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

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

Preface

These are my raw notes that include a large number of raw quotes from various source materials as well as some thoughts of mine. These are far more detailed than my writeup and again are largely just quotes. This page is a supplement and the main article can be found here.

Pedersen et al. (2004)

Pedersen, S. B., Kristensen, K., Hermann, P. A., Katzenellenbogen, J. A., & Richelsen, B. (2004). Estrogen Controls Lipolysis by Up-Regulating α2A-Adrenergic Receptors Directly in Human Adipose Tissue through the Estrogen Receptor α. Implications for the Female Fat Distribution. The Journal of Clinical Endocrinology & Metabolism, 89(4), 1869–1878. [DOI:10.1210/jc.2003-031327]

Power & Schulkin (1998)

Power, M. L., & Schulkin, J. (2008). Sex differences in fat storage, fat metabolism, and the health risks from obesity: possible evolutionary origins. British Journal of Nutrition, 99(5), 931–940. [DOI:10.1017/s0007114507853347]:

Women have greater adipose stores in thighs and buttocks⁽⁸⁾; men tend to be more likely to have significant amounts of abdominal fat, and to be more susceptible to abdominal adiposity⁽⁸⁾. Women have larger stores of subcutaneous fat; men are more likely to have visceral fat⁽¹¹⁾.

Interestingly, not only do men on average have a greater proportion of fat as visceral fat, it would appear that turnover of visceral fat is higher in men compared with women. Men have consistently been shown to have greater rates of both fatty acid release (lipolysis) and fatty acid uptake (lipogenesis) in visceral fat compared with women⁽⁶⁾. Adrenergic stimulation increases splanchnic fatty acid release in men but not in women⁽²⁴⁾. Thus, not only are men more susceptible to excess visceral fat, the effects of visceral fat on health may differ between the sexes as well.

At rest, women shunt more circulating NEFA into re-esterification pathways than do men⁽³²⁾. Women have higher VLDL-TAG production rates than men, but similar circulating concentrations⁽⁷⁾. This is further evidence that women have higher rates of re-esterfication and thus reuptake of NEFA into adipose tissue than do men. In the basal condition, women are physiologically adapted to store fat more so than are men.

Women have higher rates of fat uptake into leg fat depots than do men⁽³³⁾. Rates of fatty acid release from abdominal adipose tissue are higher in women than men, but they are lower from gluteal or femoral adipose tissue⁽⁶⁾. After feeding, fatty acid uptake is higher in abdominal adipose tissue relative to gluteal or femoral in both men and women. However, in women the majority of fatty acid uptake in abdominal adipose tissue is into subcutaneous fat, while in men a larger proportion goes into visceral fat⁽⁶⁾. These findings are consistent with women being more likely to store fat subcutaneously and preferentially in the gluteal and femoral regions compared with men.

Women have higher rates of fat oxidation than men during sustained bouts of increased energy expenditure, such as endurance training. Men are more likely to up regulate glucose and amino acid metabolism during sustained exercise bouts^(34,35). The difference is associated with oestrogen. Giving exogenous oestrogen to males decreases carbohydrate and amino acid metabolism during exercise, and increases fat oxidation⁽³⁶⁾. Thus it would appear that women are more physiologically geared to use fat as a metabolic fuel under conditions of sustained increased demand, while men rely more on glucose and protein metabolism.

Testosterone acts to increase lipolysis, inhibit lipoprotein lipase activity, and decrease TAG accumulation in adipose tissue. Lowering circulating testosterone levels in healthy young men increases total adipose tissue, with the largest percentage increase occurring in subcutaneous adipose tissue; raising circulating testosterone decreases total adipose tissue⁽³⁷⁾. Oestrogens play multiple roles in the regulation of adipose tissue, in both men and women. Oestradiol has direct effects on adipose tissue, and also acts centrally to affect food intake and energy expenditure. Androgens appear to block proliferation and differentiation of preadipocytes⁽³⁸⁾. Oestradiol enhances proliferation of preadipocytes from both men and women in vitro⁽³⁹⁾. The effect was greater in preadipoces from females compared with those from males.

Adipose tissues express both androgen and oestrogen receptors. Visceral fat has higher levels of androgen and oestrogen receptors than does subcutaneous fat, and this is true for both men and women⁽⁴²⁾. Both the a and b oestrogen receptors are found in adipose tissue⁽⁴¹⁾. In subcutaneous fat, oestradiol acts through the a receptor to up regulate α2A-adrenergic receptors which results in decreased lipolysis. In contrast, oestradiol does not appear to affect the concentration of α2A-adrenergic receptors in adipocytes from visceral fat⁽⁴¹⁾. Subcutaneous adipocytes from premenopausal women have higher α2A-adrenergic receptor density and lower lipolytic activity in response to adrenaline than do subcutaneous adipocytes from men⁽⁴³⁾.

Adipose tissue serves as an endocrine organ, producing leptin and many other regulatory peptides (Table 1). Adipose tissue is a source of steroids, either stored or metabolically converted from precursors. For example, oestrone is converted to oestradiol and androstendione is converted to testosterone in adipose tissue (Table 1).

Reubinoff et al. (1995)

Reubinoff, B. E., Grubstein, A., Meirow, D., Berry, E., Schenker, J. G., & Brzezinski, A. (1995). Effects of low-dose estrogen oral contraceptives on weight, body composition, and fat distribution in young women. Fertility and Sterility, 63(3), 516–521. [DOI:10.1016/s0015-0282(16)57419-6]:

The levels of the enzyme lipoprotein lipase (LPL) activity in adipocytes serve as a reliable indicator of fat formation and accumulation. Lypolisis, on the other hand, is the enzymatic degradation of lipids within the adipocyte. During their reproductive period of life, women have a higher femoral than abdominal LPL activity (14).

Progesterone stimulates femoral LPL activity, whereas T inhibits it. Estradiol (on a short-term basis) is lipolytic.

Nedungadi & Clegg (2009)

Nedungadi, T. P., & Clegg, D. J. (2009). Sexual Dimorphism in Body Fat Distribution and Risk for Cardiovascular Diseases. Journal of Cardiovascular Translational Research, 2(3), 321–327. [DOI:10.1007/s12265-009-9101-1]:

Lipoprotein lipase (LPL) is the major enzyme involved in the fatty acid uptake and is the key regulator of fat accumulation in various adipose tissues. Higher LPL tissue activity is associated with the development of abdominal visceral obesity. Men have a higher level of LPL activity than premenopausal women.

The lipolytic pathway involves the breakdown of energy stored in the form of triglycerides and is initiated when the energy supply from the metabolic fuels is depleted. There is a higher amount of lipolytic activity in the visceral fat when compared to the subcutaneous fat in premenopausal women as compared to the post menopausal women lacking estrogen [37, 45, 46]. Hence, in women, there is less visceral obesity in comparison to men [34]. Catecholamines trigger lipolysis via α-1, α-2, and α-3 adrenergic receptors, while they inhibit lipolysis via the α-2 adrenergic receptors [35].

In visceral adipose tissue, there is an increase in the expression of androgen receptors in males relative to estrogen receptors. Adipose tissue-specific androgen receptor knockout mice have increased intraadipose tissue estradiol levels, which precedes subcutaneous obesity [60].

Body weight is regulated through coordinated metabolic processes. This includes peripheral signals called “adiposity signals” such as leptin and insulin [59], whose circulating levels are proportional to adipose tissue mass [13, 50]. These adiposity signals interact with the brain to regulate energy homeostasis. There are critical brain regions responsible for mediating these effects, specifically in the hypothalamus [47, 49]. Leptin and insulin have receptors in these critical brain regions and influence release and activity of different neuronal populations known to be involved in body weight regulation.

Leptin is secreted at a higher rate from subcutaneous fat than from visceral fat, thus circulating leptin correlates better with total subcutaneous fat than with total body fat. Insulin secretion is better correlated with visceral fat; thus, its levels better reflect visceral rather than total body adiposity [58]. Male rats are relatively more sensitive to the catabolic action of insulin delivered into the brain [14], whereas female rats are relatively more sensitive to the catabolic action of leptin delivered into the brain [16]. A comparable phenomenon has been reported in a recent study in humans, suggesting that men lose more body weight and body fat and change their waist circumference following intranasal insulin administration when compared to women [61]. Intranasal insulin administration increases insulin concentration of the cerebrospinal fluid and thereby alters brain functions. Therefore, sexually differential sensitivity to the catabolic effects of insulin exists in rodents and humans.

Uniquely, despite having higher circulating leptin levels, females have been demonstrated to be more sensitive to the anorexigenic effects of leptin [15]. Female rats are more responsive than males to the effects of centrally administered leptin to decrease food intake and body weight, and this has been demonstrated to be due to increased leptininduced Stat3 activation in the basal hypothalamus [5, 29]. So, an increase in the Stat3 signaling translates to an increase in the energy expenditure by leptin and also increased SNS regulation.

Among the two major estrogen receptor subtypes, it is believed that ERα mediates the anti-obesity effect in both males and females [41, 43, 55]. Studies with ERα null mice demonstrated obesity and had a massive increase in the adipose tissue [32, 48], whereas ERβ null mice were not obese. Heine et al. reported that male and female mice with a targeted deletion in the ERα subunit have increased adiposity in both sexes.

Clegg et al. (2006)

Clegg, D. J., Brown, L. M., Woods, S. C., & Benoit, S. C. (2006). Gonadal Hormones Determine Sensitivity to Central Leptin and Insulin. Diabetes, 55(4), 978–987. [DOI:10.2337/diabetes.55.04.06.db05-1339]:

These data indicate that estrogen acts within the brain to increase leptin sensitivity, decrease insulin sensitivity, and favor subcutaneous over visceral fat.

Thus, when systemic estrogen is present (intact females and males or OVX females administered subcutaneous estrogen), leptin is catabolic in the brain, whereas when estrogen is low (OVX females and intact males), leptin is relatively ineffective. Conversely, estrogen reduces the sensitivity of the brain to the anorexigenic action of insulin.

An important implication from these findings is that gonadal steroids mediate body fat distribution and interact with the integrated adiposity message conveyed to the brain by leptin and insulin, resulting in differential sensitivity to these signals in males and females.

This implies that the relative amount of androgens and estrogens is a key determinant of the brain’s sensitivity to the catabolic actions of insulin and leptin, with proportionally more estrogen favoring leptin sensitivity and proportionally less estrogen favoring insulin sensitivity. Finally, our data suggest that estrogen’s direct actions in the brain determine body fat distribution.

Note: I would love to see a study of trans women who on GAHT gained or lost weight and correlations with different gene polymorphisms for estrogen receptor alpha and leptin receptors.

Mauvais-Jarvis, Clegg, & Hevener (2013)

Mauvais-Jarvis, F., Clegg, D. J., & Hevener, A. L. (2013). The Role of Estrogens in Control of Energy Balance and Glucose Homeostasis. Endocrine Reviews, 34(3), 309–338. [DOI:10.1210/er.2012-1055]:

In postmenopausal women, however, when the ovaries fail to produce E2 and in men—who have naturally low levels of circulating E2—E2 does not function as a circulating hormone; rather, it is synthesized in extragonadal sites such as breast, brain, muscle, bone, and adipose tissue where it acts locally as a paracrine or intracrine factor (8).

EST is a cytosolic enzyme that provides a molecular switch in target cells that inhibits estrogen activity by conjugating a sulfonate group to estrogens, thereby preventing binding to estrogen receptors and enhancing urinary excretion of the hormone.

Early studies of the reproductive actions of estrogens led to the establishment of a paradigm in which classical nuclear ERs acted as ligand-activated transcription factors (11). ER modulation of gene transcription is a highly dynamic process. The ER exists in 2 main forms, ER and ER, each of which has multiple isoforms and exhibit distinct tissue expression patterns and functions (12). The classical “genomic” mechanism of ER action typically occurs within hours, leading to activation or repression of target genes. In this classic signaling pathway, ligandactivated ER dissociates from its chaperone heat-shock protein and binds as a dimer either directly to an estrogen response element (ERE) in target gene promoters or indirectly to activator protein 1 or specificity protein 1 response elements through protein tethering to DNA (13). After binding, these ER dimers interact with cofactors (coactivators or cosuppressors) to regulate gene expression.

Cellular estrogenic action depends on: 1) the ER signaling and sensitivity; 2) the activity of enzymes like aromatase involved in the biosynthesis of E2 from androgenic precursors; and 3) the inactivation of E2 in E2 sulfate (E2-S) by the estrogen sulfotransferase (EST).

Although reproductive functions are mostly mediated via classical nuclear ER acting as ligand-activated transcription factors, a large component of ER actions related to energy metabolism also involves extranuclear ERs, indirectly modulating gene expression or acting independently of nuclear events (18). E2 can activate rapid signals Figure 1. Figure 1. Origin of circulating and tissue estrogens. A, In healthy premenopausal women, estrogen (E2) is produced by the ovaries and functions as a circulating hormone that acts on distant target tissues. Here WAT is represented. B, In postmenopausal women and in men, E2 does not function as a circulating hormone; rather, it is synthesized in extragonadal sites from circulating androgenic precursors such as T, androstenedione (4A), or dehydroepiandrosterone (DHEA). Cellular estrogenic action depends on: 1) the ER signaling and sensitivity; 2) the activity of enzymes like aromatase involved in the biosynthesis of E2 from androgenic precursors; and 3) the inactivation of E2 in E2 sulfate (E2-S) by the estrogen sulfotransferase (EST).

E2 can activate rapid signals that act within seconds or minutes via extranuclear and membrane-associated forms of ERs (19). ER and ER are localized to caveolae where they congregate with other signaling molecules, thereby facilitating interaction and rapid intracellular signaling. These signal proteins include G proteins, growth factor receptors, tyrosine kinases (Src), linker proteins (MNAR), and orphan G protein-coupled receptors. This multiprotein complex provides the necessary interactions for membrane ER to activate growth factor receptors and G proteins. In turn, these E2-induced rapid signals modify protein function via phosphorylation. However, they can also modulate gene expression and thus the production of proteins.

ER deficiency in both male and female mice causes increased body weight and adiposity predominately through reduced energy expenditure and slight increases in food intake.

These effects of E2 are mediated via MC4 receptor because E2 is unable to induce anorexia when the MC4 receptor antagonists Shu 9119 or agouti-related peptide (AgRP) are applied concomitantly with E2 administration in rats (70).

Mice with small hairpin RNA-mediated ERgene silencing as well as transgenic mice in which ER has been selectively deleted from SF1-containing neurons of the VMH, develop reduced sensitivity to E2-induced weight loss, increased visceral fat deposition, and reductions in energy expenditure. All of these results occur without an impact on food intake (60, 78), supporting the notion that ER signaling in VMN neurons plays an important role in regulating physical activity, thermogenesis, and fat distribution.

Collectively, these findings suggest that ER in the brainstem, and specifically the [nucleus tractus solitarius (NTS)], is an additional site mediating the anorexigenic effects of estrogens.

Subcutaneous adipose tissue permits efficient storage of maximal calories per unit volume of tissue.

Estrogens are produced in the adipocytes (via aromatization from androgenic precursors) and increase in proportion to total body adiposity (132, 133).

E2 also suppresses white adipose tissue (WAT) accumulation by decreasing fatty acid and triglyceride synthesis and lipogenesis.

Extensive evidence demonstrates that E2 has direct effects on cultured adipocytes with the overall effect of inhibiting lipogenesis and adipogenesis.

[…] suggesting that the absence of E2 promotes immune cell inflammation. Indeed, circulating levels of proinflammatory cytokines are elevated in women after natural or surgical menopause.

Macrophages are elemental players in innate and adaptive immunity; over the past decade their roles in modulating whole-body metabolism and insulin sensitivity have been topics of increasing interest (295, 296).

[…] EST terminates estrogen activity and represents an important parameter of estrogen output upstream of ER. With regard to metabolism, EST is highly expressed in WAT of male mice, but it is not detectable in WAT of normal cycling female mice (320).

Note: Interesting to see if trans folks on GAHT have different type 2 diabetes probability than normal population.

An obvious explanation for these observations is that EST expression is high in male WAT (320) to protect from excessive estrogen actions. It follows that EST suppression produces WAT estrogen excess leading to inflammation. Consistent with this possibility is the observation that E2 treatment leading to high blood concentrations produces WAT inflammation even in females (193).

Note: Makes you wonder if there is potential for higher WAT inflammation in trans folks – especially whne many have E2 levels higher than folks with estrogen producing genitals.

There are reports suggesting that oral E2 may exacerbate insulin resistance and adipocytokine parameters, worsening cardiovascular risk (329). Transdermal E2, however, has minimal effects on insulin resistance and results in higher adiponectin. This suggests that transdermal E2 may be a preferable treatment compared to oral CEE for obese women with metabolic syndrome.

The authors concluded that in women without diabetes, both oral and transdermal estrogen, with or without progestin, increase lean body mass, reduce abdominal fat, improve insulin resistance, decrease LDL/high-density lipoprotein-cholesterol ratio, and decrease blood pressure.

B. Effect of selective estrogen receptor modulators and aromatase inhibitors on metabolism.

In fact, tamoxifen therapy in a case-control study breast cancer survivor was associated with a 24% increased risk of developing diabetes.

In OVX mice, raloxifene reversed OVX-induced increases in food intake, body weight, fat mass, and hyperleptinemia to an extent similar to that of E2. This suggests that in rodents, raloxifene acts as an ER agonist in hypothalamic neurons and fat.

Sullivan et al (356) looked at the effect of a novel SERM (GSK232802A) on body weight, food intake, physical activity, and metabolic rate in an OVX nonhuman primate model. They observed that GSK232802A produced a 5% decrease in weight and reduced adiposity by suppressing food intake and increasing activity. These results occurred without changes in energy expenditure, suggesting that GSK232802A treatment may counteract postmenopausal obesity (356).

Schiffer et al. (2017)

Schiffer, L., Kempegowda, P., Arlt, W., & O’Reilly, M. W. (2017). MECHANISMS IN ENDOCRINOLOGY: The sexually dimorphic role of androgens in human metabolic disease. European Journal of Endocrinology, 177(3), R125–R143. [DOI:10.1530/eje-17-0124]:

Delineating the specific effects of androgen deprivation therapy in this patient population is clouded by co-administration of relatively large doses of oestrogen. Male-to-female transgender patients on combined estrogen and anti-androgen treatment develop an adverse lipid profile.

Cross-sectional studies analysing age-advanced men, men across different ages and obese vs non-obese men consistently support the association between low T and increased fat mass compared to eugonadal controls (107, 142, 143). BMI negatively correlates with total and free T (142, 144), and waist circumference is negatively associated with total T in men.

T administration in men reduces accumulation of visceral and retroperitoneal fat compared to controls, but not in SC depots; hypogonadal men also have increased visceral fat mass.

Mueller et al. (2011)

Mueller, A., Zollver, H., Kronawitter, D., Oppelt, P. G., Claassen, T., Hoffmann, I., Beckmann, M. W., & Dittrich, R. (2011). Body Composition and Bone Mineral Density in Male-to-Female Transsexuals During Cross-Sex Hormone Therapy Using Gonadotrophin-Releasing Hormone Agonist. Experimental and Clinical Endocrinology & Diabetes, 119(2), 95–100. [DOI:10.1055/s-0030-1255074]:

When the BMI values were compared, there was a significant increase during cross-sex hormone treatment with oestrogens in the absence of testosterone after 12 months and after 24 months. Moreover, total fat mass increased also during the study period, while total lean mass decreased significantly.

Recently, Lapauw et al. reported that in MtFs treated with female steroid hormones over an average of 8 years, total lean mass was approximately 20% lower whereas total fat mass was about 30% higher in comparison with a male control group (Lapauw et al., 2008). In this study, transsexuals had been treated with either ethinyl oestradiol, oestradiol valerate, or conjugated equine oestrogens combined with cyproterone acetate (Lapauw et al., 2008).

In MtFs treated with ethinyl oestradiol and antiandrogens, a significant increase in all subcutaneous fat depots, with a lesser but proportional and significant increase in the visceral fat depot and a decrease in thigh muscle area, was reported.

With regard to body composition and bone mineral density, there appears to be no difference when GnRH agonists are used for complete androgen deprivation in MtFs. In comparison with commonly used hormone regimens, the complication rates appear to be lower in patients receiving the treatment regimen described here, as reported earlier.