Androgen deprivation therapy

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Androgen deprivation therapy
Prostate Cancer.jpg
Differences between a healthy prostate and a prostate with a tumour
Other namesAndrogen suppression therapy
Specialty oncology

Androgen deprivation therapy (ADT), also called androgen ablation therapy or androgen suppression therapy, is an antihormone therapy whose main use is in treating prostate cancer. Prostate cancer cells usually require androgen hormones, such as testosterone, to grow. ADT reduces the levels of androgen hormones, with drugs or surgery, to prevent the prostate cancer cells from growing. [1] The pharmaceutical approaches include antiandrogens and chemical castration.

Contents

Several studies have concluded that ADT has demonstrated benefit in patients with metastatic disease, and as an adjunct to radiation therapy in patients with locally advanced disease, as well as those with unfavorable intermediate-risk or high-risk localized disease. However, in patients with low-risk prostate cancer, ADT has demonstrated no survival advantage, and significant harm, such as impotence, diabetes and bone loss. [2] [3] [4] [5] [6]

The therapy can also eliminate cancer cells by inducing androgen deprivation-induced senescence. [7] Lowering androgen levels or stopping them from getting into prostate cancer cells often makes prostate cancer shrink or grow more slowly for a time. However, this treatment needs to be combined with radiation therapy (RT) [8] because ADT itself does not eradicate the cancer; it just decreases its aggressiveness. [9]

Types

Method based on surgery

It consists of removing the testicles, the organ where androgens are synthesized, of the cancer patient. It is the most radical treatment for ending the production of androgens. Moreover it is the easiest and least expensive one. The main disadvantage is that surgical castration is a permanent method.

Methods based on drugs

Testosterone synthesizing process Testosterone synthesizing process.jpg
Testosterone synthesizing process
The synthesis of testosterone is mediated by a chain of processes that start in the brain. When the body detects a low level of testosterone, the hypothalamus starts to produce LHRH. LHRH activates the synthesis of LH (Luteinizing hormone) within the pituitary gland. LH induces testosterone synthesis within the testicles. [10] There are two different medicines, LHRH agonists and antagonists, which both lower the amount of testosterone made by the testicles. They work by inhibiting the formation of LH in the pituitary gland. The LHRH agonists produce a sudden increase on levels of testosterone followed by a huge falling, process called flare, whereas LHRH antagonists decrease directly the amount of testosterone. LHRH agonists and antagonists used in androgen deprivation therapy include leuprorelin (leuprolide), goserelin, triptorelin, histrelin, buserelin, and degarelix.
These drugs are injected under the skin achieving the same result as surgical castration. Chemical castration may be preferred to surgical castration[ citation needed ] as it keeps the testes intact.
Adrenal glands were discovered as another center of androgen production even after a castration process. Therefore a complementary treatment was developed that uses antiandrogens to block the body's ability to use any androgens. Prostate cells contain an Androgen Receptor (AR), that when stimulated by androgens like testosterone, promotes growth and maintains prostatic differentiation. These pro-growth signals, however, can be problematic when they occur in a cancer cell. Antiandrogens can enter cells and prevent the binding of testosterone to the receptor proteins, due to their higher affinity for the Androgen Receptor.
The main antiandrogens are cyproterone acetate, flutamide, nilutamide, bicalutamide, and enzalutamide which are all administered in oral pill form.
New antiandrogens that target testosterone synthesis (abiraterone acetate and seviteronel) or AR nuclear translocation (enzalutamide, apalutamide, and darolutamide), as well as combined therapies (galeterone) have been recently developed and may function to better target androgen-responsive cells in combination with ADT. [11] But these too may have negative adverse roles in the development of CRPC.

Effects on men's sexuality

Normal male sexuality seems to depend upon very specific and complicated hormonal patterns that are not completely understood. [12] One study suggests that ADT can alter the hormonal balance necessary for male sexual activity. As men age, testosterone levels decrease by about 1% a year after age 30; however, it is important to determine whether low testosterone is due to normal aging, or to a disease, such as hypogonadism. [13] Testosterone plays a significant role in sexual functioning; therefore, naturally declining levels of testosterone can lead to reduction in normal sexual functioning. Further decreases in serum testosterone can have a negative impact on normal sexual function, leading to a decline in quality of life. [14]

Erectile dysfunction is not uncommon after radical prostatectomy and men who undergo ADT in addition to this are likely to show further decline in their ability to engage in penetrative intercourse, as well as their desire to do so. [13] A study looking at the differences of using GnRH-A (and androgen suppressant) or an orchiectomy report differences in sexual interest, the experience of erections, and the prevalence of participating in sexual activity. Men reporting no sexual interest increased from 27.6% to 63.6% after orchiectomy, and from 31.7% to 58.0% after GnRH-A; men who experienced no erections increased from 35.0% to 78.6%; and men who did not report engaging in sexual activity increased from 47.9% to 82.8% after orchiectomy and 45.0% to 80.2%. [14] This study suggests that the GnRH-A and orchiectomy had similar effects on sexual functioning. A vicious cycle whereby lowering testosterone levels leads to decreased sexual activity, which in turn cause both free and total testosterone levels to decline even further. [12] This demonstrates the importance of androgens for maintaining sexual structures and functions. [12] [15]

Adverse effects

Although targeting the androgen axis has clear therapeutic benefit, its effectiveness is temporary, as prostate tumor cells adapt to survive and grow. The removal of androgens has been shown to activate epithelial–mesenchymal transition (EMT), neuroendocrine transdifferentiation (NEtD) and cancer stem cell-like gene programs. [16]

Thus, activation of these programs via inhibition of the androgen axis provides a mechanism by which tumor cells can adapt to promote disease recurrence and progression. [11]

Orchiectomy, LHRH analogs and LHRH antagonists can all cause similar side effects, due to changes in the levels of sex hormones (testosterone). [17]

A program has been developed for patients and their partners to recognize and manage the more burdensome side effects of androgen deprivation therapy. One program is built around the 2014 book "Androgen Deprivation Therapy: An Essential Guide for Prostate Cancer Patients and Their Loved Ones", which is endorsed by the Canadian Urological Association. [18]

Recent studies have shown ADT may increase the risk of Alzheimer's disease or dementia. [19] The increase in risk may be associated with duration of ADT. [20] While some studies report a decline in certain areas of cognitive function such as spatial abilities, attention, and verbal memory associated with ADT, evidence as a whole remains contradictory. [21] [22] [23] Useful preventative interventions may include social interaction, physical exercise and a "Mediterranean diet", among others. [21] There is an additional small risk of cardiac arrhythmias.

See also

Related Research Articles

<span class="mw-page-title-main">Antiandrogen</span> Class of pharmaceutical drugs

Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking the androgen receptor (AR) and/or inhibiting or suppressing androgen production. They can be thought of as the functional opposites of AR agonists, for instance androgens and anabolic steroids (AAS) like testosterone, DHT, and nandrolone and selective androgen receptor modulators (SARMs) like enobosarm. Antiandrogens are one of three types of sex hormone antagonists, the others being antiestrogens and antiprogestogens.

<span class="mw-page-title-main">Bicalutamide</span> Prostate cancer treatment

Bicalutamide, sold under the brand name Casodex among others, is an antiandrogen medication that is primarily used to treat prostate cancer. It is typically used together with a gonadotropin-releasing hormone (GnRH) analogue or surgical removal of the testicles to treat metastatic prostate cancer (mPC). To a lesser extent, it is used at high doses for locally advanced prostate cancer (LAPC) as a monotherapy without castration. Bicalutamide was also previously used as monotherapy to treat localized prostate cancer (LPC), but authorization for this use was withdrawn following unfavorable trial findings. Besides prostate cancer, bicalutamide is limitedly used in the treatment of excessive hair growth and scalp hair loss in women, as a puberty blocker and component of feminizing hormone therapy for transgender girls and women, to treat gonadotropin-independent early puberty in boys, and to prevent overly long-lasting erections in men. It is taken by mouth.

<span class="mw-page-title-main">Polyestradiol phosphate</span> Chemical compound

Polyestradiol phosphate (PEP), sold under the brand name Estradurin, is an estrogen medication which is used primarily in the treatment of prostate cancer in men. It is also used in women to treat breast cancer, as a component of hormone therapy to treat low estrogen levels and menopausal symptoms, and as a component of feminizing hormone therapy for transgender women. It is given by injection into muscle once every four weeks.

<span class="mw-page-title-main">Flutamide</span> Chemical compound

Flutamide, sold under the brand name Eulexin among others, is a nonsteroidal antiandrogen (NSAA) which is used primarily to treat prostate cancer. It is also used in the treatment of androgen-dependent conditions like acne, excessive hair growth, and high androgen levels in women. It is taken by mouth, usually three times per day.

<span class="mw-page-title-main">Nilutamide</span> Chemical compound

Nilutamide, sold under the brand names Nilandron and Anandron, is a nonsteroidal antiandrogen (NSAA) which is used in the treatment of prostate cancer. It has also been studied as a component of feminizing hormone therapy for transgender women and to treat acne and seborrhea in women. It is taken by mouth.

<span class="mw-page-title-main">Gonadotropin-releasing hormone agonist</span> Drug class affecting sex hormones

A gonadotropin-releasing hormone agonist is a type of medication which affects gonadotropins and sex hormones. They are used for a variety of indications including in fertility medicine and to lower sex hormone levels in the treatment of hormone-sensitive cancers such as prostate cancer and breast cancer, certain gynecological disorders like heavy periods and endometriosis, high testosterone levels in women, early puberty in children, as a part of transgender hormone therapy, and to delay puberty in transgender youth among other uses. It is also used in the suppression of spontaneous ovulation as part of controlled ovarian hyperstimulation, an essential component in IVF. GnRH agonists are given by injections into fat, as implants placed into fat, and as nasal sprays.

<span class="mw-page-title-main">Gonadotropin-releasing hormone antagonist</span> Class of medications

Gonadotropin-releasing hormone antagonists are a class of medications that antagonize the gonadotropin-releasing hormone receptor and thus the action of gonadotropin-releasing hormone (GnRH). They are used in the treatment of prostate cancer, endometriosis, uterine fibroids, female infertility in assisted reproduction, and for other indications.

Feminizing hormone therapy, also known as transfeminine hormone therapy, is hormone therapy and sex reassignment therapy to change the secondary sex characteristics of transgender people from masculine or androgynous to feminine. It is a common type of transgender hormone therapy and is used to treat transgender women and non-binary transfeminine individuals. Some, in particular intersex people, but also some non-transgender people, take this form of therapy according to their personal needs and preferences.

<span class="mw-page-title-main">Enzalutamide</span> Antiandrogen medication used in treatment of prostate cancer

Enzalutamide, sold under the brand name Xtandi, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is indicated for use in conjunction with castration in the treatment of metastatic castration-resistant prostate cancer (mCRPC), nonmetastatic castration-resistant prostate cancer, and metastatic castration-sensitive prostate cancer (mCSPC). It is taken by mouth.

Treatment for prostate cancer may involve active surveillance, surgery, radiation therapy – including brachytherapy and external-beam radiation therapy, proton therapy, high-intensity focused ultrasound (HIFU), cryosurgery, hormonal therapy, chemotherapy, or some combination. Treatments also extend to survivorship based interventions. These interventions are focused on five domains including: physical symptoms, psychological symptoms, surveillance, health promotion and care coordination. However, a published review has found only high levels of evidence for interventions that target physical and psychological symptom management and health promotion, with no reviews of interventions for either care coordination or surveillance. The favored treatment option depends on the stage of the disease, the Gleason score, and the PSA level. Other important factors include the man's age, his general health, and his feelings about potential treatments and their possible side-effects. Because all treatments can have significant side-effects, such as erectile dysfunction and urinary incontinence, treatment discussions often focus on balancing the goals of therapy with the risks of lifestyle alterations.

<span class="mw-page-title-main">Orchiectomy</span> Surgical removal of one or both testicles

Orchiectomy is a surgical procedure in which one or both testicles are removed. The surgery can be performed for various reasons:

The first antiandrogen was discovered in the 1960s. Antiandrogens antagonise the androgen receptor (AR) and thereby block the biological effects of testosterone and dihydrotestosterone (DHT). Antiandrogens are important for men with hormonally responsive diseases like prostate cancer, benign prostatic hyperplasia (BHP), acne, seborrhea, hirsutism and androgen alopecia. Antiandrogens are mainly used for the treatment of prostate diseases. Research from 2010 suggests that ARs could be linked to the disease progression of triple-negative breast cancer and salivary duct carcinoma and that antiandrogens can potentially be used to treat it.

Sexual motivation is influenced by hormones such as testosterone, estrogen, progesterone, oxytocin, and vasopressin. In most mammalian species, sex hormones control the ability and motivation to engage in sexual behaviours.

Darolutamide, sold under the brand name Nubeqa, is an antiandrogen medication which is used in the treatment of non-metastatic castration-resistant prostate cancer in men. It is specifically approved to treat non-metastatic castration-resistant prostate cancer (nmCRPC) in conjunction with surgical or medical castration. The medication is taken by mouth twice per day with food.

<span class="mw-page-title-main">Apalutamide</span> Chemical compound

Apalutamide, sold under the brand name Erleada among others, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is specifically indicated for use in conjunction with castration in the treatment of non-metastatic castration-resistant prostate cancer (NM-CRPC). It is taken by mouth.

A hormone-sensitive cancer, or hormone-dependent cancer, is a type of cancer that is dependent on a hormone for growth and/or survival. Examples include breast cancer, which is dependent on estrogens like estradiol, and prostate cancer, which is dependent on androgens like testosterone.

The medical uses of bicalutamide, a nonsteroidal antiandrogen (NSAA), include the treatment of androgen-dependent conditions and hormone therapy to block the effects of androgens. Indications for bicalutamide include the treatment of prostate cancer in men, skin and hair conditions such as acne, seborrhea, hirsutism, and pattern hair loss in women, high testosterone levels in women, hormone therapy in transgender women, as a puberty blocker to prevent puberty in transgender girls and to treat early puberty in boys, and the treatment of long-lasting erections in men. It may also have some value in the treatment of paraphilias and hypersexuality in men.

The side effects of bicalutamide, a nonsteroidal antiandrogen (NSAA), including its frequent and rare side effects, have been well-studied and characterized. The most common side effects of bicalutamide monotherapy in men include breast tenderness, breast growth, feminization, demasculinization, and hot flashes. Less common side effects of bicalutamide monotherapy in men include sexual dysfunction, depression, fatigue, weakness, and anemia. Bicalutamide is well tolerated and has few side effects in women. General side effects of bicalutamide that may occur in either sex include diarrhea, constipation, abdominal pain, nausea, dry skin, itching, and rash.

Comparison of the nonsteroidal antiandrogen (NSAA) bicalutamide with other antiandrogens reveals differences between the medications in terms of efficacy, tolerability, safety, and other parameters. Relative to the other first-generation NSAAs, flutamide and nilutamide, bicalutamide shows improved potency, efficacy, tolerability, and safety, and has largely replaced these medications in clinical practice. Compared to the second-generation NSAAs, enzalutamide and apalutamide, bicalutamide has inferior potency and efficacy but similar tolerability and safety and a lower propensity for drug interactions.

<span class="mw-page-title-main">Pharmacology of bicalutamide</span>

The pharmacology of bicalutamide is the study of the pharmacodynamic and pharmacokinetic properties of the nonsteroidal antiandrogen (NSAA) bicalutamide. In terms of pharmacodynamics, bicalutamide acts as a selective antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). It has no capacity to activate the AR. It does not decrease androgen levels and has no other important hormonal activity. The medication has progonadotropic effects due to its AR antagonist activity and can increase androgen, estrogen, and neurosteroid production and levels. This results in a variety of differences of bicalutamide monotherapy compared to surgical and medical castration, such as indirect estrogenic effects and associated benefits like preservation of sexual function and drawbacks like gynecomastia. Bicalutamide can paradoxically stimulate late-stage prostate cancer due to accumulated mutations in the cancer. When used as a monotherapy, bicalutamide can induce breast development in males due to its estrogenic effects. Unlike other kinds of antiandrogens, it may have less adverse effect on the testes and fertility.

References

  1. ↑ Perlmutter and Lepor (2007). "Androgen Deprivation Therapy in the Treatment of Advanced Prostate Cancer". Rev Urol. 9 (Suppl 1): S3–8. PMC   1831539 . PMID   17387371.
  2. ↑ "Prostate Cancer is Focus of 2 Studies, Commentary". JAMA Internal Medicine, Media Releases. July 14, 2014.
  3. ↑ Grace L. Lu-Yao; Peter C. Albertsen; Dirk F. Moore; et al. (September 2014). "Fifteen-Year Survival Outcomes Following Primary Androgen-Deprivation Therapy for Localized Prostate Cancer". JAMA Intern. Med. 174 (9): 1460–1467. doi:10.1001/jamainternmed.2014.3028. PMC   5499229 . PMID   25023796.
  4. ↑ Quoc-Dien Trinh; Deborah Schrag (September 2014). "Measuring the Effectiveness of Androgen-Deprivation Therapy for Prostate Cancer in the Medicare PopulationAdequate Data Are Neither the Same as Nor the Enemy of Perfect Data". JAMA Intern. Med. 174 (9): 1468–9. doi:10.1001/jamainternmed.2014.1107. PMID   25023522.
  5. ↑ Karen E. Hoffman; Jiangong Niu; Yu Shen; et al. (September 2014). "Physician Variation in Management of Low-Risk Prostate Cancer: A Population-Based Cohort Study". JAMA Intern. Med. 174 (9): 1450–9. doi:10.1001/jamainternmed.2014.3021. PMC   4372187 . PMID   25023650.
  6. ↑ ANAHAD O'CONNOR (July 14, 2014). "Study Discounts Testosterone Therapy for Early Prostate Cancer". New York Times. There are so many side effects associated with this therapy, and really little evidence to support its use," said Dr. Grace L. Lu-Yao, a researcher at the Rutgers Cancer Institute of New Jersey and the lead author of the report, published on Monday in JAMA Internal Medicine. "I would say that for the majority of patients with localized prostate cancer, this is not a good option.
  7. ↑ Burton, Dominick G. A.; Giribaldi, Maria G.; Munoz, Anisleidys; Halvorsen, Katherine; Patel, Asmita; Jorda, Merce; Perez-Stable, Carlos; Rai, Priyamvada; Agoulnik, Irina U. (27 June 2013). Agoulnik, Irina U. (ed.). "Androgen Deprivation-Induced Senescence Promotes Outgrowth of Androgen-Refractory Prostate Cancer Cells". PLOS ONE. 8 (6): e68003. Bibcode:2013PLoSO...868003B. doi: 10.1371/journal.pone.0068003 . PMC   3695935 . PMID   23840802.
  8. ↑ Warde, Padraig; Mason, Malcolm; Ding, Keyue; Kirkbride, Peter; Brundage, Michael; Cowan, Richard; Gospodarowicz, Mary; Sanders, Karen; Kostashuk, Edmund; Swanson, Greg; Barber, Jim; Hiltz, Andrea; Parmar, Mahesh K.B.; Sathya, Jinka; Anderson, John; Hayter, Charles; Hetherington, John; Sydes, Matthew R.; Parulekar, Wendy; for the NCIC CTG PR.3/MRC UK PR07 investigators (2011). "Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial". The Lancet. 378 (9809): S2104–2111. doi:10.1016/s0140-6736(11)61095-7. PMC   3243932 . PMID   22056152.{{cite journal}}: CS1 maint: numeric names: authors list (link) "Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3"
  9. ↑ Science Daily
  10. ↑ Prostate Cancer Guide
  11. 1 2 Nouri, M; Ratther, E; Stylianou, N; Nelson, CC; Hollier, BG; Williams, ED (2014). "Androgen-targeted therapy-induced epithelial mesenchymal plasticity and neuroendocrine transdifferentiation in prostate cancer: an opportunity for intervention". Front Oncol. 4: 370. doi: 10.3389/fonc.2014.00370 . PMC   4274903 . PMID   25566507.
  12. 1 2 3 Mazzola, C.R.; Mulhall, J.P. (2012). "Impact of androgen deprivation therapy on sexual function". Asian Journal of Andrology. 14 (2): 198–203. doi:10.1038/aja.2011.106. PMC   3735098 . PMID   22231298.
  13. 1 2 (2012). Testosterone therapy: Key to male vitality? Retrieved from: http://www.mayoclinic.com/health/testosterone-therapy/MC00030
  14. 1 2 Sharifi, N.; Gulley, J.L.; Dahut, W.L. (2005). "Androgen deprivation therapy for prostate cancer". The Journal of the American Medical Association. 294 (2): 238–244. doi: 10.1001/jama.294.2.238 . PMID   16014598.
  15. ↑ "Testosterone Deficiency" . Retrieved 5 May 2015.
  16. ↑ Nouri M, Caradec J, Lubik AA, Li N, Hollier BG, Takhar M, Altimirano-Dimas M, Chen M, Roshan-Moniri M, Butler M, Lehman M, Bishop J, Truong S, Huang SC, Cochrane D, Cox M, Collins C, Gleave M, Erho N, Alshalafa M, Davicioni E, Nelson C, Gregory-Evans S, Karnes RJ, Jenkins RB, Klein EA, Buttyan R (January 2017). "Therapy-induced developmental reprogramming of prostate cancer cells and acquired therapy resistance". Oncotarget. 8 (12): 18949–18967. doi:10.18632/oncotarget.14850. PMC   5386661 . PMID   28145883.
  17. ↑ Medline Abstract
  18. ↑ LIFEonADT
  19. ↑ Javadevappa, Ravishankar; Chhatre, Sumedha; Malkowicz, Bruce; Parikh, Ravi; Guzzo, Thomas; Wein, Alan (2019-07-03). "Association Between Androgen Deprivation Therapy Use and Diagnosis of Dementia in Men With Prostate Cancer". JAMA Network Open. 20192 (7): e196562. doi:10.1001/jamanetworkopen.2019.6562. PMC   6613289 . PMID   31268539.
  20. ↑ Nead, Kevin T.; Gaskin, Greg; Chester, Cariad; Swisher-McClure, Samuel; Dudley, Joel T.; Leeper, Nicholas J.; Shah, Nigam H. (2016-02-20). "Androgen Deprivation Therapy and Future Alzheimer's Disease Risk". Journal of Clinical Oncology. 34 (6): 566–571. doi:10.1200/JCO.2015.63.6266. ISSN   1527-7755. PMC   5070576 . PMID   26644522.
  21. 1 2 Cherrier, Monique M.; Higano, Celestia S. (1 February 2020). "Impact of androgen deprivation therapy on mood, cognition, and risk for AD". Urologic Oncology: Seminars and Original Investigations. 38 (2): 53–61. doi: 10.1016/j.urolonc.2019.01.021 . ISSN   1078-1439. PMID   30862408.
  22. ↑ Jamadar, Rhoda J; Winters, Mary J; Maki, Pauline M (March 2012). "Cognitive changes associated with ADT: a review of the literature". Asian Journal of Andrology. 14 (2): 232–238. doi:10.1038/aja.2011.107. ISSN   1008-682X. PMC   3735092 . PMID   22343495.
  23. ↑ McHugh, Deaglan J.; Root, James C.; Nelson, Christian J.; Morris, Michael J. (1 April 2018). "Androgen Deprivation Therapy, Dementia, and Cognitive Dysfunction in Men with Prostate Cancer: How Much Smoke and How Much Fire?". Cancer. 124 (7): 1326–1334. doi:10.1002/cncr.31153. ISSN   0008-543X. PMC   5885282 . PMID   29338083. For cognitive decline, although authors offer a biologically-sound rationale for the development of cognitive impairment on ADT, many of the studies are small, methodologically flawed, but hypothesis provoking. They do not form a body of work that can independently support a conclusion or change in practice.
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