Miscellaneous Assorted Content


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 and is largely from Reddit comments she has posted.

Spironolactone and Visceral Fat

A claim has been originated by some in the online transgender community that the antiandrogen spironolactone increases visceral fat in transfeminine people and that this effect is irreversible. Visceral fat is a type of adipose tissue located in the intra-abdominal region which surrounds the internal organs (viscera) in that area. In excess, visceral fat causes the abdomen to look bloated and unattractive. The supposed phenomenon of visceral fat accumulation with spironolactone has sometimes been referred to by people in the transgender community as “spiro belly”. The claim is based on theory—specifically that spironolactone has been found to increase levels of the corticosteroid hormone cortisol due to its antimineralocorticoid activity and cortisol is known to increase visceral fat, which together imply that spironolactone might likewise be able to increase visceral fat. It is also based on claimed anecdotal observations of transfeminine people taking spironolactone, which are said to corroborate the hypothesis. Despite these claims owever, there is no actual direct scientific or medical literature to support the idea that spironolactone increases visceral fat, and there is considerable evidence contradicting it.

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. Moreover, cortisol is an agonist of the glucocorticoid receptor (thereby producing glucocorticoid effects) and of the mineralocorticoid receptor (thereby producing mineralocorticoid effects). As already touched on, spironolactone has potent antimineralocorticoid activity (that is, mineralocorticoid receptor antagonism). Hence, even if spironolactone did increase cortisol levels enough to potentially increase visceral fat, its antimineralocorticoid activity could modify the capacity of cortisol to produce this effect. In relation to this, there is accumulating research to suggest that spironolactone may actually decrease visceral fat via its antimineralocorticoid activity. Antimineralocorticoids like spironolactone show antiadipogenic (anti-fat-accumulation) effects in vitro (Caprio et al., 2007; Caprio et al., 2011) and have been shown to decrease visceral fat in animals (Karakurt, 2008; Armani et al., 2014; Mammi et al., 2016; Olatunji et al., 2018). It is possible that they may also be able to do so in humans. Here are some notable literature excerpts relevant to this topic (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 (Tankó & 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.

A number of studies have assessed the influence of antimineralocorticoids like spironolactone and eplerenone (another antimineralocorticoid) on visceral fat in humans. Spironolactone (12.5–100 mg/day) and eplerenone (25–100 mg/day) decreased visceral fat in people with pathologically high levels of aldosterone (a major endogenous mineralocorticoid hormone) (Karashima et al., 2016). A study of cisgender girls with polycystic ovary syndrome (PCOS) found that a combination of spironolactone (50 mg/day), pioglitazone, and metformin decreased visceral fat (Diaz et al., 2018). However, this study was of course confounded by the other medications. In addition to the preceding studies, many other clinical studies (at least 10) have assessed and similarly found no indication of increased visceral or 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). I was not able to identify any studies assessing visceral fat with higher doses of spironolactone (>200 mg/day). Additional studies are also underway to assess the possibility that spironolactone could decrease visceral fat.

With regard to the anecdotal claims of spironolactone increasing visceral fat in transfeminine people, it’s important to note that anecdotes are unreliable and are considered to be the lowest form of evidence in medicine. This is for well-founded reasons—succinctly, anecdotes very often don’t hold up when rigorous studies are conducted. It’s probable that excess abdominal fat—a problem which afflicts many—has been misattributed to spironolactone rather than to the real causes in transfeminine people. It’s notable in this regard that androgens are known to increase visceral fat and that men have twice as much visceral fat as women on average (Blouin, Boivin, & Tchernof, 2008; Zerradi et al., 2014). It’s possible that many transfeminine people may have excess visceral fat due to prior androgen exposure and that this visceral fat may not fully reverse with hormone therapy. As we know, hormone therapy unfortunately isn’t able to reverse all established bodily sexual dimorphism.

Besides increased visceral fat, many other serious adverse effects with spironolactone have been claimed. However, these claimed adverse effects are likewise based on anecdotes and theory, and there is a lack of direct clinical evidence to support such side effects. In actuality, spironolactone even at high doses appears to be well-tolerated per studies and systematic reviews. The claimed side effects of spironolactone may actually largely be due to phenomena like nocebo and misattribution—which can be controlled for in systematic studies but not in the case of anecdotal observations.

To summarize, no research, animal or clinical, has found increased visceral fat with spironolactone, and there is accumulating evidence that spironolactone may cause the very opposite effect. More studies are needed to further characterize this possible benefit of spironolactone in humans however.

CYP3A4 Inhibitors for Increasing Estradiol Levels

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).

Oral Estradiol, Estrone, and Risk of Blood Clots

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.