I. Introduction Endocrine therapy for prostate cancer is one of the important tools in the treatment of prostate cancer and is recommended as the first-line treatment for advanced prostate cancer. It is applicable to progressive prostate cancer, which accounts for 85-97% of clinical prostate cancer diagnoses. Endocrine therapy can significantly prolong the progression-free period, survival and overall survival of patients with tumor. Endocrine therapy can significantly prolong the progression-free period, survival and overall survival of patients. Whether a patient with prostate cancer receives endocrine therapy or not has a significant impact on the patient’s 3-year survival. Endocrine therapy is indicated for locally progressive and metastatic “prostate cancer”, i.e. stages C and D, equivalent to TNM stages T3, N0~3 and M1, and also for adjuvant therapy before and after radical surgery and radiotherapy. The mechanism of endocrine therapy The pathogenesis of prostate cancer is not completely clear so far, especially the role of cytokines, growth factors is even less clear. It is clear that 86-98% of prostate cancer is a hormone-dependent tumor, mainly related to the stimulation of testosterone. 95% of testosterone is produced by testicular Leydig cells, and the hypothalamus produces luteinizing hormone (LHRH) which acts on the anterior pituitary gland to secrete luteinizing hormone (LH), and under the stimulation of LH, testicular Leydig cells produce testosterone. Leydig cells produce testosterone. The endocrine environment of the prostate depends on the hypothalamic-pituitary-testicular axis. 5% of testosterone is produced by the fasciculus and reticular formation of the adrenal cortex in response to stimulation by the pituitary gland producing adrenocorticotropic hormone (ACTH). 60% of androgens in men over 65 years of age are of testicular origin and 40% are of adrenal origin. III. Androgen blocking pathways 1. surgical depot; 2. pharmacological depot; 3. blocking androgens at the target cell level; 4. 5α-reductase inhibition; 5. anti-adrenal secretory drugs; 6. total androgen blockade (MAB). Expected results of endocrine therapy 1. Complete remission: tumor disappears and all relevant tumor markers are normal. 2., Partial remission: 50% reduction of original tumor, no metastases, non-palpable lymph nodes or imaging only incidental findings. Note: The minimum level of PSA before and after treatment, and the time to reach the minimum level are indicators to assess whether endocrine therapy is effective, but cannot determine whether there is metastasis. V. Methods of endocrine therapy (a) Surgical debulking Double orchiectomy is the standard treatment for advanced “prostate cancer”: a double orchiectomy; b double orchiectomy under the peritoneum; c double orchiectomy + testicular prosthesis implantation. Advantages: (1) the operation is simple, can be performed under local anesthesia, and is inexpensive; (2) the patient’s plasma testosterone level can reach the lowest level 3-12h after the operation; (3) 80% of patients can have their prostate volume and tumor reduced and their symptoms can be relieved. (2) Drug depot 1. Estrogen (1) ethylene estradiol (DES): 1mg, 3 times a day (5mg DES is equivalent to orchiectomy); (2) ethylene estradiol diphosphate: 1000mg, once a day (for hormone non-dependent prostate cancer). Ø Mechanism of action: Acts on prostate stroma, acts directly on prostate cancer cells, and reduces LHRH and LH production through feedback regulation at the hypothalamic level. ØAdverse effects: ①Small dose of DES has no effect on prostate cancer cells; ②Cardiovascular toxic effects; ③High mortality rate, mostly occurs within 1 year after treatment; ④Affects ester metabolism, coagulation system and fluid balance; ⑤40% male breast enlargement. 2.LHRH mimetic (LHRHa) (1) Goserelin (Noraid): 3.6mg, subcutaneous injection, once a month. Ø Mechanism of action: Under normal physiological conditions, LHRH is released from the hypothalamus of males in the form of pulses at intervals of about 90 minutes, which binds to LHRH receptors on the pituitary cell membranes, causing the release of LH, which in turn stimulates the production of testosterone (T) by testicular Leydig cells. Norelide is a sustained-release LHRHa implant that acts similarly to natural LHRH, but is 100 times more potent than natural LHRH. Thus, early in the course of Norad injections alone, most of the LHRH receptors are occupied by Norad, and then there is a temporary increase in plasma LH concentration and a transient increase in testicular production of testosterone. With the continuous action of Norelide with LHRH receptors, the LHRH receptors on the surface of pituitary gland disappear (down-regulation of receptors), thus inhibiting the secretion of LH by pituitary gland and also inhibiting the secretion of testosterone by testes. ØAdverse effects: When LHRHa is started, LH is stimulated and testosterone secretion is increased within 2-3 weeks, so that the patient is in the “acute exacerbation period” and the clinical symptoms may be aggravated, such as aggravation of osteoma, insufficient bone marrow storage, spinal cord compression, and even hemiplegia and death. Therefore, anti-androgen agents should be given before and during the start of LHRHa use. Hot flashes, decreased libido ED. (C) Androgen blockade on target cells 1. Anti-androgens At the level of target cells, androgen secretion is inhibited or blocked by competing for androgen receptors. (1) Anti-androgens by alcohols: (1) cyproterone acetate (CPA): 100mg/d (not yet approved for use in the United States); (2) megestrol acetate 4mg twice daily; (3) hydroxyprogesterone acetate 250mg once daily; (4) megestrol (androgestrel) 100mg three times daily, orally or 150mg intramuscularly, once a week; (5) Chlormadinone acetate 100mg once daily and 50mg once daily after three months. (2) Non-steroidal (simple anti-androgen) anti-androgen: (1) Fuzeol (retardation of tumor, fluoride) 250mg, 3 times daily, orally, can block androgen inhalation in target cells need to review liver function and sperm count regularly. Adverse effects: water retention, nausea, vomiting, diarrhea and male breast enlargement, the total incidence is 87.5%; (2) Nirumet: 300mg once daily, 150mg once daily after four weeks, visual regulation impairment, withdrawal-like effects, liver function impairment, ED; (3) Ketoconazole: 200-400mg four times daily. It can inhibit the synthesis of sterol membrane and inhibit cytochrome P450-dependent enzymes, with hydrocortisone to reduce plasma PSA by 50%; (4) Konsolid: 50mg, once daily, orally. 150mg, once daily, in oral dosing to reach depot level. Binds to androgen receptors in the prostate and pituitary gland Binds to prostate androgen receptors with an affinity four times stronger than that of Fuzeol. The affinity to pituitary androgen receptors is 10 times stronger than that of Fuzeol. It can also compete for binding to mutant and wild-type receptors. It has a long half-life (5.8 days) and is suitable for once-daily dosing levels, reaching effective blood concentrations after the first dose, with few metabolic impurities but no post-biological activity. Gynecomastia and flushing may occur, with no other endocrine effects. (iv) 5α-reductase inhibition Polyclonal: 5mg, once daily. Inhibits the conversion of testosterone to dihydrotestosterone (DHT) in the prostate gland. It has limited effect on lowering PSA in plasma, but slows down the rebound of PSA levels after radical surgery for “prostate cancer”. It has no effect on sexual function. (E) Anti-adrenal secretory drugs (1) Amphiregulin: 100mg, once daily, orally. It inhibits the formation of androgens by inhibiting cytochrome P450 and 17-hydroxylase in adrenal and testicular microsomes. It is indicated for metastatic prostate cancer after orchiectomy. The occurrence of hypokalemia should be closely monitored. (2) Aminoglutethimide: 500~1000mg, 3 times daily, orally. It can prevent the conversion of cholesterol to pregnenolone and inhibit the synthesis and production of androgens in the testes and adrenal glands, and also inhibit the synthesis of aldosterone, cortisol and estrogen, similar to adrenalectomy. It is indicated for endocrine treatment failure or recurrent prostate cancer. It has many side effects and should be used with caution. (vi) Androgen total blockade (MAB-MaximalAndrogenBlockade). The most important finding in the endocrine treatment of prostate cancer is that the testes and adrenal glands produce approximately equal amounts of dihydrotestosterone (DHT), which is the hormone that stimulates the growth and production of functionally active androgens in normal as well as cancerous prostate cells. The patient is given anti-androgen therapy at the same time to achieve the desired “prostate cancer” treatment result. 1. Options: double orchiectomy + Comstock, double orchiectomy + retardation tumor, double orchiectomy + nilumide, double orchiectomy + CPA; goserelin + CPA, goserelin + Comstock, goserelin + retardation tumor, goserelin + CPA; leuprolide + retardation tumor, leuprolide + nilumide; buserelin + retardation tumor, buserelin + CPA. 2. Recommended options: (1) double orchiectomy + Comstock, goserelin + retardation tumor, buserelin + CPA orchiectomy + Comstock 50mg once a day, + Polyclonal 5mg once a day.