without androgen stimulation, prostate cancer cells enter cell cycle arrest, reducing their ability to divide. This is especially pronounced in hormone-sensitive tumors, where AR signaling remains dominant.

In addition to halting proliferation, ADT induces apoptosis in some cancer cells by disrupting mitochondrial integrity and reducing anti-apoptotic proteins like BCL-2. However, not all cells undergo apoptosis uniformly; some persist in a quiescent state, adapting to low-androgen conditions by altering metabolic dependencies and activating compensatory survival mechanisms.

Over time, selective pressures from ADT favor androgen-independent cells that sustain growth through alternative strategies. Some amplify AR expression, making them hypersensitive to minimal androgens, while others develop AR splice variants that remain active without ligand binding. Certain tumor populations enhance intratumoral androgen synthesis, bypassing systemic suppression. These adaptations drive the transition to castration-resistant prostate cancer (CRPC), where the disease progresses despite low circulating testosterone.

Physical Effects Of Suppression

ADT impacts multiple organ systems, leading to changes in bone density, metabolism, and sexual function. These effects require proactive management to mitigate complications.

Bone-Related Outcomes

Testosterone supports bone homeostasis by promoting osteoblast activity and inhibiting resorption. ADT-induced androgen suppression accelerates bone mineral density (BMD) loss, increasing the risk of osteoporosis and fractures. Men on long-term ADT experience an annual BMD decline of 2-5%, significantly higher than the typical age-related loss of 0.3-1% per year. This is most pronounced in trabecular bone-rich areas like the spine and hips, raising the risk of vertebral and hip fractures, which are linked to increased morbidity and mortality.

To counteract these effects, guidelines recommend baseline and periodic BMD assessments using dual-energy X-ray absorptiometry (DXA) scans. Preventative strategies include calcium (1,200 mg/day) and vitamin D (800-1,000 IU/day) supplementation, weight-bearing exercises, and pharmacologic interventions like bisphosphonates (e.g., zoledronic acid) or denosumab, which reduce fracture risk.

Metabolic Shifts

ADT alters metabolism, increasing the risk of insulin resistance, dyslipidemia, and obesity. Patients frequently experience a shift in body composition, with an average fat mass gain of 2-5 kg in the first year and a reduction in lean muscle mass. This redistribution, particularly in visceral fat, raises the risk of metabolic syndrome and type 2 diabetes. A meta-analysis in the Journal of Clinical Oncology (2019) found ADT-treated patients had a 44% higher diabetes risk than non-ADT users.

Lipid profile changes include increased total cholesterol, LDL, and triglycerides, while HDL levels may remain stable or slightly elevated. These changes, combined with endothelial dysfunction and arterial stiffness, heighten cardiovascular risk. Lifestyle modifications, including dietary adjustments, regular exercise, and glucose monitoring, are essential. In some cases, medications like statins or metformin may help manage lipid abnormalities and insulin resistance.

Sexual Health Changes

Testosterone is integral to sexual function, and its suppression leads to a marked decline in libido, erectile dysfunction (ED), and changes in orgasmic sensation. Over 80% of ADT patients report significant reductions in sexual desire within months of treatment. Erectile dysfunction results from decreased androgenic stimulation and vascular changes impairing nitric oxide-mediated vasodilation. Unlike other forms of ED, ADT-induced dysfunction is less responsive to phosphodiesterase type 5 (PDE5) inhibitors like sildenafil.

Beyond erectile function, ADT can reduce ejaculation volume and orgasm intensity, with some patients experiencing anorgasmia. These changes affect emotional well-being and relationships, making open discussions with healthcare providers crucial. Strategies like penile rehabilitation, vacuum erection devices, and counseling can help patients adapt.

Psychological And Emotional Factors

ADT affects cognitive function, mood, and emotional well-being. Testosterone influences neurotransmitter activity, particularly serotonin and dopamine, which regulate mood and cognition. Its suppression increases the risk of depression, anxiety, and cognitive decline. Studies estimate ADT patients have a 20-30% higher incidence of depressive symptoms than non-ADT patients.

Cognitive effects often involve memory retention, executive function, and processing speed difficulties. Some patients report brain fog or trouble concentrating. Research suggests prolonged testosterone suppression may contribute to structural and functional brain changes, particularly in memory-related regions like the hippocampus. Psychological interventions, cognitive exercises, regular physical activity, and social engagement can help mitigate these effects.