This page is for miscellaneous assorted content that has yet to be integrated into Transfeminine Science articles but should be with time. It is intended to make this content available while integration into articles is still pending. The content here is by Aly W. and is largely from Reddit comments she has posted.
The author of that article was the person who originated the idea that spironolactone increases visceral fat (intra-abdominal fat). There is no actual scientific or medical literature to support this idea. She described the term “spiro belly” on her site and claimed that it was a commonly used term in the transgender community. But in fact it was she herself who coined the term—it never existed before she started using it (per my own social media investigations). She created the term seemingly to smear spironolactone and scare people away from it. She seems to have a vendetta against spironolactone for some reason—as well as notably against virtually anything that isn’t bioidentical estradiol or progesterone (including even GnRH modulators, which are considered very well-tolerated and safe).
Anecdotes are considered unreliable and the lowest form of evidence in science and medicine. This is for well-founded reasons—succinctly, they very often don’t hold up when studies are conducted. It’s probable that people with undesired abdominal fat for other reasons—which is notably quite a few people—misattributed their abdominal fat to spironolactone rather than to the actual causes. Her Facebook forum has in the past constituted a stream of misinformation and fear-mongering on these issues to a large number of transfeminine people. It has indoctrinated many people into thinking that spironolactone and various other hormonal medications are dangerous and have terrible side effects—including visceral fat with spironolactone. Yet spironolactone in actuality is well-tolerated per studies and systematic reviews (Table) and there is no evidence that spironolactone increases visceral fat. The claimed side effects are likely due to phenomena like nocebo and misattribution—which can be controlled for in actual scientific studies but not with anecdotes.
In relation to the point on misattribution, it’s notable that androgens are known to increase visceral fat and that males have twice as much visceral fat as females on average (Blouin, Boivin, & Tchernof, 2008; Zerradi et al., 2014). Hence, many transfeminine people may have excess abdominal mass due to prior androgen exposure. As we know, hormone therapy unfortunately isn’t always able to reverse all bodily sexual dimorphism.
Not only do studies find that spironolactone doesn’t increase visceral fat, there is accumulating research to suggest that spironolactone may actually decrease visceral/abdominal fat via its antimineralocorticoid activity (also known as mineralocorticoid receptor (MR) blockade or aldosterone antagonism). Here are some notable literature excerpts on this (Infante et al., 2019; Giordano, Frontini, & Cinti, 2016):
A possible explanation for [MR antagonists reducing cardiovascular morbidity and mortality more in patients with abdominal obesity] may be that patients with heart failure and abdominal obesity have higher aldosterone concentrations due to excessive secretion of specific aldosterone-releasing factors from [visceral adipose tissue]. […] Several studies on murine models of genetic and diet-induced obesity have widely reported beneficial effects of MR antagonism in terms of metabolic outcomes, such as body weight, fat mass, adipose tissue inflammation, insulin sensitivity, and lipid metabolism (Armani, Cinti, et al., 2014; Armani, Marzolla, et al., 2014; Garg & Adler, 2012; Guo et al., 2008; Hirata et al., 2009). Nevertheless, data on the outcomes of MR pharmacological blockade for prevention and treatment of obesity and metabolic syndrome are still scarce in humans (Tirosh et al., 2010). Of note, Tanko et al. demonstrated that the powerful MR antagonist drospirenone, in combination with estradiol, leads to a significant reduction of central fat mass and central fat mass/peripheral fat mass ratio in healthy post-menopausal women (Tanko´ & Christiansen, 2005). Moreover, another study has reported that MR antagonists significantly reduce body mass index and visceral fat area in patients with primary aldosteronism after a 1-year treatment period (Karashima et al., 2016). […] In light of these data, MR antagonism may be a useful therapeutic tool for prevention and treatment of cardiometabolic derangements observed in metabolic syndrome, even though additional studies are deemed necessary to confirm its impact on larger clinical settings.
An anti-obesity drug whose primary mode of action is to induce browning should act predominantly on visceral fat, thereby directly counteracting the major cause of obesity-associated metabolic disorders. Accumulation of abdominal visceral fat is, to some extent, linked to increased local levels and/or activity of androgen and glucocorticoid steroid hormones145,146. These hormones are also ligands of the mineralocorticoid receptors, which are found on white and brown adipocytes and could have a role in abdominal visceral fat accumulation and BAT to WAT conversion147–151. […] In this context, mineralocorticoid receptor antagonism has been shown to protect mice from the adverse obesogenic and metabolic effects of a high-fat diet via conversion of a substantial amount of visceral and subcutaneous WAT into BAT153. Given that mineralocorticoid receptor antagonists are widely prescribed diuretics, used to manage chronic heart failure, hyperaldosteronism and female hirsutism154, patients receiving such drugs should also be assessed for weight loss and metabolic parameters to establish whether these compounds have anti-obesity properties.
Accordingly, antimineralocorticoids like spironolactone are antiadipogenic (anti-fat) in vitro (Caprio et al., 2007; Caprio et al., 2011) and decrease visceral fat in animals (Karakurt, 2008; Armani et al., 2014; Mammi et al., 2016; Olatunji et al., 2018). Spironolactone (12.5–100 mg/day) and eplerenone (25–100 mg/day) (another antimineralocorticoid) decreased visceral fat in people with pathologically high aldosterone levels (Karashima et al., 2016). A study of girls with polycystic ovary syndrome (PCOS) found that a combination of spironolactone (50 mg/day), pioglitazone, and metformin decreased visceral fat, although this study was of course confounded by the other medications (Diaz et al., 2018). Other clinical studies likewise have found no indication of increased visceral/abdominal fat with spironolactone (25–200 mg/day) (as measured by visceral fat directly or by indirect related measures like waist circumference or waist–hip ratio) (Wild et al., 1991; Lovejoy et al., 1996; Ganie et al., 2004; Meyer, McGrath, & Teede, 2007; Karakurt et al., 2008; Vieira et al., 2012; Ganie et al., 2013; Harmanci et al., 2013; Leelaphiwat et al., 2015; Alpañés et al., 2017). No studies could be identified for higher doses of spironolactone (>200 mg/day).
Hence, to summarize, no research, animal or clinical, has found increased visceral fat with spironolactone, and there is accumulating evidence that spironolactone may do the very opposite. More clinical research is needed to further characterize this in humans however.
[This is about Dr. Will Powers’s claims regarding when to test hormone levels with injectables.]
Your trough value which is the only meaningful reading is not high, there no value in doing a blood test just after the injection.
A lot of people inject every 5 days, it’s closer to the meds half life and reduces fluctuation, you could do that with a lower dose thus reducing the peak. [By u/Charlie_Rebooted]
Powers is full of shit (link). And here specifically his reasoning is BS. The hormones don’t slowly get taken up into your cells, leading to early inflated levels. After taking the injection hormones are slowly released from the site of injection into the blood stream and from there quickly eliminated, but blood stream levels are representative for global levels. [By u/Aver1y]
I read the link, couldn’t find anything about trough value not being more useful than peak. Are you suggesting that blood tests should be taken immediately after medication? [By u/Charlie_Rebooted]
As the author of that linked Transfeminine Science page, I can confirm that Powers is mistaken on this issue. u/Aver1y and I have explored this topic together before in fact and I’ve also discussed it privately with Powers (though I’m not sure whether the discussion actually changed his opinion).
What Powers said in that post isn’t in accordance with existing scientific understanding and data. Drugs including steroid hormones are rapidly distributed into tissues and tissue levels proportionally track blood levels with only a short delay. Distribution takes place over a matter of hours at most, not days or weeks. This is probably most subjectively obvious with psychoactive drugs (e.g., alcohol, cannabis, stimulants, opioid analgesics, etc.), but it applies equally to other agents like steroid hormones as well.
Here is an example of tissue distribution with the anesthetic sodium thiopental:
(Note that both thiopental and steroid hormones are lipophilic substances and hence have analogous physicochemical properties in this regard. Lipophilic drugs are more readily distributed than hydrophilic substances as they more easily cross cell membranes and hence permeate tissues (Lin, 2006).)
And here are some graphs showing tissue distribution with estrogens in animals (Wiki):
Estradiol levels in these graphs are higher in many tissues than in blood because estrogen target tissues like the vagina and uterus retain and concentrate estradiol due its binding to estrogen receptors (which it stays bound to for many hours). Levels of estrone in target tissues are proportionally much lower than with estradiol due to its very low binding affinity for the estrogen receptors.
The available data are mostly from animals as it’s much harder and more expensive to do this kind of research in humans. But theoretically it should be little different in humans. And indeed the more limited data we have in humans confirms this (e.g., Deshpande et al., 1967):
Additionally, here are some pharmacokinetic model simulations of estradiol distribution within tissues following intravenous injection of estradiol in humans from a recent paper (Sier, Thumser, & Plant, 2017):
|Predicted or simulated tissue distribution of estradiol in humans with a 0.3 mg i.v. bolus of estradiol using three different pharmacokinetic models (PBPK, LiverODE, and GSMN).|
Since steroid hormones are fairly rapidly eliminated from tissues following distribution, tissues also don’t really serve as a reservoir (or “ocean” as Powers puts it) for steroid hormones.
Powers came to his idea about trough testing based on a personal anecdote of him injecting himself with a large dose of testosterone cypionate intravenously—resulting in extremely high blood testosterone levels for a relatively short time—and not feeling any different subjectively despite those levels. He concluded that the reason he didn’t feel anything is because hormones take a very long time to distribute into tissues including the brain and hence that while his blood testosterone levels were strongly elevated, his brain and tissue testosterone levels were essentially unchanged.
In reality however, Powers’s brain testosterone concentrations were rapidly and profoundly elevated. This is supported by our established knowledge of drug and sex hormone distribution discussed above. It is also more directly evidenced by a notable study that showed that intravenous injection of testosterone in monkeys resulted in levels of testosterone both in blood and cerebrospinal fluid (CSF)—and hence in the brain—peaking almost immediately following injection (Dubey et al., 1984):
|“Mean (± SEM) concentrations of testosterone in serum and [cerebrospinal fluid (CSF)] in 4 castrated adult male rhesus monkeys following a bolus [intravenous (i.v.)] injection of testosterone (150 μg/kg) in saline at 0 min. Either (a) or (b) 14 testosterone capsules were in situ.”|
Powers’s perceived effects of the testosterone cypionate he injected simply weren’t an accurate way to quantify his brain testosterone levels and misled him. There are several reasons underlying this:
The subjective effects of sex hormones are subtle and hard to accurately discern.
Steroid hormones act mainly via nuclear receptors and hence by producing changes in gene expression, which manifest slowly. It generally takes days or longer for them to build up and be properly established. Moreover, this requires sustained exposure to increased hormone levels.
There are only so many receptors that are available for occupancy. Hence, at a certain point in terms of ligand concentration, the receptors become saturated and incapable of exerting any further effect. Most of the effects of hormones are notably already established at physiological levels (Example).
Intravenous injection of testosterone has a very short duration. The blood half-life is said to only be about 10 minutes (Wiki). Studies of intravenous estradiol (which likewise has a very short though longer half-life) (Wiki) and Powers’s testosterone levels 6 hours post-dose (4,000 ng/dL) suggest that his blood testosterone levels were likely back essentially to baseline in less than a day.
In accordance with the above, animal studies have found that multiple short-acting (bolus) injections in divided doses or one long-lasting (depot) injection of sex hormones are profoundly more potent and effective than one high-dose short-acting (bolus) injection (Parkes, 1937).
Based on the preceding, the vast majority of Powers’s testosterone cypionate dose was essentially wasted and had little opportunity to exert effects. Moreover, measuring such effects subjectively would be a haphazard and unreliable means of quantifying them. Extrapolating said subjective effects to infer brain testosterone levels and pharmacokinetic theory for the purpose of informing therapeutic practices is further problematic. The idea that only trough levels matter has the potential to be harmful because it can lead to the incorrect idea that peak hormone levels—as well as everything but the absolute lowest point with injections—are inconsequential. This has safety implications, since, for instance high levels of estradiol even when taken non-orally, have health risks like blood clots (Aly W., 2020).
Testing at trough does make sense however if the goal is to specifically keep estradiol levels above a certain minimum at all times in case that is important for testosterone suppression. But that is only theoretical—it might not actually matter all that much in practice in terms of testosterone suppression if for instance estradiol levels with injectable estradiol dip below a certain ideal minimum level for a short time during each injection interval. We don’t currently have the data needed to answer this question.
Aside from keeping estradiol levels above a certain level for testosterone suppression, levels of estradiol should be tested at whichever part of the injection curve one cares about. If one wants to know how high their estradiol levels go, then they should test around when peak would be expected to occur. If one wants to know what their average estradiol levels are, then they should test perhaps around midway between whenever peak is likely to be and trough. And if one wants to know how low their estradiol levels go, then they can test at trough. Personally, I think that aiming for average estradiol levels makes the most sense in terms of testing as it’s most representative of one’s overall estradiol exposure. A literature excerpt that I largely agree with in this regard: “Timing of blood sampling should reflect the average level of [estradiol], which implies that sampling should be performed halfway between two [estradiol] administrations” (Glintborg et al., 2021). But the choice is up to the person and their preferences.
Is height loss from hrt real?
Hi i will be starting hrt soon and i have a concerns about my height. I am already short (171 cm) And i don’t want get any shorter than that. Is this change coused by antiandrogens and if so which types? Can it be reversed once medication stops? I just became 18 years old so i dont know my bone plates closed or not.
Have never seen any evidence to support this supposed phenomenon no. It’s probably a myth.
I dropped from 5’11-3/4” to 5’-10-1/2” loss of 1-1/4” in one year, measured at the doctor’s office.
Again I’ve never seen any data or literature to support this idea. Theory can sound great on paper but doesn’t necessarily translate to reality. Anecdotes aren’t data.
Lol, OK, 99% of trans science is anecdotal.
The fact that this is a widely reported phenomenon suggests it has merit, can’t see anyone throwing money at studying it any time soon either.
Like eye color change, it’s theoretically possible and reported by some… does it only become true when it’s shown in peer reviewed papers? Or would my pics be enough??
My old shoes don’t fit 🤷♀️
Please see the following:
The second article by Gooren and Bunck (18) from 2004 compared 17 female to male against 19 male to female transgender patients before and after transition along the following variables: testosterone levels, muscle mass, hemoglobin, and insulin-like growth factor. While the male to female participants after transition retained more muscle mass than the female to male participants before transition, there was overlap between the two groups. Specifically, the retained muscle mass in the transgender female was within the limits of the cisgender females in the study. The authors noted that height as well as hand and foot size did not change during transition and suggest possible relevance for certain sports.
In Gooren & Bunck (2004), height in 19 transfeminine people was 177.8 ± 7.9 cm before hormone therapy and 177.8 ± 7.9 cm after 1 year of hormone therapy. I.e., it did not change. Testosterone was fully suppressed (went from 21.5 nmol/L [620 ng/dL] to 1.0 nmol/L [29 ng/dL]).
Given the maintenance of BMD and the lack of a plausible biological mechanism by which testosterone suppression might affect skeletal measurements such as bone length and hip width, we conclude that height and skeletal parameters remain unaltered in transgender women, and that sporting advantage conferred by skeletal size and bone density would be retained despite testosterone reductions compliant with the IOC’s current guidelines.
Again, anecdotes are not data. There is a lot of room for wishful thinking and cognitive errors with these things and studies are critical as you can see.
This isn’t a good idea due to potentially higher blood clot risk (Canonico et al., 2008):
Overall, oral but not transdermal estrogen increased VTE risk [odds ratio (OR) = 4.5, 95% confidence interval (CI) = 2.6–7.6, and OR = 1.2, 95% CI = 0.8–1.8, respectively]. The allele frequency of CYP3A5_1 was 9 and 10% among cases and controls (OR = 1.0; 95% CI = 0.6–1.5) and that of CYP1A2_1F was 72 and 71% among cases and controls (OR = 1.5; 95% CI = 0.8–2.8). Compared with nonusers, OR for VTE in users of oral estrogen was 3.8 (95% CI = 2.1–6.7) among patients without CYP3A5_1 allele and 30.0 (95% CI = 4.4–202.9) among patients with this allele (test for interaction P = 0.04). By contrast, there was no significant interaction between CYP3A5_1 allele and transdermal estrogen on VTE risk. There is no interaction between CYP1A2 genetic polymorphism and hormone therapy on VTE risk.
(CYP3A4 and CYP3A5 are closely related and grapefruit juice has been reported to inhibit or decrease both enzymes.)
Also as another case in point (Bouligand et al., 2011)
Data from the Estrogen and Thromboembolism Risk (ESTHER) study were used to investigate the effects of the genetic polymorphism of NFE2L2 rs6721961, which may impair Nrf2‐dependent hepatic conjugation of estrogen metabolites. As compared with nonusers, the odds ratio (OR) for VTE in current users of oral estrogens was 2.5 (95% confidence interval (CI): 1.3–4.8) in patients with wild‐type NFE2L2 and 17.9 (95% CI: 3.7–85.7) in those with the polymorphism (interaction, P = 0.01).
(NFE2L2 is important for UDP-glucuronosyltransferase (UGT) expression in the liver and hence for inactivation of E2 into glucuronide conjugates.)
Polymorphisms in CYP2C9, another enzyme that metabolizes estradiol, have been associated with blood clot risk as well (Douxfils, Morimont, & Bouvy, 2020).
There are contradicting findings like this though (Blondon et al., 2013):
In this population‐based study, we found no evidence of gene–drug interaction of oral HT with variants in NFE2L2 and CYP3A5 on the risk of VT in postmenopausal women. Our findings contrast with those of the ESTHER study (Table 1), where associations between oral HT and VT differed markedly by these variants. Our data cannot exclude a modest supra‐additive interaction between non‐O blood group and the use of HT; however, it would be much smaller than reported in the ESTHER study.
In any case, the idea that inhibition of estradiol metabolism would result in greater estradiol levels in the liver and consequent stronger impact on coagulation and blood clot risk has strong theoretical plausibility. It’s basically turning estradiol into a metabolism-resistant form of estrogen analogous to synthetic/non-bioidentical estrogens like ethinylestradiol (EE).
There is a notion in some circles that estrone is responsible for adverse health effects of estradiol, like breast cancer risk and risk of blood clots. This makes little sense though, and is very likely false.
The idea that estrone is responsible for increased coagulation and hence blood clots with estradiol to my knowledge derives from essentially only a single study:
- Bagot, C. N., Marsh, M. S., Whitehead, M., Sherwood, R., Roberts, L., Patel, R. K., & Arya, R. (2010). The effect of estrone on thrombin generation may explain the different thrombotic risk between oral and transdermal hormone replacement therapy. Journal of Thrombosis and Haemostasis, 8(8), 1736–1744. [DOI:10.1111/j.1538-7836.2010.03953.x]
Here is the relevant finding from the paper:
Serum estrone concentration correlated significantly with peak [thrombin generation] in women using oral HRT (R = 0.451 and P = 0.004, respectively; Fig. 2). Serum estradiol concentration had a tendency to show a similar correlation (R = 0.299 and P = 0.06).
Basically, with oral estradiol, there was a moderate and significant correlation between increased coagulation and estrone levels, and a weaker and non-significant but nearly significant correlation between increased coagulation and estradiol levels.
The problem is that this was merely correlational, and there is a better explanation than the increased coagulation being due to estrone. It is well-accepted that activation of the estrogen receptors is responsible for increased coagulation with estrogens, including estradiol, other estrogens (e.g., conjugated estrogens, ethinylestradiol, diethylstilbestrol, etc.), and even selective estrogen receptor modulators (SERMs) (e.g., tamoxifen, raloxifene). This is in spite of these medications having diverse chemical structures, being both steroidal and nonsteroidal in structure and including multiple distinct nonsteroidal chemical families. Likewise, we see a low rate of blood clots with fulvestrant, an estrogen receptor silent antagonist (FDA label). Increased blood clots with estrogens and SERMs is specifically due to excessive estrogen-receptor activation in the liver. Estrone is well-known to have very weak estrogenic activity, so it doesn’t make sense that it would be responsible.
The better explanation is that estradiol is indeed responsible and that the correlation observed with estrone was really a correlation demonstrating exposure of the liver to estradiol. This is because the liver is responsible both for producing the circulating proteins that mediate estrogen-induced procoagulation and for metabolism of estradiol into estrone. If one happens, the other also happens. This would readily explain why the correlation was stronger with estrone than with estradiol. Estradiol was the culprit and then disguised itself, so to speak. Correlation does not equal causation; a correlation can actually be due to a third variable that is responsible for both effects. This study is likely an example of this—in this case, the third and actually causative variable being exposure of the liver to estradiol.
The conclusions of the authors of the paper in my opinion were premature and unwarranted (particularly stating the “effect” of estrone on coagulation in the title and elsewhere). Nonetheless, their study was widely cited in the literature.
As to why the researchers thought that it was estrone that was responsible, aside from the correlation being stronger with estrone than with estradiol, it was because increased coagulation doesn’t occur with transdermal estradiol (at menopausal-replacement doses at least), in contrast to oral estradiol, and because estradiol levels were the same with the two routes but estrone levels were markedly higher with oral estradiol relative to transdermal estradiol. What the authors didn’t take into account however is the hepatic first-pass effect that occurs with oral estradiol. Essentially, estradiol goes through the liver first with oral administration, and this results in about 4- or 5-fold increased exposure of estradiol to the liver and by extension hepatic estrogen-receptor activation. Conversely, this first-pass effect is bypassed with transdermal estradiol, since it doesn’t go through the liver before hitting the bloodstream. The presence versus absence of the first-pass effect explains the difference between oral and transdermal estradiol in terms of influence on coagulation. This is well-known (see e.g. Kuhl, 2005), but apparently the researchers weren’t aware of this.
Update: More on this topic in my article on estrogens and coagulation here.