Trait: Estrogen Production
Dr Haran Sivapalan
December 16, 2019
What is estrogen?
Estrogen is one of the primary female sex hormones (the other being progesterone).
We’ve previously explained what primary sex hormones are in your testosterone level trait. To recap: sex hormones are chemical messages that regulate the growth and function of reproductive organs (e.g. ovaries and testes) and govern the development of secondary sexual characteristics.
Secondary sexual characteristics include features like the development of breasts and wider hips in females, or the growth of facial hair in males. These characteristics emerge during puberty and differ between the sexes.
Estrogen is responsible for secondary sexual characteristics in females, such as: the enlargement of breasts, enlargement of uterus and vagina, widening of the hips, higher-pitched voice and a female distribution of body fat.
Despite being termed a ‘female’ sex hormone, estrogen is produced by and plays several important roles in both men and women. Such roles include the regulation of bone health, reproductive health, inflammation and sugar and fat metabolism.
- Estrogen is a sex hormone which plays key roles in reproductive health, bone health and metabolism.
- Estrogen is important in BOTH men and women.
What are the different forms of estrogen?
There are actually 4 types of estrogen:
- Estrone (E1) – the main form of estrogen in post-menopausal women.
- Estradiol (E2) – the main form of estrogen in men and pre-menopausal women.
- Estriol (E3) – a weak form of estrogen whose levels rise during pregnancy.
- Estetrol (E4) – an estrogen only found in pregnant women.
Estradiol (E2) is the most potent form of estrogen responsible for most of estrogen’s effects in the body. As a result, when used in health and fitness, the term ‘estrogen’ typically refers specifically to estradiol (E2).
- There are 4 different types of estrogen.
- Estradiol (E2) is the most important form of estrogen.
- The term ‘Estrogen’ typically refers specifically to estradiol (E2).
What are the functions of estrogen?
In addition to producing changes during puberty, estrogen plays several important roles in adult men and women.
- Reproductive function
In females, estrogen regulates the menstrual cycle. Specifically, a rise in estrogen during the first part of the cycle (the follicular phase) causes thickening of the lining of the endometrial lining of the uterus.
In males, estrogen helps to regulate the production of sperm (a process called spermatogenesis). It also plays a role in erectile function.
Estrogen (along with testosterone) influences sex drive in both men and women.
- Bone health
Estrogen plays a key role in the maintenance of healthy bones. It does this in two main ways. Firstly, it limits the breakdown of bone (a process called ‘bone resorption’) by inhibiting a particular type of bone cell called osteoclasts. Secondly, estrogen promotes the growth and activity of another type of bone cell called osteoblasts, which lay down new bone.
- Blood flow
Interestingly, the incidence of cardiovascular disease (e.g. heart attack and stroke) is lower in women compared to men. One explanation for this phenomenon is that women produce more estrogen - which has a protective effect on the heart and blood vessels. Studies suggest that estrogen promotes vasodilatation(widening of blood vessels) and helps to prevent the formation of plaques within blood vessel walls (a process called atherosclerosis).
- Glucose and fat metabolism
Estrogen influences the storage, breakdown and use of glucose and fats for energy. There are several complex mechanisms by which estrogen does this. Estrogen’s effect on the production and function of insulin thought to be one key mechanism. Insulin is the hormone that allows sugar (glucose) circulating in the bloodstream to be taken up by tissues such as skeletal muscle and the liver. Estrogen is thought to stimulate the production of insulin by beta cells in pancreas, as well as increasing the sensitivity of tissues to insulin.
- Immune function
Estrogen regulates the activity white blood cells, which help to fight infection and cause inflammation.
Where is estrogen produced?
In pre-menopausal women, the majority of estrogen is produced by the ovaries. Specifically, estrogen (estradiol [E2]) is produced by the theca cells and granulosa cells of ovarian follicles.
Estrogen is also produced by the corpus luteum, a temporary structure in the ovary that forms from ovarian follicles in the first two weeks of the menstrual cycle. After the menopause, estrogen production by the ovaries drops dramatically.
A smaller amount of estrogen is produced by so-called ‘peripheral tissues’ outside of the ovary. Such tissues include: breast tissue, fat cells, bone, skin and blood vessels. Rather than produce estrogen directly from cholesterol, these tissues convert androgens such as testosterone (T) or androstenedione into estrone or estradiol (E2). They do this by using an enzyme called aromatase.
The production of estrogen by peripheral tissues is much more significant in post-menopausal women (as estrogen production directly by the ovaries declines).
As men lack ovaries, they produce significantly less estrogen than women. Estrogen in men is produced from the conversion of androgens (e.g. testosterone) by an enzyme called aromatase. This process occurs in various peripheral tissues, including in the testes (Leydig and Sertoli cells), bone, and fat (adipose) tissue.
- In pre-menopausal women, estrogen is mainly produced by the ovaries.
- In post-menopausal women and men, estrogen is produced in peripheral tissues such as fat, bone, brain tissue and blood vessels.
How is estrogen produced?
Like other sex steroid hormones (e.g. testosterone), estrogen is derived from cholesterol – a fat-like substance made in the liver and contained in various foods.
The chemical pathways involved in producing estrogen differ significantly between pre-menopausal women, post-menopausal women and men.
Pre-menopausal women produce the majority of estrogen in the ovaries as part of the menstrual cycle. This process is regulated by a cycle of hormones released by two structures in the brain: the hypothalamus and the pituitary gland.
Specifically, the hypothalamus releases a hormone called GnRH (Gonadotropin Releasing Hormone) in brief bursts (or pulses). In response to GnRH, the pituitary gland releases two hormones that act on the ovaries: LH (luteinizing hormone) and FSH (follicle-stimulating hormone).
In the first stage of estrogen production, LH stimulates theca cells in the ovary to convert cholesterol into pregnenolone. Pregnenolone is then converted by enzymes (including the 17 alpha hydroxylase enzyme) into various intermediary androgen hormones, including DHEA, androstenodione and testosterone.
In the second stage, androstenodione and testosterone are converted into estrogens by the aromatase enzyme. This process occurs in the granulosa cells of the ovary and is stimulated by FSH (see diagram).
Post-menopausal women and men
In post-menopausal women, estrogen production by the ovaries drops dramatically, so estrogen must be produced locally by other tissues. Similarly, men (who do not have ovaries) must also rely on the local production of estrogen in peripheral tissues.
In peripheral tissues, estrogen is made from the conversion of androgen hormones (e.g. testosterone). Tissues such as fat, brain, bone and blood vessels produce an enzyme called aromatase. Aromatase converts testosterone directly into estradiol (E2), the most potent form of estrogen.
Aromatase also converts another androgen, androstenodione, into estrone (E1), a weaker form of estrogen. Another enzyme, 17β-HSD, then converts estrone (E1) into estradiol (E2).
- Estrogen is a sex steroid hormone.
- Estrogen is derived from cholesterol.
- In pre-menopausal women, estrogen is made in the ovaries under the control of LH (luteinizing hormone) and FSH (follicle-stimulating hormone).
- In pre-menopausal women and men, estrogen is made in peripheral tissues by the conversion of androgens.
- Aromatase is the enzyme that converts androgens (e.g. testosterone and androstenodione) into estrogen.
Do men produce estrogen?
Yes, albeit in significantly lower levels than women. An enzyme called aromatase in peripheral tissues (e.g. fat, bone) converts testosterone into estrogen (estradiol / E2).
How is estrogen transported in the blood?
Like testosterone, the vast majority (about 98%) of circulating estrogen is bound to one of two carrier proteins: sex-hormone binding globulin (SHBG) or albumin. The remaining 2% of circulating estrogen is free and unbound.
When estrogen is tightly bound to SHBG, it is not free to enter cells and exert its effects on the body. In other words, estrogen bound to SHBG is inactive. Only free estrogen is active.
Given this, your SHBG levels have an influence your level of circulating estrogen.
Post-menopausal women and men
In men and post-menopausal women, there is very little estrogen circulating in the bloodstream. Rather, estrogen is produced locally in various peripheral tissues by the aromatase enzyme.
Nevertheless, these tissues require androgens (e.g. testosterone) to make estrogen. These androgens circulate in the bloodstream.
- In pre-menopausal women, circulating estrogen is bound to SHBG and albumin.
- Estrogen bound to SHBG is inactive.
- Free, unbound estrogen is active.
- In post-menopausal women and men, there is very little circulating estrogen (as it is made peripherally).
How does estrogen exert its effects in the body?
Like testosterone, estrogen is a sex steroid hormone. As they are fat soluble, steroid hormones are able to penetrate the outer lipid membrane and enter the inside of cells, where they exert their effects by binding to special steroid receptors.
Estrogen binds to special steroid receptors called estrogen (ER) receptors. When estrogen binds to ER receptors, the receptors move into the nucleus (the central part of the cell containing DNA and genetic material). They then alter the way different genes are switched on and off and converted into proteins (a process called ‘gene expression’).
There are two main types of ER receptors: ERα and ERβ. These are coded for, respectively, by your ESR1 and ESR2 genes. Variations of these genes can alter the function of your estrogen receptors, and thereby influence the effects of estrogen in your body.
- Estrogen is a steroid hormone.
- Estrogen binds to estrogen receptors (ER) inside cells.
- Estrogen changes the way various genes are switched on and off by cells.
- Variations in the genes for estrogen receptors (ER) influence the effects of estrogen in the body.
Estrogens and aging
Estrogen (estradiol) levels fluctuate over the course of a lifetime. This differs between men and women.
Estrogen levels rise rapidly in adolescence, where estrogen produced by the ovaries stimulates the development of secondary sexual characteristics (e.g. development of breasts). They then remain high during adulthood and help maintain regular menstrual cycles.
When women reach the menopause, which is typically between ages 45 and 55, estrogen production by the ovaries drops significantly. Estrogen levels remain low thereafter.
In contrast to women, estrogen levels in men only gradually rise during adolescence. They then remain fairly stable for the remainder of adulthood.
What are the consequences of low estrogen production?
Estrogen plays vital roles in fat and glucose metabolism, bone health, immune function and blood flow. When estrogen production is low, these processes may be compromised.
- Impaired fat and glucose metabolism
Studies suggest that low levels of estrogen are linked to poorer insulin sensitivity in both men and women. Insulin is the hormone that allows tissues to take up and use glucose from the bloodstream. When tissues in the body are less sensitive to insulin, it becomes more difficult for tissues to take up glucose. Consequently, glucose levels in the blood rise. Elevated blood glucose levels in the long term can cause damage to blood vessels and also increase the risk of cardiovascular disease and type II diabetes.
Low estrogen levels are also associated with increased fat deposition, particularly in visceral fat stores. Excessive amount of visceral fat (which surrounds internal organs in the abdomen) is linked to inflammation, poorer insulin sensitivity and a higher risk of cardiovascular disease.
- Loss of bone density
Estrogen acts to both stimulate the formation of new bone and limit the breakdown (or ‘resorption’) of existing bone.
When estrogen production is low, bone mass may subsequently decrease. This increases the risk of osteoporosis – a condition characterised by increasingly fragile bones which are more susceptible to fracture.
- Poorer blood flow
Estrogen has a ‘vasoprotective’ effect on the cardiovascular system – it helps to prevent the build up plaques (called atheroma) on blood vessel walls. People (particularly men) with low levels of estrogen may be at increased risk of atherosclerosis – a cardiovascular disease where plaques build on arterial walls.
What are the consequences of high estrogen production?
Excessively high estrogen production can also have negative effects on the body. This may be independently due to high levels of estrogen. Alternatively, it may result from high levels of estrogen relative to levels of other sex hormones (e.g. testosterone and progesterone).
In pre-menopausal women, high levels of circulating estrogen has been linked to:
- irregular menstrual cycles.
- weight gain.
- changes in mood.
In men, high levels of estrogen (particularly in relation to testosterone) has been associated with:
- Erectile dysfunction.
- Poorer fertility.
- Gynecomastia – the enlargement of breast tissue in men.
The production of estrogen is a complex process with both environmental factors (e.g. diet, lifestyle, body composition, medication) and genetics playing major roles.
If you go back to the “How is estrogen produced section?” you will recall that several different enzymes are involved in the production of estrogen. If the activity of these enzymes is altered, your production of estrogen will also change.
At FitnessGenes, we analyse common variations (SNPs) in the genes encoding these enzymes. Certain gene variants may affect the activity of these enzymes, and thereby influence your production of estrogen.
Two such genes are:
This gene encodes the aromatase enzyme, which is responsible for producing estrogen from androgens (e.g. testosterone and androstenodione). Variations in the CYP19A1 gene may influence how effectively the ovaries (in pre-menopausal women) and peripheral tissues (in men and post-menopausal women) convert androgens into estradiol (E2).
This gene encodes the 17β-HSD enzyme. This enzyme converts the weak estrogen, estrone (E1), into the more potent estradiol (E2). It is also involved in converting the androgen androstenodione into testosterone, which is part of the estrogen production pathway. Variations in the CYP17A1 gene may influence how effectively the ovaries (in pre-menopausal women) and peripheral tissues (in men and post-menopausal women) make estradiol (E2).
We also analyze several other gene variants related to estrogen metabolism. For example, we look at variants of the SHBG (sex-hormone binding globulin) and estrogen receptor genes (ESR1, ESR2).
- Your CYP19A1 and CYP17A1 genes influence estrogen production.
- Estrogen production is influenced by both environmental and genetic factors.