Androgen suppression

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Androgen suppression, also known as testosterone suppression, is a medical treatment to suppress or block the production or action of male sex hormones, typically used against certain cancers that rely on male growth hormones. This a done by castration (sometimes chemical castration) or by prescribing female sex hormones and drugs called antiandrogens. It is employed in androgen deprivation therapy for prostate cancer, feminizing hormone therapy for transgender women, PCOS, acne and hirsutism in women, and against other androgen-dependent conditions. [1]

Contents

Role in gender affirming care

An important goal for many transgender women is to live in society as women, [2] as secondary sex characteristics are vastly impacted by sex hormones, the modulation and suppression of certain sex hormones like testosterone and DHT are important to accomplish this goal. Further anti-androgenic effects can be caused by the suppression of hormones that trigger the release of androgens such as DHEA and gonadotropin-releasing hormone (GnRH). [3] This can be achieved in a number of ways including hormone therapy and surgery. [4]

Anti-androgen medication

Supplementation of estrogens, which is already a primary aspect of feminizing hormone therapy, has some anti-androgenic effects due to negative feedback on the hypothalamic–pituitary–gonadal axis. [2] This is usually used in conjunction with specific anti-androgen medication for the sole purpose of androgen suppression as most patients require additional anti-androgen medication to decrease testosterone production. While all antiandrogens exist to suppress androgens, different antiandrogens have different mechanisms of action which may act on specific or multiple portions of the androgen metabolic pathway in order to either halt the production of androgens or block androgen receptors. [5] [6] Several subclasses of anti-androgen medication which are differentiated by mechanism of action include the following. [7] [8]

Spironolactone 50mg pill. Spironolactone 50 mg.jpg
Spironolactone 50mg pill.

Androgen receptor antagonists

AR antagonists are drugs that directly block androgen receptors by binding to them. [8] Among this class of medication, the most commonly prescribed include cyproterone acetate, bicalutamide and spironolactone. [9]

Androgen synthesis inhibitors

Androgen synthesis inhibitors are drugs which directly inhibit the production of androgens instead of blocking the receptors. [10] This class of drug also contains cyproterone acetate, bicalutamide and spironolactone which have direct suppressive effect on testosterone synthesis at higher doses as well as 5-alpha reductase inhibitors which most commonly include finasteride and dutasteride which only blocks conversion of testosterone into the potent androgen dihydrotestosterone. [6] 5-alpha reductase inhibitors for that reason are useful for patients seeking only partial feminization or as a secondary agent to further suppress androgen activity. [6]

Antigonadotropins

Antigonadotropins are drugs which suppress the effects of either follicle-stimulating hormone, luteinizing hormone or both. [3] This results in anti-androgenic effects due to negative feedback on the hypothalamic–pituitary–gonadal axis [2] which consequently suppress gonadal androgen production. Common medications prescribed for this purpose include progestogens and estrogens which have the dual purpose of also being responsible for the development of secondary sex characteristics. [6]

Surgery

The usage of bilateral orchiectomy to remove the androgen producing organs as a means of androgen suppression is a procedure that some individuals may use as a standalone protocol or a step before a full vaginoplasty. [11] This procedure is considered as a more cost effective as it is regarded as a simple procedure with a low chance of post-surgery complications and negates the necessity of additional anti-androgen medication. A bilateral orchiectomy requires thoughtful consideration, informed consent and the patient to be ready for irreversible change. [12]

Androgen Suppression in Biological Females

Causes and Symptoms of Female Hyperandrogenism

Androgen excess, also referred to as hyperandrogenism, is the presence of heightened androgenic steroids in patients with female biology. [1] PCOS, polycystic ovary syndrome, affecting roughly 10% of biological females, is the most common cause of long-term and mild to moderate hyperandrogenism. [1] [13] Common symptoms include hirsutism, acne, and androgenic alopecia. [1] [13] [14] [15] Other causes of androgen excess include congenital adrenal hyperplasia, severe insulin resistance (SIR), and impaired glucose tolerance. [1] [14] These conditions, along with menstrual history, should be taken into consideration when evaluating a patient. [1] [14] PCOS causes the deregulation of the 5a-reductase (5aR), which can lead to weak androgens such as dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and androstenedione (A4) secreted by the ovaries and adrenal cortex to be synthesized into the more potent androgens testosterone and active dihydrotestosterone (DHT). [1] [13] [14]

Treatments

The type of treatment recommended for androgen excess is dependent on the condition's specific pathology, as well as the patient's age and lifestyle. [1] [13] In many cases, a combination of multiple treatments show higher effectiveness than a single treatment alone. [1] [13] [14] Many treatments for androgen excess interfere with fertility and gestation, and should not be used if a patient wishes to conceive. [1] [15]

Surgical Treatments

Cases of severe hyperandrogenism due to ovarian and adrenal tumors are eligible for treatment through surgical removal. [14] If ovarian tumors are present, a bilateral oophorectomy may also be performed. [14] For premenopausal patients who wish to get pregnant, cytoreductive surgery is an option. [14] Adrenal tumors can be treated both surgically or non-surgically by radiofrequency ablation and cryoablation. [14]

Hormonal Treatments

Hormonal combination contraceptives (HCCs) are commonly prescribed for patients with hyperandrogenism. HCCs target the biochemical causes while also showing effectiveness in treating hirsutism and hyperandrogenic acne. [13] [14] Progestins in HCCs suppress luteinizing hormone (LH) levels and androgen synthesis, and inhibit 5α-R. [13] All progestins have seemingly similar effectiveness in androgen suppression, and there is no professional consensus on what specific type of HCC is the most effective. [13] [14] Ethinylestradiol in hormonal contraceptives also suppresses LH and helps to increase sex hormone-binding globulin (SHBG) which decreases ovarian androgen production and the concentration of free testosterone. [14] Over 60% of women on hormonal contraceptives show improvements specifically in hirsutism related to androgen excess. [13] Usual side effects of hormonal combination contraceptives include nausea, bloating, and mood swings. [13]

Antiandrogens

Two forms of antiandrogens used in androgen suppression are androgen receptor antagonists and androgen synthesis inhibitors. Androgen receptor antagonists work by blocking androgens from binding to receptors, while androgen synthesis inhibitors work by blocking the production and biosynthesis of androgens. [1] [13] Common antiandrogens are spironolactone, finasteride, cyproterone acetate, and dutasteride. [14] [15] These treatments may take up to 9 to 12 months for full effectiveness and side effects include decreased libido, irregular menstrual cycle, muscle weakness, dizziness, hypotension, and hyperkalemia. [13] [14] [15] Antiandrogens can have side effects on a developing fetus, so it is generally recommended to use a hormonal contraceptive to prevent pregnancy as well as help mitigate menstrual fluctuations. [14] [15]

Lifestyle Modification

For women with PCOS experiencing obesity, weight loss has shown small decreases in testosterone, but should not be relied on alone as a comprehensive treatment for androgen excess. [13] [14] Obesity reduces the synthesis of SHBG, leading to higher androgen concentrations. [13] A higher weight may also have negative effects on other treatments for symptoms of hyperandrogenism. [13] Lifestyle modification is beneficial in reducing androgens and increasing SHBG, but full data on its effectiveness is limited. [13]

References

  1. 1 2 3 4 5 6 7 8 9 10 11 Cussen, Leanne; McDonnell, Tara; Bennett, Gillian; Thompson, Christopher J.; Sherlock, Mark; O'Reilly, Michael W. (2022-03-29). "Approach to androgen excess in women: Clinical and biochemical insights". Clinical Endocrinology. 97 (2): 174–186. doi:10.1111/cen.14710. ISSN   0300-0664. PMC   9541126 . PMID   35349173.
  2. 1 2 3 Tangpricha, Vin; den Heijer, Martin (April 2017). "Oestrogen and anti-androgen therapy for transgender women". The Lancet. Diabetes & Endocrinology. 5 (4): 291–300. doi:10.1016/S2213-8587(16)30319-9. ISSN   2213-8595. PMC   5366074 . PMID   27916515.
  3. 1 2 "Gonadotropin Releasing Hormone (GnRH) Analogues", LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases, 2012, PMID   31643199 , retrieved 2025-12-09
  4. ↑ "Hormone Therapy for Prostate Cancer Fact Sheet - NCI". www.cancer.gov. 2024-10-10. Retrieved 2025-12-10.
  5. ↑ Lieberman, Ronald (August 2001). "Androgen deprivation therapy for prostate cancer chemoprevention: current status and future directions for agent development". Urology. 58 (2): 83–90. doi:10.1016/S0090-4295(01)01247-X. PMID   11502457.
  6. 1 2 3 4 "Overview of feminizing hormone therapy | Gender Affirming Health Program". transcare.ucsf.edu. 2016-06-17. Retrieved 2025-12-09.
  7. ↑ "Radiation with Hormonal Therapy", Prostate Cancer, Academic Press, pp. 387–398, 2016-01-01, doi:10.1016/b978-0-12-800077-9.00043-8 , retrieved 2025-12-10
  8. 1 2 Jacob, Aasems; Raj, Rishi; Allison, Derek B.; Myint, Zin W. (2021-10-28). "Androgen Receptor Signaling in Prostate Cancer and Therapeutic Strategies". Cancers. 13 (21): 5417. doi:10.3390/cancers13215417. ISSN   2072-6694. PMC   8582395 . PMID   34771580.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  9. ↑ Sehgal, Inder (2023-07-04). "Review of adult gender transition medications: mechanisms, efficacy measures, and pharmacogenomic considerations". Frontiers in Endocrinology. 14 1184024. doi: 10.3389/fendo.2023.1184024 . ISSN   1664-2392. PMC   10355117 . PMID   37476490.
  10. ↑ Stein, Mark N.; Patel, Neal; Bershadskiy, Alexander; Sokoloff, Alisa; Singer, Eric A. (2014). "Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer". Asian Journal of Andrology. 16 (3): 387–400. doi: 10.4103/1008-682X.129133 . ISSN   1745-7262. PMC   4023364 . PMID   24759590.
  11. ↑ Francis, Courtney; Grober, Ethan; Potter, Emery; Blodgett, Nolan; Krakowsky, Yonah (2020-07-01). "A Simple Guide for Simple Orchiectomy in Transition-Related Surgeries". Sexual Medicine Reviews. 8 (3): 492–496. doi:10.1016/j.sxmr.2019.11.004. ISSN   2050-0521. PMID   31959532.
  12. ↑ Meningaud, J.-P. (November 2023). "[Ethical issues of gender reassignment surgery]". Annales de Chirurgie Plastique et Esthetique. 68 (5–6): 404–410. doi:10.1016/j.anplas.2023.08.004. ISSN   1768-319X. PMID   37648589.
  13. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Sharma, Anu; Welt, Corrine K. (2021). "Practical Approach to Hyperandrogenism in Women". Medical Clinics of North America. 105 (6): 1099–1116. doi:10.1016/j.mcna.2021.06.008. PMC   8548673 . PMID   34688417.
  14. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Lizneva, Daria; Gavrilova-Jordan, Larisa; Walker, Walidah; Azziz, Ricardo (2016). "Androgen excess: Investigations and management". Best Practice & Research Clinical Obstetrics & Gynaecology. 37: 98–118. doi:10.1016/j.bpobgyn.2016.05.003. PMID   27387253.
  15. 1 2 3 4 5 Masood, Sadia; Hashmani, Shayana Rukhsar (2024), "Pharmacologic management for polycystic ovary syndrome: Hirsutism and acne", Polycystic Ovary Syndrome, Elsevier, pp. 117–121, doi:10.1016/b978-0-323-87932-3.00024-4, ISBN   978-0-323-87932-3 , retrieved 2025-12-08

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