Beverly Cosgrove, 2/15/2023, Version 23

What’s wrong with Spironolactone? Lots.

Spironolactone (“Spiro”) is a potassium-sparing diuretic and steroid drug frequently prescribed in the US to assigned-male-at-birth (AMAB) trans women as part of their HRT. However, the drug has a number of mild to severe mental side effects, can lead to bodily changes which most trans women might consider disfiguring, and may interfere with breast development and other feminization.

Spiro began being prescribed to trans women in the early 90’s, when the dangers of taking estrogens in the form of Ethinyl Estradiol or Premarin became known. The use of Estradiol alone, without any kind of antiandrogen, is well known to be capable of suppressing testosterone to female levels. (Refs 2,3,4,5) However in the 90’s, the Estrogen-related dangers were known to be proportional to dose, and several studies demonstrated an elevated risk of cardiovascular disease within the first 1-2 years of HRT initiation. (Ref 6) Studies at the time unfairly lumped all estrogens together, and all progestins together, as having the same dangers, a mistake which still lingers today. (7) As a result of their unwillingness to treat trans women with high levels of estrogen, Spiro was added to many HRT regimens in the US to assist in suppressing testosterone levels and blocking testosterone effects.  Its use has persisted despite the availability of safe and effective human-identical estradiol.

Spironolactone does NOT feminize significantly, though it is known to encourage some gynecomastia in males.  Its sole use in trans patients is to reduce the effect of testosterone, and also testosterone levels, a job that estradiol would do if a suitable estradiol-only regimen were used instead.  Today, AMAB transsexuals often begin their HRT in the US with an “orthodox protocol” consisting of 2-4mg a day of estradiol in pill form plus 200mg a day of Spironolactone. Physicians favor this approach because it gives a fairly quick reduction in erectile capability which can give some fast relief to genitally dysphoric transsexuals.

But there are problems associated with Spiro that your doctor may not tell you about.

Spiro makes it more difficult for patients to reach a normal female hormone balance. There are two effects, (1) Inability to achieve female level testosterone, and (2) resistance to normal utilization of estradiol. These two effects happen concurrently.

The first effect is that Spiro doesn’t work well in reducing testosterone.  A long term study of New York clinic patients showed that Spiro was unhelpful in achieving basic HRT goals. “We unexpectedly did not find that Spironolactone aided in testosterone suppression and further found that it seemed to impair the ability to reach desired serum 17-β estradiol levels.” (26) and “Spironolactone did not enhance testosterone suppression, and finasteride was associated with higher testosterone levels.” (28)  In another recent study of patients following a Spironolactone and estradiol protocol, followed for as long as 3.5 years showed that the majority did not attain female levels of testosterone in the first couple of years, with only about half attaining it by year 3. “Patients with normal BMI started with the highest level of testosterone and demonstrated the steepest decline between initial visit and 9 months but seemed unable to achieve levels of testosterone in the female physiological range overall.” Obese patients whose testosterone was already lower than average had somewhat better success with lowering testosterone, but results were still poor. (23)   In the chart below, taken from the same study, the yellow band shows the female normal testosterone level.  Only after 3 years of treatment did at least half of patients fall into that band.  Compare this to the profound drop in testosterone caused by even a single injection of estradiol, in as little as 36 hours. “Suppression of plasma testosterone levels from a mean of 760 ng/dl… in normal young adult men… to 123 ng/dl was noted 36 h after estradiol administration.”(2)  In this sense, a single estradiol injection accomplishes what the Spiro-based protocol may need over 3 years to do.

The second effect: taking Spiro, for reasons that are not well understood, appears to interfere with the patient achieving expected blood levels of estradiol. In a recent study, patients taking Spiro were found to be unable to achieve expected estradiol levels. “Estradiol levels of patients did not correspond with estradiol dosage administered or BMI. There was no discernable change in serum estradiol levels despite the fact that patients commenced and then continued to take what was believed to be supra-physiologic exogenous estradiol.” (23) and “Spironolactone, but not finasteride, use was associated with impairment of obtaining desired 17-β estradiol levels.” (28)

Spironolactone causes patient cortisol levels to rise. (Ref 1) Patients taking Spiro at doses as low as 25mg a day experience significantly elevated cortisol levels within a few weeks. (8) However, typical dose for trans women is 200mg per day, despite it being known that doses over 100mg have diminished effect. (9) Normally, the circulating levels of cortisol are tightly controlled by the hypothalamic-pituitary-adrenal (HPA) axis. A key feature of the HPA axis is negative feedback regulation, whereby cortisol suppresses its own secretion. Spiro activates the HPA axis.  However, chronic activation of the HPA axis may play a pathogenic role in a wide range of common metabolic and psychiatric disorders, including obesity, depression, and age-associated cognitive dysfunction. (1) In particular, depression which does not respond to common anti-depressant therapy has been noted in patients with hypercortisolism due to disruption of the HPA axis, which generally resolves itself once the cause is removed. (16,18)

The effects of Spiro on the brain’s mineralocorticord system are complex. The primary result as cortisol is raised is a crippling of certain thinking processes, selective attention, visuospatial memory, and mental flexibility/set shifting. There is also a modulation, both up and down, of panic and anxiety and ability to withstand stress. (10) Considering that the time of beginning of a transsexual’s hormonal transition may be one of the most stress-inducing periods of the person’s life, it is not surprising that patients receiving Spironolactone complain of “brain fog”, poor memory, irritation, anxiety and panic attacks. This also begs the question: could the start of Spiro-based HRT also explain increased incidence in the transgender community of self harm, addictive behavior, and suicide? Data to answer this question is lacking, but the risk seems rational and clear, and this complex of issues — brain fog, poor memory, lethargy, depression, anxiety and panic attack — are widely known in the transgender community. (11) [and Chart (15)] Especially worrying is the evidence that, if a patient is already depressed, adding Spironolactone greatly accelerates the level of hypercortisolism it induces, creating feedback which traps the individual in a depressive state which does not respond to antidepressants. (18)

But Spiro can actually sabotage the very physical changes that trans women seek through HRT. Increased cortisol is associated with accumulation of visceral fat — hard fatty deposits interlaced with internal organs which causes a swollen belly. It is important to discriminate between belly adipose fat, which is soft “jelly like” fat directly under the skin, and visceral fat which is behind the abdominal wall. Visceral fat requires significant effort with diet or exercise to remove and cannot be removed with any kind of ordinary plastic surgery. (20)  This visceral fat is caused by raised cortisol. The informal term “Spiro belly” arose because of the perception that those on high doses of Spiro for long term (200mg/day for over a year) seem to often have the characteristic protruding belly. Once visceral fat has accumulated, it is difficult to achieve an ideal waist-to-hip size ratio again, even if Spiro is stopped and diet and exercise is tried. Research on young girls with poor Waist/hip measurements correlate to higher cortisol levels and visceral fat, as well as mobilization of fat from elsewhere in the body to the central region — the opposite of the desired fat mobilization sought by trans women. (12) The association between hypercortisolism, major depressive illness, and deposits of visceral fat has been well established. (17)

Finally, Spiro use is associated with poor breast development in trans women. A preliminary study showed that patients using Spiro instead of another antiandrogen (such as Cyproterone) had significantly more dissatisfaction with breast development. (13) At this point, the causation is uncertain. The cause could be the known tendency for Spiro to interfere with the blood levels of estradiol, as verified in multiple studies (23,28). However, it is also known that elevated cortisol suppresses Human Growth Hormone, resulting in smaller stature (14) and therefore possibly, reduced breast growth even in later life. Regardless of the exact explanation, if appears that Trans women are doubly penalized for Spiro use in this respect, because chest measurement to waist measurement ratio may be sabotaged at BOTH ends – the very opposite of an “hourglass figure”.

If you are taking Spironolactone now, and wish to quit, please be warned — quitting Spiro suddenly without preparation is difficult and hazardous, and your doctor is very unlikely to understand some of the problems you will encounter.  You should be able to find some peer coaching on the practical aspects of quitting in the Facebook HRT group for more information. Also, experience suggests that most trans women on megadoses of Spiro (200mg or higher) can successfully suddenly drop to 100mg a day without rebound effects (speak to your doctor), but following that, a slower reduction schedule may be required. But the best solution regarding Spiro is to never start.

Medical specialists and providers have seen the evidence and are finally reconsidering Spiro. A leading Transgender hormone specialist, Dr. Will Powers, has become outspoken in his opposition to the orthodox low-estrogen high-Spiro legacy/orthodox treatment protocol. (27)  With over 1000 patients in his practice, Dr. Powers has established avoidance of antiandrogens, especially Spiro, as a key to his “Powers Method”.  Another key provider with a somewhat similar approach is Dr. Kristen Vierregger.  Both these doctors were an influence on, and were probably indirectly influenced by, this very article you are reading since its first version in 2014.

Permit me to digress a little here with some commentary. Spironolactone was made part of HRT based on standards set by The Endocrine Society (19,21) among others. By setting a standard for estradiol levels based on 90’s-era risk data about Premarin and Provera, the most dangerous forms of HRT, and ignoring the risk reduction of estradiol 17b given parenterally, they created an artificial standard based on what they did not know rather than what they did know. But we know much more now. The risks of injected estradiol levels in the 300-500 pg/ml range are far lower than the risks of suicide or psychotic episodes or sustained mental illness due to mood disturbances from the antiandrogens the prescribers are now offering their patients to keep them below that level. The prescribers are saving their patients from a small risk by exposing them to a larger risk. It is bad risk-benefit judgement. I have written more on this elsewhere. (7) It is notable that the 2009 version of The Endocrine Society guidelines even include a mention of estradiol injection (19) but still refer to Spironolactone. One final thought, this time a speculation: it seems possible based on observations that high levels of testosterone provide some protection against the cortisol-raising properties of Spironolactone, such that testing of the drug on male volunteers might not have shown such a large side effect when the drug was originally tested, leading to a situation where heavy dosing of trans women led to these oversized effects. Would the original manufacturer’s dosing advice have been different if the drug had been more thoroughly tested with female patients? Something worth looking into, perhaps.

The TransFemScience site has responded to points made in this article regarding visceral fat with a detailed rebuttal.  It is well worth reading. It states in part, “The influence of spironolactone on cortisol levels in clinical studies is variable and the magnitude of effect is limited. Hence, the clinical significance of increased cortisol levels with spironolactone is uncertain.”  And also points out, correctly, that detailed studies have not been done which support our visceral fat suspicions.  Even though Spiro use is known to be associated with raised cortisol levels, and even though high cortisol is proven to be capable of causing visceral fat, the TFS site is suggesting that “the dots are not connected” in the way I have proposed.  I continue to assert that Spiro use can lead, in some cases, to accumulations of visceral fat.  Studies are cited at the TFS site, but note that the data is largely for low dose Spiro.   Our observation is that these effects do not begin until the patient is taking doses of 100-400 mg a day, and takes these doses for at least 12 months.  Transgender women are being exposed to doses which far exceed the studied levels being used to claim safety.  Our own observations seem to indicate that taking less than 100mg daily, or taking Spiro for 12 months or shorter time usually does NOT lead to visceral fat accumulation.  We are raising the red flag on a patient population exposed to a MUCH greater dose.  Finally, there is the inevitable labeling of our observations as “anecdotal evidence” (or even drug-blaming from patients unhappy about unrelated issues). Let me just point out that much important medical knowledge starts out as anecdotal. Collect a large group together, and those anecdotes become “group knowledge”, which can progress to shared beliefs and practices, and then to clinical experience, and from there it may become accepted into the bulk of accepted medical science. New knowledge always starts somewhere.

The medical community owes it to the transsexual community to take a second look at the overall risk/benefit ratio for the use of Spironolactone as an antiandrogen. Not only is there evidence that Spiro may be interfering with the primary goal of HRT, but Spiro may be directly responsible for patient harm by crippling the cognitive ability of patients and compromising their ability to withstand stress — a terrible burden for this highly stressed minority.

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SOME ANECDOTAL EXPERIENCES
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“The short term memory deficit and cognitive impairment were debilitating side effects of 25mg over a month’s time. This along with unusual bruising,dizziness/unsteadiness, and chronic exhaustion prompted me to stop taking it. I can’t imagine what might have happened with the common higher doses.”, MT, December 2016
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“Was on that crap for 21 months. Lowered it from 200mg/day to 100, then 50, then 0. This was in Oct. of this year. Since then all the symptoms are going away. I also stopped using finasteride. Switched from pills and oral P4 to injectable EV and P4. 5mg EV and 20mg P4 every 3.5 days. Feeling much better.”, KA, Dec 2016.
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“After taking it for about 4 years it started to just quit blocking T all together. I was on injected estradiol valerate and yet my T was at 400! Believe me that Spiro is bad shit. It cost me my job. The brain fog and short term memory loss may be permanent. Depression was increased and not to mention the long term memory I lost.”, SL, Dec 2016.
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“I had a lot of emotive/cognitive issues with Spiro that noticeably improved when I dropped it after two years (my high E2 level allowed this).” BRB, Dec 2016.
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“I had a bout of severe dizziness and got a very itchy rash which my housemates initially thought was a bug bite then later confirmed it was not like any bug bite they’d ever seen. The rash grew larger and more itchy over the course of a week, it disappeared completely a day or two after I stopped taking Spiro. While on Spiro I experienced greater difficulty with organizing thought, more frequent thought derailment, and more reactionary and unclear thinking. These severely impacted my job performance as I rely heavily on memorized diagnostic procedures to solve computer problems. The mental side effects of Spiro dissipated quickly for me after I stopped taking it.”, RM, Dec 2016.
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“I personally can’t stand Spiro! Been on it since May…tomorrow is 7 months. I’ve had severe side effects since the beginning. Here is my list: tired, memory loss, brain fog, light headed, anxiety, poor breast development, severe depression, constipation, dehydration, and low blood pressure. I’ve been a mess since the beginning. I take the pill form. Looking into asking my doctor about moving over to injections and switching to progesterone and keeping my estradiol going.”, JMS, Dec 2016.
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“I was on it for 6 months at a low dose, stopped taking and upped my. Estridol and progesterone. I don’t and didn’t want to start down the road. Had the mental side effects.”, DBS, Dec 2016.
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“my endo started me on 200mg spiro daily with estradiol and i started getting spells of difficulty breathing, debilitating migraines (which i have never experienced before/not a headachey person), increased anxiety, fatigue, yadda yadda. she really didnt think it was the spiro (and theres not too much info about spiro online??) but we cut it out and i cant begin to tell you how much better i feel” DS, 1-5-18
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“Started on Estradiol and Spiro pills… Wasn’t getting anywhere with my E and T levels. After 6 months, switched to EV injections and dropped the Spiro, because of this forum. Now I’m consistently in ideal range of E and T. It’s very possible with no Spiro.”, AA, 1-5-18
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“I switched from spiro to cypro only a few days ago. Ok, its still an AA, but its the lesser of two evils as Beverly pointed out in a previous thread when I asked. In that few days, the brain fog has already gone, I have elevated energy levels and i’m not feeling tired constantly. I no longer pee like a race horse. Getting off spiro will only benefit your health. If my E levels are right next week when I go for my bloods, i’ll be dropping the cypro too.” EC, 1-5-18
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“I have a bad reaction to antiandrogens. I’m now completely off of spironolactone, feminizing rapidly, feel very healthy, and have no brain fog or other symptoms typical to longer term exposure to anti androgens. I’m just taking injectable estradiol valerate at a normal dosage, subcutaneous twice a week to keep levels more stable, and micronized progesterone. I am pre-op and my testosterone is actually lower than the female index range without antiandrogens.”, JM, 1-6-2017
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“I dropped 200mg of daily Spiro. Increased my E from 4mg to 8mg. My E increased and T dropped and got my libido back. Worked for me. In two weeks at next DR. appt, I am going to ask to switch from pills to injections.”, SK, 8-1-2018.
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“I too feel 1000 times better since dropping Spiro and taking no AAs, I like the E and p only for T suppression, works way better that I had ever expected, almost too good actually.”, RS, 1-8-2018.
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“I was only on it about 1.5 months and already had bad brain fog and possibly other developing issues. I THINK am in the clear for any permanent negative effects from it, but I worry.”, NK, 6-1-2020.
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“I hate Spiro and only took it for a couple of months. It caused sharp pains in my muscles, and also caused deep depression. I will never take it again. There are several alternatives to Spiro. Another I will not take is Finasteride, due to it’s side effects.”, AT, 5-27-2020.
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“I was on both low E doses and high spiro. Thought I was done with my programming career. Now I’m on EV, progesterone and no blockers. My brain is back.” K.L., 4-30-2021
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“I’m a lot better since dumping spiro. I started to calm down upon starting E, but brain fog got worse – not to mention I was constantly dehydrated. Estrogen – WITHOUT spiro – has vastly improved the cognitive issues I had in the 10 years prior to HRT, killed the rhoid rages, and continues to heal the depression and other emotional issues I had had since starting puberty.”, J.D., 4-30-2021

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REFERENCES and LINKS
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(2) “ Direct inhibition of Leydig cell function by estradiol.”, Jones TM, J Clin Endocrinol Metab. 1978 Dec;47(6):1368-73.
(3) “ The effect of oestrogen administration on plasma testosterone, FSH and LH levels in patients with Klinefelter’s syndrome and normal men.” Smals AG, Acta Endocrinol (Copenh). 1974 Dec;77(4):765-83.
(4) “In men, peripheral estradiol levels directly reflect the action of estrogens at the hypothalamo-pituitary level to inhibit gonadotropin secretion.”, Raven G, J Clin Endocrinol Metab. 2006 Sep;91(9):3324-8. Epub 2006 Jun 20.
(5) “Sex steroid control of gonadotropin secretion in the human male. II. Effects of estradiol administration in normal and gonadotropin-releasing hormone-deficient men.”, Finkelstein JS, J Clin Endocrinol Metab. 1991 Sep;73(3):621-8.
(6) “Hormone Therapy Dose, Formulation, Route of Delivery, and Risk of Cardiovascular Events in Women: Findings from the WHI Observational Study”, Shufelt C, Menopause. 2014 Mar; 21(3): 260–266.
(7) “What Went Wrong With MTF Hormonal Therapy?“, Cosgrove, B.
(8) “Effect of eplerenone versus spironolactone on cortisol and hemoglobin A₁(c) levels in patients with chronic heart failure”, Yamaji M, Am Heart J. 2010 Nov;160(5):915-21
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(11) “Hormone Therapy is Lifesaving — But Why is No One Studying Its Long-Term Effects?“, Out Magazine, Tourjee D, 2016-09-20 09:38
(12) “Stress and Abdominal Fat: Preliminary Evidence of Moderation by the Cortisol Awakening Response in Hispanic Peripubertal Girls”, Donoho C, Obesity (2011) 19, 946–952
(13) “Predictive Markers for Mammoplasty and a Comparison of Side Effect Profiles in Transwomen Taking Various Hormonal Regimens”, Seal LJ, The Journal of Clinical Endocrinology & Metabolism, Volume 97, Issue 12, 1 December 2012, Pages 4422–4428
(14) “Cortisol and growth hormone: clinical implications of a complex, dynamic relationship”, Stratakis CA, Pediatr Endocrinol Rev. 2006 Apr;3 Suppl 2:333-8.
(15) Chart from active survey of over 200 Spironolactone patients, from Online Facebook Group, “The MTF Trans HRT Hormone Forum“, founded Dec. 2014, membership approx 9800.
(16) “Handbook of Stress and the Brain: Stress: integrative and clinical aspects”, Elsevier. pp. 440–
(17) “Increased Intra-Abdominal Fat Deposition in Patients with Major Depressive Illness as Measured by Computed Tomography”, Thakore J, BIOL PSYCHIATRY 1997;41:1140-1142
(18) “Mineralocorticoid receptor function in major depression”, Young EA, Arch Gen Psychiatry. 2003 Jan;60(1):24-8.
(19) “Endocrine Treatment of Transsexual Persons:An Endocrine Society Clinical Practice Guideline”, Hembree W, The Journal of Clinical Endocrinology & Metabolism, Volume 94, Issue 9, 1 September 2009, Pages 3132–3154
(20) “High visceral fat mass and high liver fat are associated with resistance to lifestyle intervention.”, Thamer C, Obesity (Silver Spring). 2007 Feb;15(2):531-8.
(21) “Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline”, Hembree WC, The Journal of Clinical Endocrinology & Metabolism, Volume 102, Issue 11, 1 November 2017, Pages 3869–3903
(22) “The 45-year story of the development of an anti-aldosterone
more specific than spironolactone”, Menard J, Molecular and Cellular Endocrinology 217 (2004) 45–52
(23) “Testosterone Levels Achieved by Medically Treated Transgender Women in a United States Endocrinology Clinic Cohort”, Liang J, Endocrine Practice: February 2018, Vol. 24, No. 2, pp. 135-142.
(24) “The effect of oestrogen administration on plasma testosterone, FSH and LH levels in patients with Klinefelter’s syndrome and normal men.” Smals AG, Acta Endocrinol (Copenh). 1974 Dec;77(4):765-83.
(26) “Hormonal Treatment of Transgender Women with Oral Estradiol“, Leinung M., https://doi.org/10.1089/trgh.2017.0035
(27) Dr. Will Powers, Video lecture, “Anti-Androgens and Spironolactone issues in MTF HRT | Dr Will Powers @ OUWB” Youtube link: https://youtu.be/LX8AdkL7u0s
(28) Leinung M.C., Feustel P.J., Joseph J. Hormonal treatment of transgender women with oral estradiol. Transgend. Health. 2018;3:74–81. doi: 10.1089/trgh.2017.0035.[PubMed]