Part 1: Sex hormones 101 – what do they do, how are they made and metabolised?

On the other hand, when our hormones are out of balance, they can set the stage for poor health and disease, and they are affected by many different lifestyle factors such as sleep, exercise, diet, circadian rhythms, stress and relationships as well as some of the most common synthetic chemicals that are a ubiquitous part of modern life. This is especially important for women considering many of these compounds can act like estrogens (or the British spelling: oestrogens) in the body making it more difficult to maintain homeostasis, especially in the presence of poor liver and gut health.

So in this article, I’m going to focus on the steroid hormones with a brief overview of what they are, what they do and how they are made and metabolised together with the main lifestyle factors that impact them.

What is a hormone?

Hormones are signalling molecules that get produced by certain cells in certain tissues, and then travel to other cells where they create an effect. The effects can be autocrine (having an effect on the same cell), paracrine (having an effect on nearby cells) and endocrine (hormones secreted directly into the bloodstream which can affect cells all around the body). You may also hear the word Exocrine, which is used for products that are secreted onto the skin’s surface like sweat from sweat glands, even if these products are usually not hormonal in nature.

What do hormones do?

Broadly speaking, hormones are messengers that keep all parts of the body in constant communication and in tune with itself and the outside world so that we can adapt to changing situations in order to survive, thrive and procreate. For example, if we’re faced with a stressful situation, the brain triggers a nervous and hormonal stress response which prepares the body to overcome the stressor with hormones like cortisol and adrenaline. If we feel safe on the other hand, sex hormones help prepare us to have offspring and pass on our genes. 

Hormones and the rhythms of life

A key concept when thinking about hormones is their rhythmical nature. Rhythms represent the dynamism of life on earth, and the ability of our endocrine system to adapt to and follow these rhythms is a key component of health. We have daily cycles with cortisol rising in the morning and falling at night, while melatonin can be found highest during darkness. We also have monthly cycles – a carefully orchestrated rise and fall of FSH, LH, estradiol and progesterone to prepare the female body for ovulation and procreation. There are also yearly cycles as we adjust to the seasons and cycles that last a lifetime like the rise and fall of growth hormone. Many of these changes respond to constant cycles such as the sun and the moon and the orbit of the earth while others respond to less constant stimuli such as insulin’s response to fasting and feeding. If we take a moment to consider this, it is an amazing thought that hormones represent our connection to the natural world and the universe around us. They mirror internally what’s going on outside in our environment, so one of the most important considerations when trying to improve hormonal health is to ask how am I out of sync with nature?

How do hormones have their effects?

Hormones bind to receptors that are usually found inside the cell in the cytoplasm or on the nucleus, which trigger gene expression and other reactions which differ from cell to cell. For example, estradiol acts on special kidney cells in the nephron to increase water and sodium retention, which is why women’s water weight changes throughout the cycle, but it acts on the pituitary in a different way: to stimulate hormone release such as prolactin. Some hormones have opposing effects on certain tissues. For example, progesterone may decrease the number of oestrogen receptors, thereby decreasing oestrogen’s effects. And conversely, as oestrogen stimulates prolactin, it may lead to less progesterone due to decreased ovulation. These interactions are infinitely complex and remind us that it’s never about just one hormone, but always about the network of different hormones working together.

Where do they come from?

All steroid hormones originate from cholesterol which is mostly made in the liver, with some coming from our diet. It is then transformed to different hormones via a series of different enzymes which are found in the mitochondria, and this happens mostly in the gonads (the ovaries and testes) and the adrenals, but also in other tissues like the nervous system. Each of these hormones has different characteristics and different effects before being transformed into the next hormone in the chain. Eventually they are metabolised and excreted from the body, so hormonal balance depends on 3 things: the ability to make the hormones, to transform them from to the other depending on demand and to break them down and excrete them when done.

“…hormonal balance depends on 3 things: the ability to make the hormones, to transform them from to the other depending on demand and to break them down and excrete them when done.”

To visualise this process, let’s take a look at a map which shows each step of steroid production and where they go when metabolised. Below I’ll explain the importance of some of these steps as well as of phase I, phase II and phase III detoxification.

Pregnenolone: Pregnenolone is the master hormone as all other steroid hormones are made from it. It provides the raw materials and is itself made from cholesterol. This happens in the adrenals, the gonads and the brain. Intracellular cholesterol is transported into the inner mitochondrial membrane where a series of CYP450 enzyme reactions turns it into pregnenolone using NADPH as an electron donor (a product of the pentose phosphate pathway). NADPH is reduced when oxidative stress is increased, so right away we can see that steroid hormone production isn’t going to be optimal in the presence of oxidative stress and mitochondrial dysfunction. Sources of oxidative stress include things like refined, junk food diets, smoking, drinking alcohol and disrupted day-night cycles, so we can already see that the way we live has a great deal to do with our hormones.

GnRH: Gonadotropin releasing hormone is the main regulator of the reproductive axis and is produced by the hypothalamus (brain) in response to stimuli received from the body. It tells the anterior pituitary to start producing luteinizing hormone and follicle stimulating hormone.

FSH and LH: Follicle stimulating hormone and Luteinizing hormone are the two conductors of the orchestra and produced by the anterior pituitary (also in the brain). They travel around the body to act on the gonads: the ovaries in women and the testes in men. In men, LH stimulates the Leydig cells in the testes to produce testosterone, and FSH stimulates the Sertoli cells together with testosterone to produce regulatory substances and nutrients that aid the creation of sperm. In women, LH stimulates estradiol production in the ovary in the first 2 weeks of the menstrual cycle, before rising sharply to stimulate ovulation: the release of an egg. In the remaining 2 weeks, LH helps stimulate the corpus luteum to produce progesterone. FSH stimulates the growth of ovarian follicles which allow the maturation and release of an egg also helps stimulate estradiol production.

Progesterone: Progesterone is known as the pregnancy hormone, but has many other important functions. It rises in the luteal phase of a woman’s cycle following ovulation as the corpus luteum starts to make it and prepares the lining of the uterus for potential implantation. Following successful implantation, the placenta takes over progesterone production around weeks 8-12 of the pregnancy and remains elevated for the entire pregnancy, reducing somewhat in the third trimester. Progesterone is also made by the adrenals in both men and women and is an important precursor to cortisol and aldosterone. Under acute stress, progesterone rises with cortisol, but may become depleted under chronic stress. It opposes many of the effects of androgens and estrogens, and may also inhibit adrenaline and insulin to some degree. Progesterone is also associated with better sleep and lower anxiety, and it is also synthesised in the nervous system and converted to allopregnenalone, a neurosteroid which acts on GABA receptors to calm us down. Animal studies have also shown progesterone to have anti-inflammatory and antioxidant actions. 

Androgens: Androgens are often thought of as the male hormones, but they’re also important for women, and include DHEA, androstenedione, androstenediol, testosterone and dihydrotestosterone (DHT). Testosterone and DHT have the strongest effects and higher levels in men give the classic anabolic male features of hair growth, muscle development, larger structure, a deeper voice and determination, whereas excess levels may lead to acne, sweating and aggression. In both men and women, testosterone is important for drive, motivation and good mental health, as well as being an important anti-inflammatory, antioxidant and metabolic regulator. Androstenedione and testosterone then get transformed into estrone and estradiol respectively by the enzyme aromatase. This is an important enzyme to remember and one that I’ll come back to, because when dealing with increased estrogens and/or reduced aromatase activity in women, the androgens start to build up causing many typical symptoms such as sweating, acne, aggression and frustration and sometimes facial hair growth.

Primary estrogens: These include estrone (E1), estradiol (E2) and estriol (E3) and as mentioned above are made from androgens by the enzyme aromatase. They are made in the ovaries and also in the adipose tissue which expresses the aromatase enzyme. Estrone is a weak oestrogen, and may act as a storage hormone to be converted into estradiol when needed. Estradiol is the strongest oestrogen whose main task is to help mature and maintain the female reproductive system. It is highly anabolic and promotes breast tissue, bones and cartilage. During the cycle, estradiol increases and stimulates LH which leads to the maturation of the egg. During pregnancy, it is also produced by the corpus luteum and later on the placenta. In excess, it may cause headaches, water retention, an increase in prostaglandins and therefore inflammation and pain, bloating, tender breasts, PMS symptoms, mood swings and decreased sex drive. Having said that, estrogen’s relationship with inflammation is complex, and it may also have anti-inflammatory effects on the brain. Estriol is the third naturally occurring oestrogen and is normally very low, rising up during pregnancy. 

Phase I estrogen metabolites: primary estrogens are broken down into metabolites which include the estrone metabolites, 2-OH-E1, 4-OH-E1 and 16-OH-E1 (which can be transformed into estriol). Other common metabolites cited in the research include 2-OH-E2 and 4-OH-E2 and come from estradiol, although there are probably many more. These metabolites are intermediaries, produced mostly in the liver by CYP450 enzymes which need to be further broken down to avoid them building up, and if this doesn’t happen, they can cause health issues having not only estrogenic effects, but potentially increasing the chances of DNA damage and cancer risk. 2-OH-E1 is thought to be protective in this respect, whereas 4-OH-E1 is thought to increase cancer risk by producing unstable quinones that have the potential to damage DNA if not detoxified by glutathione. Other studies have since found that 16-OH-E1 doesn’t represent the same risk, but seems to be more estrogenic than the others and may be linked for many of the ‘high-estrogen’ symptoms that get reported. It may also protect against osteoporosis. 

Phase II Conjugated estrogens: after hydroxylation, the oestrogen metabolites get conjugated. Conjugation is typically a Phase II liver reaction but also happens elsewhere, including the gut. Hormones are bound to a chemical group which renders them much less active and more water soluble so they can be either stored or excreted easier in the urine, and this includes methylation, sulfation and glucuronidation. 

Phase I, II and III detoxification

Understanding the different phases of detoxification is key to achieving good hormonal balance and good health in general. After hormones have done their job, they need to be broken down and removed from the body, and the majority of this happens in the liver. It’s not only hormones that get removed in this way, but also all of the usual things that we think of as toxic: cigarette smoke, alcohol, pesticides, air pollution and so on. Along with the many benefits of the modern world, we also unfortunately have a wealth of harmful, synthetic substances that find their way into our bodies that need to be broken down and eliminated to avoid health issues and I believe that doing things to help these biological processes is essential for good health and longevity and has never been more important. This process can be broken down into 3 distinct phases: 

Phase I: in phase I substances are transformed in the liver by the CYP450 enzymes. This renders them more water soluble but at the same time most chemicals end up being more toxic, so if they don’t get conjugated in Phase II and excreted, they can build up and cause health issues. Hydroxylation is a common phase I reaction, and with estrogens this results in the most common oestrogen metabolites, 2-OH-estrone and 4-OH-estrone as well as 16α-OH-estrone. Estradiol also gets hydroxylated to 2-OHE2 and 4-OH-E2 as mentioned above. Different CYP450 enzymes have affinity for different substances – so for example, CYP1A1 produces 2-OH-E1, CYP1B1 produces 4-OH-E1 and finally CYP34A produces the 16-OH-E1 metabolite. Why is this important? The 2-OH metabolites are generally thought of as protective while the ‘4-OH’ metabolites have been found to increase cancer risk. Some people have genetic predispositions to one pathway or another, which is being researched as a genetic risk factor for cancer – but perhaps more importantly, our lifestyle and environment can speed up and slow down these enzymes. For example, a high sugar diet may slow down the first enzyme, whereas cruciferous vegetables, fish oil, thyroxine and rosemary might speed it up, leading to higher levels of the protective ‘2-OH’ metabolite. Furthermore, inflammation, smoking and PAHs (toxic substances from fossil fuel burning, wood fuels and burnt meats) may speed up the second enzyme leading to higher levels of the potentially more dangerous ‘4-OH’ metabolites, whereas certain flavonoids may slow this down. In other words, many of the things that we think of as healthy or harmful may in fact have those effects because they modulate pathways like this – speeding up and slowing down enzymatic processes that impact our health in significant ways.

Phase II: phase II is made up of conjugation reactions whereby chemical groups are added in order to make the compounds less toxic and easier to excrete through the kidneys or the bowel. One such conjugation reaction is methylation, and in the case of oestrogen detox is carried out by the enzyme COMT, which also breaks down dopamine and adrenaline. Being a methylation enzyme, COMT is dependent on the availability of SAMe, our main methyl donor, which relies on many different nutrients such as certain B vitamins, methyl groups from our diet and the proper management of homocysteine and methionine in the methylation cycle. There are also genetic polymorphisms which seem to render the COMT enzyme either faster or slower in function, meaning higher or lower levels of these chemicals that it breaks down which may have implications for people’s personality – the so called ‘warrior vs worrier’ – but as with all enzymes there are also many different environmental factors that affect how well COMT is working, which means that whatever our genetic predisposition, lifestyle factors will always play a big role in how well they work. 

Another conjugation reaction is sulfation, which adds a sulphate group. Many steroids, including cholesterol, are sulfated in order to be stored in a less active form so that they can be quickly converted back to the active form, but in some cases like with PCOS, this conversion happens too much, leading to an excess of active hormones. A lack of sulphur in the diet as well as adequate sunshine may also impact our ability to sulphate things, and this may well have broad implications for health as detailed in the work of Stephanie Seneff, a senior researcher at MIT. 

The third conjugation reaction worthy of mention in steroid detox is glucuronidation. This reaction happens mostly in the liver but also in the gut and is possibly the most active in getting rid of oestrogen metabolites, even though it is rarely one or the other as these different reactions work together. The methylated and hydroxylated metabolites can go on to be glucuronidated, but primary hormones and a range of toxic substances are also deactivated via this process and it is key to keeping our body clean and functional. The gut is not only a site for this reaction to take place, but also for the reverse to happen though: certain bacteria species in the gut can produce an enzyme called beta glucuronidase which liberates substances from the glucuronic acid they were bound to, enabling these substances to be reabsorbed and reactivated. This has led to the term ‘estrobolome’ which describes a subset of the microbiome bacterial species that are particularly good at recycling oestrogen by reversing processes like glucuronidation, and one of the challenges with normalising hormones is in also tackling any gut issues that may be leading to this phenomenon.

“So an overgrowth of certain bacteria in the gut can mean that instead of leaving the body, hormones get reabsorbed leading to higher levels. This seems to be particularly prevalent with oestrogen dominance symptoms”

Phase III: so phase III refers to the gut and the kidneys as the metabolised hormones are excreted through the stool and urine. As mentioned above, certain changes in the gut microbiome can disrupt this process, but apart from favourable gut flora, we also need to have good digestive function, good bile flow, proper peristalsis and good bowel movements, and for most people this also means eating a diet rich in fibre and polyphenols and other nutrients as well as considering other key aspects of health such as thyroid function. Kidney function is also vital, and the kidneys are really the unsung heroes of detoxification given the huge quantity of blood they filter every single day. They also need specific nutrients and good blood flow, and both the kidneys and the gut work much better if we are managing our stress, following good circadian rhythms and avoid refined, junk food diets.

How do they maintain balance? 

So far I’ve talked about how they are made and how they are broken down after they’ve been used, but how do these two connect to keep our hormones at the right level at the right time? The answer is that our body is equipped with many complex feedback mechanisms that communicate with each other to adjust our levels up and down. This process is called homeostasis and it describes a dynamic balance that is contextualised to our needs at that moment in time.

Our brain, and in particular our hypothalamus and pituitary glands, are constantly listening into signals that arrive and adjusting their nervous and endocrine outputs. Here are some common feedback loops:

• Estradiol inhibits FSH and LH: For most of the female cycle, estradiol feeds back to the hypothalamus and pituitary to reduce FSH and LH levels, which reduce the production of estrogens and progesterone.
  
• Estradiol increases FSH and LH: around day 12-14, the opposite occurs, and this causes a rise in FSH and LH which helps prepare the reproductive system for ovulation.
  
• Estradiol increases prolactin secretion: at high levels, this can suppress ovulation and progesterone production.
  
• Progesterone decreases LH: progesterone inhibits GnRH which decreases LH and subsequent oestrogen production
  
• High cortisol suppresses LH: in times of stress, the body shifts resources to stress hormone production, and one way this happens is via cortisol’s suppression of GnRH stimulated LH secretion.
  
• Low cortisol may increase DHEA: low cortisol signalling leads to increased ACTH which may stimulate DHEA production.

There are of course many more feedback loops involving many more hormones, but the basic concept is that the brain is constantly listening to signals coming in, both from the bloodstream and our thoughts and emotions, and adjusting its output to match the context.

A change in our hormones, then, is either the result of an intelligent adaptation – for example, in stressful times we prioritise survival over reproduction – or, the result of dysfunction – for example, a deficiency of zinc that stops key enzymes doing what they need to do, leading to lower levels of certain hormones and changes in these feedback loops.

So for example, people who have suffered emotional trauma as children may have higher baseline levels of cortisol, and that can skew the whole system slightly. Add in high-sugar diets and other inflammatory insults and we may see a change in the ratios of those oestrogen metabolites mentioned before. This will then likely go on to negatively affect other areas of life like sleep quality, which increases cortisol further. So we can see that it is rarely just one thing – that these things get stacked as part of life – but in order to improve these symptoms, we need to back and figure out why all this started and think about root causes, both physical, psycho-emotional and energetic, which is why I believe a naturopathic approach can be so valuable. 

How can we make sense of this information when dealing with hormonal issues?

We’ve covered a lot of ground so far, and we also touched on some fairly advanced topics, but it is very useful to understand these issues when dealing with your own hormone problems. So what does it mean for taking action?

In naturopathy, the focus is on uncovering and dealing with root causes, but it is also important to support the body through change, and for this, naturopaths also have an important educational role in making suggestions about lifestyle changes to help give the body everything it needs in order to heal and function optimally.

This nearly always involves a process of self-discovery – a journey towards a deeper understanding of oneself – but on a physical level it is important to underline that when dealing with any hormonal issues where detoxification may be a problem, we should start with gut health, particularly if there are symptoms of digestive distress, bloating and so on. So we start with Phase III, the gut – then move on to phase II, and then finally phase I, which should ensure that we don’t get an accumulation of those toxic phase I metabolites which might make things much worse! It is always prudent to remember that these situations often take many years to manifest, and so we must be mindful and gentle with the body.

When people hear that they need to improve detoxification, they may reach for various detox products on the market. While some see this as a waste of money, the reality is more complex. In some cases, they can truly be a waste of money doing nothing. In others, they may be very beneficial. And yet still in others, they may actually make things worse, as oftentimes these products can speed up phase I without properly addressing Phase II & III, which leads to greater toxicity and symptoms. For example, it is a fast phase I coupled with a slow phase II that makes hangovers much worse, because it leads to the build up of highly toxic intermediate compounds like acetaldehyde – and this can be a clue to how people’s detox systems are working, particularly if the person used to do just fine with alcohol. It is absolutely true that things we ingest and changes we make to our lifestyle can significantly modulate our detox pathways, but there is no magic bullet solution. A better approach is to create a personalised plan that gives your body everything it needs to the job while paying attention to particular areas that need support. And this individualised approach is central to a naturopathic approach.

To summarise so far…

In summary, all steroid hormones are created from cholesterol. They are transformed into different hormones by enzymes, do their job by binding to receptors and are then broken down and escorted out of the body. When we cultivate a balanced lifestyle individualised to our own needs, we give our body what it needs to maintain homeostasis of this network and keep everything working well. With poor lifestyle choices, stressful life events and normal ageing, we begin to lose the capacity to maintain homeostasis of these systems, and symptoms start to arise.

In part 2, I’ll take a look at some of the common female hormone imbalances and how a naturopathic approach can aid us in restoring and maintaining healthy hormones.