Estrogen Metabolism and the Concept of Estrogen Dominance

Few ideas in popular women’s health are as widespread as oestrogen dominance, spelled estrogen dominance in American English. It is offered as an explanation for heavy periods, breast tenderness, weight gain, bloating, mood swings, fibroids, endometriosis and fatigue, and treated with supplements, detox protocols and progesterone creams. The biology it draws on is real: oestrogen is produced, metabolised and cleared through well described pathways, and its balance with progesterone matters. But the concept as usually presented is broader and vaguer than the evidence supports. This article describes oestrogen metabolism accurately and then examines the concept honestly.

The oestrogens

The body produces several oestrogens.

• Oestradiol (E2) is the most potent and the main oestrogen of the reproductive years, produced mainly by the ovaries.
• Oestrone (E1) is weaker and becomes the predominant oestrogen after menopause, produced mainly in fat tissue.
• Oestriol (E3) is weak and produced in large amounts by the placenta in pregnancy.
• Estetrol (E4) is produced by the fetal liver during pregnancy and has been developed for use in contraception.

Oestrogens are made from androgens by the enzyme aromatase. Before menopause, most oestradiol comes from the ovaries. After menopause, aromatase in fat tissue becomes the main source, which is why higher body fat is associated with higher oestrogen levels in postmenopausal women and in men.

How oestrogen is metabolised

Phase one: hydroxylation

In the liver and other tissues, cytochrome P450 enzymes add hydroxyl groups to oestrogens, producing 3 main pathways:

Phase 2: conjugation

Hydroxylated oestrogens are then methylated by catechol O methyltransferase, COMT, or conjugated with glucuronic acid or sulphate, making them water soluble for excretion in urine and bile.

The gut and the estrobolome

Conjugated oestrogens excreted in bile can be deconjugated in the gut by bacterial enzymes, particularly beta glucuronidase, allowing them to be reabsorbed. The collection of gut bacterial genes involved in this process has been called the estrobolome. The concept is biologically plausible and an active area of research, but its clinical implications are not yet established.

Oestrogen and progesterone in balance

During the menstrual cycle, oestrogen stimulates growth of the endometrium, and progesterone, produced after ovulation, transforms and stabilises it. When ovulation does not occur, progesterone is not produced, and the endometrium is exposed to oestrogen without progesterone’s opposing effects. Prolonged unopposed oestrogen increases the risk of endometrial hyperplasia and cancer. This is a genuine and clinically important form of relative oestrogen excess.

Where relative oestrogen excess is real

• Anovulatory cycles, as in polycystic ovary syndrome, adolescence and perimenopause, cause unopposed oestrogen exposure of the endometrium.
• Obesity increases oestrogen production in fat tissue and is a major risk factor for endometrial cancer and postmenopausal breast cancer.
• Perimenopause is marked by highly variable oestrogen levels, sometimes higher than in earlier reproductive years, alongside falling progesterone, contributing to heavy periods, breast tenderness and mood symptoms.
• Oestrogen only hormone therapy in women with a uterus increases endometrial cancer risk, which is why a progestogen is added.
• Oestrogen dependent conditions such as endometriosis and fibroids are influenced by oestrogen, although they involve many other mechanisms and are not simply caused by excess oestrogen.
• Alcohol raises circulating oestrogen levels and is an established risk factor for breast cancer.
• Liver disease can impair oestrogen clearance.

The concept of oestrogen dominance

The term oestrogen dominance was popularised in the 1990s in books promoting progesterone creams. As commonly used, it describes a state in which oestrogen is too high relative to progesterone, said to explain a very wide range of symptoms and to be widespread in modern women because of stress, diet and environmental chemicals.

The concept has several problems.

• It is not a recognised medical diagnosis, and there are no agreed criteria for it.
• The symptoms attributed to it are common and nonspecific, with many possible causes.
• Oestrogen and progesterone levels vary greatly across the cycle, so single measurements are difficult to interpret, and ratios lack validated reference values.
• It groups together distinct conditions with different causes and treatments, such as anovulation, fibroids, endometriosis and perimenopause, under one label.

The underlying intuition, that the balance of hormones matters and that some women experience symptoms related to that balance, is not wrong. It is better expressed through specific diagnoses that point to specific treatments.

Testing

Blood tests of oestradiol and progesterone have specific uses, such as confirming ovulation with a mid luteal progesterone, or assessing ovarian function in certain contexts. Their interpretation depends on timing in the cycle. Salivary hormone testing is not validated for most clinical purposes.

Urinary hormone metabolite tests, which report oestrogen metabolites and pathway ratios, are popular in functional practice. They provide research grade information about metabolism, but the clinical significance of particular patterns has not been established in outcome studies. The ratio of 2 hydroxy to 16 alpha hydroxy oestrone, once proposed as a breast cancer risk marker, has shown inconsistent associations in prospective studies. Results should not drive major decisions.

What influences oestrogen metabolism

A note on progesterone creams

Over the counter progesterone creams are widely used to counter oestrogen dominance. Absorption through the skin produces variable and often low blood levels, and these creams have not been shown to protect the endometrium in women using oestrogen. They should not replace prescribed progestogens in hormone therapy.

An illustrative case

A 46 year old woman with heavy, irregular periods, breast tenderness, poor sleep and mood swings has been told she has oestrogen dominance on the basis of a urine hormone test and has started a progesterone cream and several supplements. Her doctor assesses the heavy bleeding with a blood count, which shows iron deficiency, and a pelvic ultrasound, which shows a fibroid. Her symptoms fit perimenopause with anovulatory cycles. She is offered treatment options for heavy bleeding, including a levonorgestrel intrauterine system, which also provides endometrial protection. Her iron deficiency is treated, alcohol is reduced and she increases fibre and exercise. The cream and most supplements are stopped. Her symptoms improve considerably. Specific diagnoses led to specific treatments.

Precision over labels

Oestrogen metabolism is a genuine and fascinating area of physiology. Its clinical value lies in recognising specific situations of relative oestrogen excess, such as anovulation, obesity and perimenopause, and addressing them with established treatments, rather than in a broad label that obscures more than it explains.