Gonadotropin-releasing hormone (GnRH) analogs are among the most clinically versatile drugs in endocrinology, used to suppress gonadal hormones in prostate cancer, endometriosis, and uterine fibroids, to trigger ovulation in assisted reproduction, and to restore fertility in hypogonadotropic hypogonadism through pulsatile delivery. This apparent paradox resolves entirely through receptor pharmacology: the same receptor activated in a pulsatile pattern stimulates the hypothalamic-pituitary-gonadal (HPG) axis, while continuous occupancy by a GnRH agonist drives receptor downregulation and gonadotropin suppression, and competitive antagonists block the receptor immediately without any initial stimulation. This module covers the complete clinical pharmacology of GnRH agonists, injectable antagonists, oral antagonists, and pulsatile GnRH therapy across all major non-ART indications. Assisted reproductive technology applications are covered in Ova-03 and Ova-04 of the Gonadal and Ovarian Pharmacology series.
GnRH agonist analogs are structural modifications of native GnRH decapeptide that bind the GnRH receptor (GnRHR) with higher affinity and resist peptidase degradation, producing prolonged, non-pulsatile receptor occupancy. At agonist initiation, receptor activation is indistinguishable from an endogenous GnRH pulse: the Gq/11 protein cascade activates phospholipase C beta (PLC-beta), generating IP3 (inositol trisphosphate) and DAG (diacylglycerol), mobilizing calcium and activating protein kinase C (PKC), driving an initial surge of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion that lasts 1 to 2 weeks. In men with prostate cancer, this testosterone flare produces serum testosterone values 50 to 80% above baseline, with the clinical risk of disease flare, increased bone pain, urinary obstruction, and spinal cord compression in patients with vertebral metastases.1
The transition from stimulation to suppression proceeds in two mechanistic phases. In phase one, occurring within hours of continuous agonist exposure, GnRHR undergoes homologous desensitization through PKC-mediated phosphorylation of intracellular receptor domains, uncoupling the receptor from Gq/11 without significant surface receptor loss. Because the GnRHR uniquely lacks an intracellular carboxyl-terminal tail (unlike nearly all other G protein-coupled receptors), this uncoupling proceeds more slowly than for other GPCRs (G protein-coupled receptors), but the consequence is prolonged signal reduction per molecule of receptor. In phase two, occurring over days to weeks, internalization of GnRHR via a clathrin-independent, dynamin-dependent pathway reduces surface receptor density by 80 to 95%. The loss of surface receptors, combined with post-receptor uncoupling, constitutes the pharmacodynamic basis for medical castration: serum testosterone falls to castrate levels (below 50 ng/dL) within 3 to 4 weeks of depot agonist initiation.12
Prevention of the testosterone flare in prostate cancer requires co-administration of an anti-androgen beginning 7 to 14 days before the first depot agonist injection and continued for 4 weeks afterward. First-generation non-steroidal anti-androgens such as flutamide, bicalutamide, and nilutamide competitively block the androgen receptor (AR) at the prostate and other target tissues, preventing testosterone and dihydrotestosterone (DHT) from driving tumor growth during the flare period. Bicalutamide 50 mg daily is the most commonly used agent for this purpose. Combined androgen blockade (CAB), defined as continuous GnRH agonist plus anti-androgen, provides marginally superior progression-free survival over agonist alone in some analyses but at the cost of substantially increased adverse effects from sustained AR blockade. The clinically accepted standard in most guidelines is to use anti-androgen coverage only for flare prevention at agonist initiation, discontinuing after 4 weeks.23
The kinetics of testosterone recovery after GnRH agonist discontinuation are determined by the time required to restore surface GnRHR density to levels sufficient for physiological pulsatile signaling. After a single 3-month depot injection, testosterone recovery to normal levels typically requires 3 to 6 months in younger patients with intact hypothalamic-pituitary-gonadal axis function, but may be delayed 12 to 18 months or longer in older patients or those who have received prolonged androgen deprivation therapy (ADT). Approximately 15 to 20% of men who receive GnRH agonist therapy for more than 2 years fail to recover normal testosterone levels even after 18 months off therapy, a phenomenon attributed to permanent suppression of testicular Leydig cell function compounded by age-related hypogonadism. For women treated for endometriosis or fibroids, return of menstrual cycles typically occurs within 3 to 4 months after stopping a 3-month depot, though ovarian function suppression may persist longer in perimenopausal women.112
Anti-androgen flare coverage is mandatory in prostate cancer patients with high disease burden: skeletal metastases (vertebral compression fracture or cord compression risk), bulky nodal disease, or severe lower urinary tract obstruction. In patients with no high-risk features, anti-androgen coverage is still standard of care in most guidelines. Oral anti-androgen: bicalutamide 50 mg daily, begin 7–14 days before first depot injection, continue 4 weeks. Alternatively, a GnRH antagonist (degarelix or oral relugolix) avoids the flare entirely and may be preferred in these high-risk patients. Do not use anti-androgen monotherapy as a substitute for depot agonist; it provides inferior testosterone suppression.
Leuprolide acetate is the most widely used GnRH agonist in North America, available in multiple depot formulations that differ substantially in dosing interval, injection route, and pharmacokinetic profile. The leuprolide microsphere depot (Lupron Depot) is formulated using poly(lactic-co-glycolic acid) (PLGA) microsphere technology: biodegradable polymer microspheres encapsulate leuprolide acetate and are suspended in a sterile diluent for intramuscular (IM) injection. Upon injection, the microspheres undergo slow hydrolysis at body temperature, releasing leuprolide at a controlled rate. Available formulations provide 1-month (7.5 mg IM), 3-month (22.5 mg IM), 4-month (30 mg IM), and 6-month (45 mg IM) dosing intervals. Subcutaneous (SC) leuprolide depot formulations (Eligard) use an atrigel polymer delivery system in which the drug is mixed at the injection site and gels upon contact with tissue fluids, providing 1-month (7.5 mg SC), 3-month (22.5 mg SC), and 6-month (45 mg SC) options. Native leuprolide plasma half-life is 3 to 4 hours; from depot formulations, terminal elimination extends over the entire dosing interval with sustained low plasma concentrations maintaining receptor downregulation.5
Goserelin acetate (Zoladex) is formulated as a preloaded, rod-shaped biodegradable implant containing drug in a glycolic acid-lactic acid copolymer matrix, placed subcutaneously in the anterior abdominal wall using a specialized trocar device. The 1-month formulation contains 3.6 mg and the 3-month formulation contains 10.8 mg. No mixing or reconstitution is required. The implant matrix degrades progressively, releasing goserelin over the designated interval. Peak plasma concentrations occur within 12 to 15 days of the 1-month implant; testosterone castration is achieved within 21 to 28 days of the initial injection. Goserelin is eliminated primarily renally (90%), and mild renal impairment has minimal impact on clinical efficacy, though dose adjustment is not typically required. The need for SC abdominal placement with a trocar-equipped device is a practical consideration: proper technique is required to ensure subcutaneous (not intramuscular) placement, as IM injection of the implant prevents controlled release and may result in unpredictable pharmacokinetics.5
Triptorelin (Trelstar) is available as a microsphere depot for IM injection in 1-month (3.75 mg), 3-month (11.25 mg), and 6-month (22.5 mg) formulations. Triptorelin has a slightly higher receptor binding affinity than leuprolide, which may confer a modest pharmacodynamic advantage in achieving testosterone suppression below 20 ng/dL (profound castration) compared with the 50 ng/dL threshold, though this distinction lacks robust comparative clinical evidence. Triptorelin is metabolized primarily by hepatic peptidases and eliminated renally. Buserelin is used predominantly in Europe, available as SC injection or intranasal spray for daily use, or as a depot implant. The intranasal formulation (Suprecur) requires three to four times daily application owing to lower bioavailability via the nasal mucosa (approximately 1 to 5%), and patient compliance is a practical limitation. Buserelin depot microspheres (Profact Depot) are implanted SC for 2-month or 3-month release intervals.5
Across all GnRH agonist depot formulations, the essential pharmacokinetic requirement is maintenance of plasma drug concentrations sufficient to sustain GnRHR downregulation continuously between injections. Breakthrough testosterone elevation occurs if the depot is exhausted before the next scheduled injection, or if subcutaneous fibrosis from repeated injections impairs absorption. Clinically, this manifests as PSA (prostate-specific antigen) rise in prostate cancer patients or symptom recurrence in endometriosis patients. Rotating injection sites, confirming correct SC or IM administration technique, and maintaining strict injection intervals are important quality-of-care measures. Testosterone should be checked before each depot injection in prostate cancer patients receiving androgen deprivation therapy (ADT), at least annually once castrate levels are confirmed, to detect non-castrate testosterone levels (testosterone above 50 ng/dL despite depot therapy), which occur in approximately 4 to 13% of patients depending on the assay used and study population.5
Serum testosterone above 50 ng/dL (the traditional castration threshold) despite ongoing GnRH agonist depot therapy is termed non-castrate testosterone on therapy. More recent data suggest outcomes are worse even at testosterone levels between 20 and 50 ng/dL, leading some guidelines to adopt a 20 ng/dL threshold as the target for optimal ADT. Causes include depot delivery failure (incorrect injection, site fibrosis), late testosterone rise before next injection (end-of-dose escape), and in rare cases, primary LH receptor resistance. Clinical action: check injection technique, rotate sites, and consider switching to an antagonist (degarelix or relugolix), which maintains castrate levels more consistently in some comparative studies.
GnRH receptor antagonists compete with endogenous GnRH and GnRH agonist analogs for binding at the GnRHR, acting as competitive reversible blockers that suppress gonadotropin secretion immediately without any initial receptor activation or luteinizing hormone (LH) surge. This mechanistic distinction from agonists has direct clinical consequences: testosterone suppression begins within 24 to 72 hours of the first antagonist dose, without the flare that characterizes agonist initiation, making antagonists the preferred choice when rapid testosterone suppression is required. Degarelix (Firmagon) is the first GnRH antagonist approved specifically for prostate cancer, administered as a subcutaneous injection of a loading dose (240 mg given as two 120 mg injections on day 1) followed by monthly maintenance doses of 80 mg subcutaneous (SC). The initial loading dose produces castrate testosterone levels (below 50 ng/dL) in more than 96% of patients within 3 days, without any testosterone flare.6
Degarelix has important pharmacokinetic and adverse effect features that distinguish it from agonist depots. After SC injection, degarelix forms a depot gel at the injection site (the drug is a decapeptide that aggregates into a hydrogel in aqueous tissue environments), releasing drug over approximately 28 days. Plasma half-life from the depot is approximately 28 days for the maintenance dose. Elimination is primarily via hepatic peptide metabolism; no dose adjustment is required for mild to moderate renal or hepatic impairment. The key limitation of degarelix is injection site reactions: injection site pain, erythema, and nodule formation occur in approximately 35 to 40% of patients, substantially more frequently than with intramuscular (IM) leuprolide or goserelin. These reactions are related to the depot-gel mechanism at the SC injection site and are generally self-limited but may require rotating injection sites or using warm compresses. Long-acting formulations and subcutaneous injection techniques that minimize discomfort are important clinical management considerations.67
Cetrorelix and ganirelix are peptide GnRH antagonists used exclusively in assisted reproductive technology (ART) protocols, administered as daily subcutaneous injections to prevent premature LH surges during controlled ovarian stimulation. Their absorption, distribution, metabolism, and excretion (ADME) and clinical applications in ART are covered in detail in Ova-03 of the Gonadal and Ovarian Pharmacology series. Abarelix, an earlier antagonist withdrawn from the US market owing to serious systemic allergic reactions (including anaphylaxis in approximately 0.9% of patients) related to complement activation by the peptide backbone, is of historical interest as the first injectable GnRH antagonist approved for prostate cancer. Its withdrawal highlighted the importance of the histamine-releasing potential of first-generation antagonist peptide structures and drove development of degarelix, which has substantially lower histamine-releasing activity.7
Pulsatile GnRH therapy represents the therapeutic opposite of agonist depot therapy: rather than continuous suppression, small doses of native GnRH are delivered in a pulsatile pattern mimicking hypothalamic secretion to restore hypothalamic-pituitary-gonadal (HPG) axis function in patients with hypogonadotropic hypogonadism (HH). HH caused by isolated GnRH deficiency (Kallmann syndrome with anosmia, or normosmic idiopathic HH) results in absent or deficient pulsatile GnRH secretion, leading to low LH, low follicle-stimulating hormone (FSH), and low sex steroids with prepubertal testicular or ovarian function. A GnRH pump (portable infusion device) delivers GnRH subcutaneously or intravenously in pulses of 2.5 to 20 mcg every 60 to 120 minutes. Pulsatile GnRH therapy reliably induces spermatogenesis in HH men (sperm counts adequate for natural conception in approximately 75 to 80% of treated patients) and ovulation and pregnancy in HH women (cumulative pregnancy rates of 80 to 90% over multiple cycles). The pump requires patient education, device maintenance, and regular monitoring of hormone levels and gonadal response but avoids the supraphysiological gonadotropin levels and multiple follicular development that complicate exogenous gonadotropin therapy in HH women.8
Prefer antagonist (degarelix or oral relugolix) over agonist depot when: (1) high-risk prostate cancer with vertebral metastases or bulky disease where testosterone flare is dangerous; (2) rapid testosterone suppression is needed for symptom control; (3) patient has prior cardiovascular events within 6 months (relugolix showed 54% lower MACE risk vs. leuprolide in the HERO trial); (4) non-castrate testosterone on agonist depot therapy. Antagonists are also preferred when testosterone recovery speed after treatment completion is important (oral antagonists, particularly relugolix with its t½ of approximately 25 hours, allow recovery in weeks rather than months).
Elagolix (Orilissa) is a non-peptide, small molecule GnRH receptor antagonist approved for the management of moderate to severe endometriosis-associated pain. Its non-peptide structure eliminates the oral bioavailability barrier that precludes the peptide-based antagonists from oral use, because non-peptide molecules are not subject to hydrolysis by intestinal peptidases. Elagolix has oral bioavailability of approximately 57%, a plasma half-life of 4 to 6 hours, and achieves dose-dependent hypothalamic-pituitary-gonadal (HPG) axis suppression: the 150 mg once-daily dose produces partial suppression of estradiol (to early follicular phase levels of approximately 12 to 73 pg/mL), which reduces endometriosis pain while preserving a degree of ovarian function and minimizing bone mineral density (BMD) loss; the 200 mg twice-daily dose produces near-complete suppression (estradiol below 12 pg/mL, equivalent to surgical menopause) with superior pain control but greater BMD loss. This dose-dependent partial vs. complete suppression is the key clinical differentiator of elagolix from depot agonists, which invariably produce profound, non-titratable suppression.10
Elagolix undergoes extensive hepatic metabolism primarily via cytochrome P450 3A4 (CYP3A4), with secondary contributions from CYP2C8 (cytochrome P450 2C8). It is also a substrate of the organic anion-transporting polypeptide 1B1 (OATP1B1) hepatic uptake transporter and an inhibitor of P-glycoprotein (P-gp). The CYP3A4 interaction carries major clinical significance: strong CYP3A4 inhibitors (ketoconazole, ritonavir, clarithromycin) substantially increase elagolix exposure; the 200 mg twice-daily dose is contraindicated with strong CYP3A4 inhibitors because plasma levels reach potentially harmful concentrations. Moderate CYP3A4 inhibitors increase elagolix exposure by approximately 2-fold and require dose reduction or close monitoring. Conversely, strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin) reduce elagolix exposure and may impair therapeutic efficacy. OATP1B1 inhibitors (cyclosporine) significantly increase elagolix concentrations. Elagolix also inhibits P-gp, potentially increasing plasma concentrations of P-gp substrates with narrow therapeutic windows such as digoxin.10
Relugolix (Orgovyx for prostate cancer; Myfembree when combined with estradiol and norethindrone acetate for uterine fibroids and endometriosis) is an oral non-peptide GnRH antagonist with oral bioavailability of approximately 12%, a plasma half-life of approximately 25 hours enabling once-daily dosing, and rapid onset of testosterone suppression. In the pivotal HERO (Relugolix Combination Therapy for Advanced Hormone-Sensitive Prostate Cancer) phase 3 trial, relugolix at 120 mg once daily (after a 360 mg loading dose) achieved sustained castrate testosterone levels (below 50 ng/dL) in 96.7% of patients at 48 weeks, compared with 88.8% for injectable leuprolide, with no testosterone flare. The relugolix arm had a 54% lower rate of major adverse cardiovascular events (MACE) compared with leuprolide, an advantage attributed to faster testosterone recovery with relugolix after treatment completion (mean testosterone 288 ng/dL in the relugolix group vs. 58 ng/dL in the leuprolide group at 90 days post-discontinuation) and to the avoidance of the sustained testosterone suppression-related metabolic effects seen with agonist depots.12
Relugolix is a substrate and moderate inhibitor of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). This generates a clinically important drug interaction profile. Strong P-gp inhibitors (amiodarone, clarithromycin, itraconazole, ritonavir, verapamil) increase relugolix exposure up to 4-fold, raising the risk of prolonged testosterone suppression and adverse effects; these combinations are contraindicated or require relugolix dose reduction. Strong P-gp inducers (rifampin, carbamazepine, St. John's wort) reduce relugolix exposure and may result in inadequate testosterone suppression. Relugolix is not significantly metabolized by CYP3A4, which differentiates its drug interaction profile from elagolix. Linzagolix (Yselty) is a third oral antagonist approved in Europe for uterine fibroids, with a similar mechanism but a longer half-life (approximately 18 hours), also metabolized by CYP3A4, requiring dose adjustment with strong inhibitors or inducers.10
Elagolix: CYP3A4 substrate (major) and CYP2C8 substrate (minor); P-gp inhibitor; OATP1B1 substrate. Strong CYP3A4 inhibitors (ketoconazole, ritonavir): contraindicated with 200 mg twice-daily dose. Rifampin (CYP3A4 inducer): reduces efficacy. Cyclosporine (OATP1B1 inhibitor): increases elagolix levels. Relugolix: P-gp and BCRP substrate; not a major CYP substrate. Strong P-gp inhibitors (amiodarone, clarithromycin, verapamil): up to 4-fold exposure increase; contraindicated or dose-reduce. Strong P-gp inducers (rifampin, carbamazepine): reduce relugolix efficacy; avoid combination. Both agents: monitoring for hypoestrogenic effects (vasomotor symptoms, BMD) and mood changes during therapy.
In advanced prostate cancer, androgen deprivation therapy (ADT) with a GnRH agonist or antagonist is the cornerstone of treatment for metastatic hormone-sensitive disease, biochemically recurrent disease after local therapy, and locally advanced disease in combination with radiotherapy. The clinical goal is sustained testosterone suppression below 50 ng/dL (or preferably below 20 ng/dL). Intermittent ADT (alternating periods of treatment and treatment holidays guided by PSA levels) is an option for biochemically recurrent disease without metastases, offering similar overall survival to continuous ADT in selected patients while allowing partial testosterone recovery between cycles and potentially mitigating some long-term adverse effects. Continuous ADT is required for metastatic disease. Duration of ADT combined with radiotherapy for localized high-risk disease is typically 18 to 36 months based on randomized trial data. The HERO (Hormonal Treatment with Relugolix in Men with Prostate Cancer) trial established relugolix as an alternative to leuprolide with cardiovascular advantage, which is clinically relevant because cardiovascular disease is the leading non-cancer cause of death in men with prostate cancer receiving ADT.11
In endometriosis, the therapeutic goal is suppression of estrogen-dependent endometrial implants, which grow, bleed, and generate inflammatory mediators in response to ovarian estradiol. GnRH agonist depots (leuprolide 3.75 mg monthly or 11.25 mg every 3 months, goserelin 3.6 mg monthly) reduce dysmenorrhea, non-menstrual pelvic pain, and dyspareunia in approximately 85% of patients, comparable to surgical management in symptom control.9 Treatment is limited to 6 months of continuous use without add-back therapy owing to hypoestrogenic bone mineral density (BMD) loss (approximately 4 to 6% at the lumbar spine over 6 months). Add-back therapy with low-dose estrogen plus progestin (norethindrone acetate 5 mg daily, or conjugated equine estrogen 0.625 mg plus norethindrone acetate 5 mg) maintains pain control while substantially attenuating BMD loss by keeping estradiol in the 20 to 40 pg/mL range, below the threshold for endometriosis stimulation but adequate for bone protection. Elagolix 150 mg daily (partial suppression) can be used for up to 24 months; elagolix 200 mg twice daily is limited to 6 months without add-back therapy but up to 12 months with add-back norethindrone acetate 1 mg daily.10
In uterine fibroids (leiomyomata), GnRH agonists reduce fibroid volume by 35 to 65% over 3 to 6 months of treatment through hypoestrogenic shrinkage, a response that is useful preoperatively to reduce surgical bleeding and facilitate laparoscopic or uterine-sparing procedures. Fibroid regrowth occurs within 3 to 6 months of stopping therapy in most patients, limiting the utility of GnRH agonists as definitive fibroid treatment. The oral antagonist combination product Myfembree (relugolix 40 mg plus estradiol 1 mg plus norethindrone acetate 0.5 mg once daily) provides sustained fibroid symptom control with add-back therapy built into the formulation, enabling use beyond 6 months with BMD monitoring. Linzagolix 100 mg daily (without add-back) or 200 mg daily (with add-back) provides similar outcomes in clinical trials. The combination approach with add-back built in represents an important therapeutic advance over agonist monotherapy, which required separate add-back prescription and was limited to 6 months.12
In central precocious puberty (CPP), defined as activation of the hypothalamic-pituitary-gonadal (HPG) axis and appearance of secondary sexual characteristics before age 8 in girls and age 9 in boys, GnRH agonist depot therapy is the standard of care. By creating continuous HPG suppression, depot agonists halt pubertal progression and protect final adult height by extending the time for skeletal growth before epiphyseal fusion. Leuprolide depot (Lupron Depot-Ped) at 0.3 mg/kg (minimum 7.5 mg) intramuscular (IM) every 4 weeks is the most commonly used regimen in children; a 3-month formulation (11.25 or 30 mg) is also approved. Histrelin acetate subcutaneous implant (Supprelin LA) implanted annually provides continuous agonist delivery, achieving consistent luteinizing hormone (LH) suppression with the convenience of annual replacement. Adequacy of HPG suppression is confirmed by stimulated LH below 2 IU/L (IU per liter) after GnRH or GnRH agonist stimulation at 30 to 60 minutes. Treatment continues until the child reaches an age-appropriate stage for puberty to resume; withdrawal of therapy is followed by resumption of gonadotropin secretion and progression of puberty in 3 to 6 months.13
Endometriosis implants require estradiol above approximately 20 pg/mL to grow and produce symptoms. Bone loss from hypoestrogenia occurs at estradiol below approximately 30–40 pg/mL. The therapeutic window of add-back therapy is the range of 20–40 pg/mL estradiol: low enough to suppress endometriosis while preventing bone loss. Norethindrone acetate 5 mg daily alone (without estrogen) provides bone protection via progestin-mediated effects and is an alternative in women who cannot take estrogen. In clinical practice, add-back does not significantly reduce pain control efficacy when used appropriately, and GnRH agonist therapy with add-back is approved for up to 12 months total (some protocols up to 24 months with monitoring).
The most important drug interaction class for GnRH agonists and degarelix in prostate cancer is QT interval (QT) prolongation. Androgen deprivation therapy (ADT)-induced testosterone suppression prolongs the cardiac action potential duration and increases the QTc (corrected QT interval); pooled data suggest GnRH agonist therapy increases QTc by approximately 10 to 20 milliseconds on average. Concurrent use of other QT-prolonging agents substantially amplifies this risk. High-risk combinations include antiarrhythmic drugs (amiodarone, sotalol, quinidine), certain antipsychotics (haloperidol, quetiapine), antimicrobials (fluoroquinolones, azithromycin, fluconazole), and methadone. A baseline electrocardiogram (ECG) is prudent before starting ADT in patients on any QT-prolonging medication, with repeat ECG at 1 to 3 months. Patients with congenital long QT syndrome or QTc above 500 milliseconds at baseline should not receive GnRH agonists without cardiology input. Relugolix has a similar QT-prolonging risk via testosterone suppression, but its short half-life allows faster QTc normalization after discontinuation than depot agonists.11
Bone mineral density (BMD) loss is the most clinically significant long-term adverse effect of GnRH-mediated estrogen and testosterone suppression in both sexes. In men on ADT for prostate cancer, BMD declines by approximately 2 to 3% per year at the lumbar spine and femoral neck during testosterone suppression, with fracture risk increasing significantly after 12 months of treatment. Calcium supplementation (1,000 to 1,200 mg daily) and vitamin D supplementation (800 to 1,000 IU daily) are recommended for all patients on ADT, with baseline dual-energy X-ray absorptiometry (DEXA) scanning and repeat DEXA at 12 months in men on continuous ADT. In high-risk patients (T-score below –1.0 at baseline, history of fragility fracture, or ADT duration exceeding 12 months), bisphosphonates (zoledronic acid 4 mg IV every 12 months) or denosumab (60 mg SC every 6 months) are standard bone-protective agents. In women on GnRH agonist therapy for endometriosis or fibroids, add-back therapy as described in Section 5 substantially mitigates BMD loss; annual DEXA is appropriate for treatments exceeding 6 months without add-back.413
The metabolic syndrome that develops during ADT is a well-characterized consequence of sustained hypogonadism in men, comprising increases in body fat (particularly visceral adiposity), decreases in lean muscle mass, insulin resistance, dyslipidemia (elevated triglycerides, reduced HDL (high-density lipoprotein) cholesterol), and hypertension. The combination of these factors increases the risk of type 2 diabetes by approximately 40% and major cardiovascular events by 10 to 20% over 1 to 5 years of ADT. Lifestyle intervention (regular aerobic and resistance exercise, dietary modification) meaningfully attenuates ADT-induced metabolic changes and is recommended for all patients. The Endocrine Society and major oncology societies recommend screening for diabetes and cardiovascular risk factors at baseline and every 3 to 6 months during ADT. Statin therapy should be continued or initiated according to cardiovascular risk guidelines; new-onset diabetes during ADT should be managed with standard antidiabetic therapy. Hot flashes, the most common symptomatic adverse effect of GnRH-mediated hypogonadism (occurring in 50 to 80% of men on ADT), can be treated with venlafaxine, gabapentin, or medroxyprogesterone acetate; estrogen-based hot flash therapy is contraindicated in prostate cancer patients.3
Monitoring during GnRH analog therapy is indication-dependent. In prostate cancer, the standard monitoring schedule includes PSA (prostate-specific antigen) every 3 to 6 months, testosterone before each injection (or every 3 to 6 months for oral agents) to confirm castrate levels, a metabolic panel (fasting glucose, lipids, hemoglobin A1c (HbA1c)) every 3 to 6 months, and DEXA annually. In endometriosis and fibroid treatment, BMD monitoring with DEXA is appropriate at 6 to 12 months when using agents without add-back therapy or at 12 to 24 months with add-back therapy, along with symptom reassessment. In central precocious puberty, hormonal monitoring with stimulated luteinizing hormone (LH) every 3 to 6 months confirms ongoing suppression; bone age X-ray of the left hand and wrist annually tracks skeletal maturation. For all indications, the treating clinician should assess for depression and sexual dysfunction, which are common and often underreported adverse effects of sustained sex steroid suppression.34
ADT increases cardiovascular risk through metabolic syndrome, QT prolongation, and (with agonists) testosterone flare. Relugolix (HERO trial): 54% lower MACE vs. leuprolide at 48 weeks in men with advanced prostate cancer. Prefer relugolix for patients with established cardiovascular disease, prior MI or stroke within 6 months, heart failure, or high baseline cardiovascular risk. GnRH agonist depots: avoid in men with congenital long QT or QTc above 500 ms. All ADT patients: baseline ECG if on QT-prolonging drugs; regular exercise and statin therapy per guidelines; screen for diabetes at every visit. Do not delay necessary ADT for cardiovascular concerns without oncology input; untreated prostate cancer is also life-threatening.
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