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On the Impact of Sex Hormones on Fat Metabolism with an Eye Towards Transfeminine Hormone Therapy

By Lain M. | First published September 4, 2019 | Last modified October 5, 2020

Preface

If you are into the technical details I would urge you after reading through this to look through my notes as they go into even more gory details.

Much like my previous post this post is inspired by my personal journey in HRT and my desire to understand how HRT will impact me along with my attempts to optimize it for my desired bodily outcome. I have tried to provide an ultra high level summary / abstract, an in-depth writeup of my literature review and finally my raw notes and quotes upon which I based this article on. As always I welcome feedback. I found writing this to be especially challenging both because I struggled to find the right ‘voice’ and technical level in my writeup, and also with translating cis-focused academic literature into trans-inclusive language. Please know that while all mistakes are mine, my intentions are never to offend, erase, or exclude.

Summary

Within the context of transfeminine hormone therapy it’s often stated that people will have a more feminine fat distribution, gaining fat around their thighs, buttocks (a gynoid fat distribution).

This appears to occur due to both the presence of estrogens as well as the absence of testosterone. Some ways in which estrogens cause this to happen are by directly acting on estrogen receptors in fat deposits in these areas and increasing fat cell growth (adipogenesis) and decreasing fat metabolism in the aforementioned areas (lipolysis).

In addition to directly acting on fat cells, estrogens also act on parts of the brain, specifically the hypothalamus, a center for regulating body fat and body metabolism. In the hypothalamus estrogen receptors interact with leptin - a hormone associated with body fat regulation as well as a number of other hormones and elements that modify the hypothalamus. In general estrogens effects on the hypothalamus seem to reduce appetite and increase fat metabolism.

These two major actions of estrogens on fat metabolism seem to result in the understanding that estrogens cause subcutaneous fat distributed gynoid, that is resistant to metabolise, while at the same time reducing hunger and increasing overall metabolism.

In keeping with this there is some research to indicate that transfeminine populations increase their total body fat % under HRT, however, there is some research that shows there is also an increase in total BMI as well.

My review of the literature has made me consider that looking at the genes of trans feminine individuals about to start (or already taking) HRT could possibly help people understand if they are at risk for disproportionate weight gain due to HRT and whether other interventional actions could be taken.

The rest of this post will go into much greater detail on how estrogens impact fat metabolism and deposition.

Background

When talking about fat distribution in humans we often talk about a feminine (gynoid) or masculine (android) distribution of fat. Gynoid fat distribution is typically characterized as fat deposited in the thighs and buttocks whereas an android fat distribution is characterized by abdominal fat. In addition a gynoid fat distribution is characterized by having a much higher percentage of subcutaneous fat (fat under the skin) as opposed to visceral fat (fat inside the abdominal cavity - for instance around the organs). This seems to likely be due to the fact that subcutaneous fat depots are among the most efficient ways to store calories per volume of tissue[4]. This is an especially important distinction as visceral fat is highly correlated with cardiovascular disease. Following along with that research shows that pre-menopausal natal women are far less likely to experience cardiovascular disease.

These different fat distributions are ultimately achieved by fat being metabolised (lipolysis) and synthesized (lipogenesis) at different levels in different fat tissues.

There are many ways in which sex hormones mediate lipolysis (fat metabolism) and lipogenesis (fat generation). These effects can be categorized broadly as either direct or peripheral. Direct actions typically mean estrogen or androgen receptor modulation on fat cells (adipocytes) directly whereas peripheral actions are the effects of estrogen or androgen within the brain to cause downstream impact on various aspects of metabolism including rate of fat metabolism, rate of fat uptake and hunger.

As fat is the major store of energy in the body, fat can be viewed as an organ and in fact an endocrine organ[1]. It produces leptin, a hormone that is central to maintaining body fat percentage as it is part of the leptin / ghrelin / insulin hormone system involved in hunger, and energy homeostasis. Leptin along with insulin are peripheral “adiposity signals” and their circulating levels are relative to the percentage of body fat.

Direct Effects

Direct effects of sex hormones on fat distribution are those which directly modulate fat cells as opposed to peripheral affects which result from downstream modulation of other signaling pathways. Adipose tissue contains both estrogen and androgen receptors with visceral fat having a higher concentration of both receptors[1].

Below are some of the direct effects of hormones

  • In subcutaneous fat estradiol acts through the Estrogen receptor alpha subtype (ERα) to upregulate α2A-adrenergic receptors (increase the density of this receptor in the fat cells) which result in decreased lipolysis whereas estradiol does not seem to impact the concentration of α2A-adrenergic receptors in visceral fat[1].

  • Fatty acid uptake is the incorporation of fatty acids into fat cells. Rates of fatty acid uptake are lower in natal women compared to men, in the buttocks and thighs - and after eating, fatty acid uptake is higher in both natal women and men in the abdomen but with women it is stored largely subcutaneously vs. viscerally (interabdominally) in natal men[1].

  • Estrogen is associated with higher rates of fat metabolism during sustained bouts of increased energy usage whereas natal men are more likely to up regulate glucose and amino acid metabolism. When given exogenous estrogen natal men decrease carbohydrate and amino acid metabolism and increase fat metabolism.[1]

  • Testosterone increases lipolysis (breakdown of fat), inhibits lipoprotein lipase activity (an enzyme that converts triglycerides into fatty acids suitable for cellular metabolism), and decreases triglyceride (TAG - a fatty acid) accumulation in adipose tissue. With this occurring largely in subcutaneous adipose tissue[1]

  • The estrogen receptor α subunit (ERα) appears to be responsible for anti-obesity effects[3]

  • Androgens also appear to block the proliferation and differentiation of preadipocytes - this ties in with them also directing stem cells to create muscle cells[1]

  • Conflictingly somewhat,there is also evidence to support the fact that estradiol suppresses white adipose tissue accumulation by decreasing triglyceride (TAG) and fatty acid synthesis as well as lipogenesis (fat uptake and storage)[1]

Peripheral Effects

Peripheral effects of hormones are those mediated largely through the brain. Rather than acting directly on fat cells both androgens and estrogens act on parts of the brain - often the effect is on the hypothalamus - a center for regulating various metabolic activities like fat metabolism, (more broadly called energy homeostasis). Some of the effects hormones may cause include regulating hunger, regulating the rate of various tissues metabolism, and regulating the uptake of fat into tissues.

Leptin and Hormones

Leptin is a hormone secreted from fat and is one of the ways in which hunger is mediated. Increased leptin correlates with decreased hunger and decreased total weight. Leptin is secreted from subcutaneous fat at a higher rate than visceral fat[1], thus as estrogen mediates a higher proportion of subcutaneous fat more leptin is found in the body. In addition estrogen in the hypothalamus causes increased sensitivity to leptin which results in decreased hunger (anorexigenic effects)[3,4,5]. The brainstem (specifically the NTS - nucleus tractus solitarius) is also a source of anorexigenic effects via the estrogen receptor[5] . In addition leptin can also cause an increase in energy expenditure - via the Stat3 signaling pathway in the hypothalamus[3]. When estrogen is not present but androgens are, insulin signaling pathways are far more responsible for mediating hunger and energy expenditure[3]. In natal men, low testosterone is correlated with increased fat mass, probably because neither the insulin pathway for reducing hunger or the leptin one is very active[6].

Obviously any conclusions we wish to draw about how a standard transfeminine hormone therapy regimen of androgen suppression and estrogens addition is speculative and based upon knowledge of how hormones interact with fat. Despite this, I think we can make some statements which are reasonable (and also backed up by observational evidence):

  • As testosterone decreases, overall body fat increases, (because testosterone inhibits fat cell formation and decreases fat uptake overall[1]).

  • Subcutaneous fat deposits begin to increase.

    • This likely occurs by increased lipogenesis mediated by upregulation of α2A-adrenergic receptors and decrease LPL (lipoprotein lipase) in SC fat.
  • Visceral fat may decrease relative to total body fat possibly because of leptin pathways[3,4]. While visceral fat may decrease relative to total body fat the rate of turnover of visceral fat decreases, so both the uptake as well as the metabolism of visceral fat decreases[1].

  • The leptin pathway becomes sensitized and the insulin pathway becomes less sensitive

  • Total body fat increases, especially subcutaneous fat causing total overall leptin to increase. This may cause a decrease in appetite and weight loss in general.

  • When undergoing exercise more fat will be burned than amino acids (proteins) and carbohydrates

However, somewhat at odds with what the actions of transfeminine hormone therapy seem likely to be, the research we have on transgender populations suggests an overall increase in weight.

  • During HRT over 12-24 months total fat mass increased and total non fat mass decreased[7]

  • Over an average of 8 years total lean mass (not body fat) was approximately 20% lower whereas total fat mass was about 30% higher in comparison with a control group of cis men[7]

  • When treated with ethinyl estradiol and anti-androgens subcutaneous fat depots increased significantly and a proportional increase in visceral fat was also observed[7]

There is at least some evidence[8] to suggest that this maybe due to cyproterone acetate, a commonly prescribed anti-androgen outside of the US, causing weight gain. I believe that there is not nearly enough research to draw really solid conclusions as there are so many confounding factors related to weight loss.

In addition I would love to see studies that relate genetics to the effects of HRT on weight and body mass. For instance it may be possible to identify in advance, genetic polymorphisms that would cause say weight gain under HRT (due to a specific phenotype of something involved in leptin signaling pathways) and create an intervention prior to or during HRT.

References

  1. Sex differences in fat storage, fat metabolism, and the health risks from obesity: possible evolutionary origins

  2. Effects of low-dose estrogen oral contraceptives on weight, body composition, and fat distribution in young women

  3. Sexual Dimorphism in Body Fat Distribution and Risk for Cardiovascular Diseases

  4. Gonadal Hormones Determine Sensitivity to Central Leptin and Insulin

  5. The Role of Estrogens in Control of Energy Balance and Glucose Homeostasis

  6. MECHANISMS IN ENDOCRINOLOGY: The sexually dimorphic role of androgens in human metabolic disease

  7. Body Composition and Bone Mineral Density in Male-to-Female Transsexuals During Cross-Sex Hormone Therapy Using Gonadotrophin-Releasing Hormone Agonist

  8. Clinical efficacy and safety of cyproterone acetate in severe hirsutism: results of a multicentered Canadian study