Testosterone Needs to Be Converted into Estradiol to Prevent Fat Accumulation

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How Targeting Fat Cells’ Estrogen Receptors Could Fight Obesity
Tracy Hampton, PhD


In adipocytes, fat cells, a particular estrogen-receptor appears critical for energy supplying mitochondria to function properly
. The discovery points to a potential drug target for boosting fat tissue metabolism, which could help combat obesity and other metabolic conditions.

The research addresses a vexing problem that many middle-aged adults face as they get older—added fat tissue and weight gain due to a slowing metabolism.
The problem is especially prominent for women, as estrogen deprivation after menopause leads to an increase in total body fat.

Previous studies have offered a potential explanation in a link between fat accumulation, mitochondria-related dysfunction, and lower expression of the gene ESR1, which encodes a form of the estrogen receptor called ERα. Indeed, healthy identical twins who differ by body mass index have different mitochondria-related RNA signatures in their fat cells, indicating a link between mitochondrial dysfunction and adiposity. In addition, ESR1 expression is reduced in fat tissue from women with obesity, and adipocyte ERα deletion disrupts the metabolic balance in rodents.

With this knowledge in mind, investigators first examined the clinical relationships between ESR1 expression and markers of metabolic health. “We hypothesized that low ESR1 expression in adipose tissue— both variability in genetic inheritance as well as reduced expression as a consequence of environmental factors and aging—underlies susceptibility for obesity and metabolic dysfunction,” Andrea Hevener, PhD, a professor in the division of endocrinology, diabetes, and hypertension at the University of California, Los Angeles (UCLA) David Geffen School of Medicine, said in an interview.

In a study published in Science Translational Medicine, Hevener and her colleagues discovered that ESR1 fat tissue expression among more than 700 women and nearly 800 men were inversely associated with abdominal fat mass and positively correlated with insulin sensitivity. Therefore, people with lower levels of ESR1 expression tended to have higher fat stores and insulin resistance, clinical features of metabolic dysfunction. The findings in males were unexpected and suggest that men’s estrogen levels could affect their body weight more than is currently appreciated. “Although it is known that estrogen action is important for metabolic health because tissue ESR1 expression and estradiol levels are much lower in men than women, many have assumed that estrogen action is less important for men compared with women,” Hevener said. “Our findings do not support this notion.”

The team next examined the mechanistic links between ERα absence, mitochondrial function, and obesity.
In mice, selectively deleting the Esr1 gene from energy-storing white adipocytes and energy-burning brown adipocytes impaired mitochondria. The deletion reduced the expression of Polg1, a subunit of the polymerase enzyme that replicates and transcribes mitochondrial DNA. This led to increased fat in white adipocytes and reduced energy burning in brown adipocytes.

The investigators have now pivoted to studying mice that overexpress Esr1 in their white and brown adipose tissue. “We want to know if these mice will be protected against high-fat diet-induced weight gain and insulin resistance,” Hevener explained. Her team is also studying the relationship between aerobic exercise training and adipose tissue ESR1 expression. Their goal is to learn if people need ERα and healthy mitochondrial function in adipocytes to lose weight from exercising.

The researchers seek to translate their findings into clinical interventions to help counter obesity and metabolic dysfunction. Targeting ERα and its effects—along the lines of selective estrogen receptor modulators currently used to treat breast cancer and osteoporosis—may be especially promising among women during the menopausal transition. Although premenopausal women are less prone to metabolic disease than men, menopause reverses this protection.


The study’s potential implications for men are also intriguing, said Franck Mauvais-Jarvis, MD, PhD, director of the Diabetes Discovery Research and SexBased Medicine Laboratory at Tulane University School of Medicine. We know that testosterone needs to be converted to estrogens to prevent abdominal fat accumulation in men and that men with mutations in ERα accumulate abdominal fat,” he said in an email. More research is needed to explore the full range of metabolic effects of estrogens and their receptors in both women and men, he added.
 

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Nelson Vergel

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Estradiol May Prevent Fat Accumulation


At least in female rodents...


"administration of supplemental doses of estradiol appeared to prevent fat accumulation and overcome leptin resistance in ovarian-intact and ovariectomized female high-fat-diet mice, they wrote online in the journal Endocrinology.
But response to estradiol treatment in the high-fat-diet animals depended on endogenous estrogenic status, they cautioned.
"When estradiol (E2) was cyclically administered to ovarian-intact HFD-fed mice for 12 weeks, the animals gained significantly less weight than ovarian-intact vehicle controls (P<0.01)," the researchers wrote. "This difference was mainly due to reduced caloric intake and not to an increase in energy expenditure or locomotor activity."


This study shows what happens to sexual function and body composition at different blood levels of testosterone and/or estradiol.


Gonadal Steroids and Body Composition, Strength, and Sexual Function in Men

N Engl J Med. Sep 12, 2013; 369(11): 1011;1022.

All participants received goserelin acetate (Zoladex, AstraZeneca), at a dose of 3.6 mg subcutaneously at weeks 0, 4, 8, and 12, to suppress endogenous gonadal steroids. Participants were then randomly assigned to receive 0 g (placebo), 1.25 g, 2.5 g, 5 g, or 10 g of a topical 1% testosterone gel (AndroGel, Abbott Laboratories) daily for 16 weeks. Participants in cohort 2 also received anastrozole (Arimidex, AstraZeneca) at a dose of 1 mg daily to block the aromatization of testosterone to estrogen. Participants were unaware of the study-group assignments.
Participants were seen every 4 weeks. At each visit, fasting blood samples were obtained to measure gonadal steroid levels, and questionnaires were administered to assess physical function, health status, vitality, and sexual function. At baseline and week 16, body fat and lean mass were assessed by means of dual-energy x-ray absorptiometry (DXA); subcutaneous- and intraabdominal-fat areas and thigh-muscle area were measured by means of computed tomography (CT); and lower-extremity strength was determined by means of a leg press. Data on bone homeostasis (bone-turnover markers and bone mineral density), risk factors for cardiovascular disease (blood pressure, lipids, and insulin sensitivity), and levels of leptin and prostate-specific antigen were also collected but are not included in the present report.

"...we found that lean mass, muscle size, and strength are regulated by androgens (testosterone); fat accumulation is primarily a consequence of estrogen deficiency (low estradiol); and sexual function is regulated by both androgens and estrogens. Delineation of the degrees of hypogonadism at which undesirable consequences develop and of the relative roles of androgens (testosterone) and estrogens in each outcome should facilitate the development of more rational approaches to the diagnosis and treatment of hypogonadism in men."



Source: Gonadal Steroids and Body Composition, Strength, and Sexual Function in Men
 

Nelson Vergel

Founder, ExcelMale.com
There was a recently published groundbreaking study about the role of estradiol in men. No optimal ranges of estradiol were noted but low levels were associated with increased fat and decrease in sexual desire and erectile function compared to higher levels (the highest average estradiol was 35 pg/ml, unfortunately, so no conclusions can be made for levels above this).

Men had their hormones blocked by a gonadotropin-releasing hormone antagonist. All of them then received testosterone supplementation with Androgel. Half were also treated with anastrozole to block estradiol conversion from the testosterone. Please refer to the attached graphs.

All participants (Cohorts 1 and 2) received goserelin acetate (Zoladex, AstraZeneca), at a dose of 3.6 mg subcutaneously at weeks 0, 4, 8, and 12, to suppress endogenous gonadal steroids (testosterone and estradiol). All participants (Cohort 1 and 2) were then randomly assigned to receive 0 g (placebo), 1.25 g, 2.5 g, 5 g, or 10 g of a topical 1% testosterone gel (AndroGel, Abbott Laboratories) daily for 16 weeks. Participants in cohort 2 also received anastrozole (Arimidex, AstraZeneca) at a dose of 1 mg daily to block the aromatization of testosterone to estrogen. Participants were unaware of the study group assignments.

Findings:

Higher blood levels of testosterone decreased the percentage of body fat (P = 0.001), intra abdominal fat area (P = 0.021), and subcutaneous fat area (P = 0.029), and increased sexual desire (P = 0.045) and erectile function (P = 0.032).

Low blood level of estradiol was associated with significant increases in the percentage of body fat (P<0.001), subcutaneous fat area (P<0.001), and intra abdominal fat area (P = 0.002), and relative less improvement in sexual desire (P<0.001) and erectile function (P = 0.022). These findings provide additional evidence of an independent effect of estradiol on these variables.

"Our finding that estrogens have a fundamental role in the regulation of body fat and sexual function, coupled with evidence from prior studies of the crucial role of estrogen in bone metabolism, indicates that estrogen deficiency is largely responsible for some of the key consequences of male hypogonadism and suggests that measuring estradiol might be helpful in assessing the risk of sexual dysfunction, bone loss, or fat accumulation in men with hypogonadism. For example, in men with serum testosterone levels of 200 to 400 ng per deciliter, sexual desire scores decreased by 13% if estradiol levels were 10 pg per milliliter or more and by 31% if estradiol levels were below 10 pg per milliliter. "

Reference:

Gonadal Steroids and Body Composition, Strength, and Sexual Function in Men
N Engl J Med 2013;369:1011-22.
 

Nelson Vergel

Founder, ExcelMale.com
But see what happens when testosterone is suppressed and men were given estrogen

 
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