Poly-cystic ovarian syndrome (PCOS)

Introduction

Few women will have perfect periods all the time.

Some women will have a cycle lasting 28 days and the period is always on time. Some women will have a longer cycle that is still regular. In both cases, sometimes the period simply comes late, or skips until the next cycle for no apparent reason.

This is all fairly normal.

For some women though, the period is completely erratic and unpredictable. This might mean that every cycle varies by days or weeks or the period only comes a few times a year.

We call these irregular periods.

Irregular periods, whether all the time or sometimes, are generally caused by changes in how the body creates and gets rid of hormones. After all, the menstrual cycle is a cycle between the brain telling the ovaries to make more hormones and those ovarian hormones telling the brain ‘we have enough hormones for now thanks’ and switching off the cycle for a while.

As one goes up, the other goes down and then vice versa and the cycle keeps running. This article talks about those imbalances.

Polycystic Ovarian Syndrome; the bigger hormone problem

For some women, it is not just irregular periods that bother them. Some women with irregular periods will notice other hormone related issues in their body; this might look like hair loss, acne, difficulties shifting weight, painful periods and sometimes problems with their blood sugar.

Women with this picture often have a set of hormone problems whereby the body goes down a different hormone path. Instead of the brain telling the ovaries to make the usual estrogen and then progesterone sex hormones, their body will react in a way that creates too much testosterone and too much insulin instead.

This can result in delayed periods, acne, hair loss, sugar problems like diabetes and leads to the egg not being released on time and being stuck in the ovary. This is called polycystic ovary because an ultrasound of the ovary will show lots of egg cysts lined up that are not being released.

Women with an irregular period with signs of high testosterone, high insulin and cysts on ovaries are referred to as having poly cystic ovarian syndrome or PCOS for short. It is a multi system hormone imbalance caused by how the body responds to brain signals to make hormones.

 PCOS can cause significant distress, and confusion, and may make it harder to get pregnant. This guide discusses PCOS and the hormones involved.

What is polycystic ovarian syndrome?

Polycystic Ovarian Syndrome is a disorder of the menstrual cycle. Instead of the brain telling the ovaries to make the key sex hormones estrogen and progesterone in the right amounts, the cells decide to create more testosterone and insulin instead.

What are estrogen and progesterone?

After sexual development, the menstrual cycle in women is regulated by the activity of two major hormones; estrogen and progesterone.

On day 0, the brain releases a hormone signal to tell the ovaries to start making hormones and start developing a new egg for fertilisation. The brain releases Luteinising Hormone (LH) and Follicle Stimulating Hormone (FSH) to do this.

(Picture, hypothalamus with FSH and LH going to the ovary)

These hormones travel in the bloodstream and reach the ovary. At the ovary, they cause the ovary to start making estrogen first which  rises in the first half of the cycle before the egg is released

(Picture of the menstrual cycle over 28 days with the hormones and a circle around the first half of the cycle)

Estrogen causes the uterus, the womb, to build up its inner lining and thicken. This is to prepare for any fertilised egg implanting should pregnancy occur.

On day 14, the egg is released from the ovary to await fertilisation.

After day14, progesterone is released. It’s important to note that if there is no egg release, then there is no progesterone.

(Picture, similar to above but with the circle for day 14 and where progesterone is released and a big X)

From days 14-21, the estrogen and progesterone hormones will start to fall. Once both progesterone and estrogen drop low enough, the thickened inner layer of the uterus will start to shed. This leads to bleeding called the period.

 (Picture circling day 0-6 where the period is)

Once estrogen and progesterone are low enough for the period to happen, the brain will start releasing FSH and LH to start the whole cycle again.

What do the sex hormones do?

Estrogen plays an important role in multiple parts of the body.

(Picture: a graphic showing the effects of estrogen; there are heaps on google I’m sure)

 Even though estrogen falls in the second half of the cycle, it is always present in at least small amounts.

Estrogen has a role in:

• Thickening the lining of the uterus
• Increasing blood supply in the uterus
• Helping blood to clot
• Mood
• Bone health

Progesterone has a role in:

• Counteracting estrogen activity at the uterus
• Bone health
• Mood
• Slight testosterone like effect
• Breast development
• Sleep

How do these sex hormones influence women’s health.

 Estrogen and progesterone exist in a balance. Generally, progesterone will counteract some of the impacts of high estrogen in the second half of the cycle.

If a woman has higher estrogen for any reason, the extra estrogen will dominate the amount of progesterone and can lead to estrogen dominance.

To read more about the balance of estrogen and progesterone and what problems it can cause, please click here (Estrogen and progesterone balance)

 (Picture, estrogen dominance symptoms chart-heaps on google we can rip off)

What can go wrong in the period to make it irregular?

Many things in our health and environment can change how the body processes the hormones involved in the menstrual cycle.

Any derangement to the hormones whether it is too much estrogen, too little brain signal, too much testosterone will delay the period.

Let’s talk about high estrogen.

What causes high estrogen?

High estrogen can be caused by slow metabolism of estrogen, excess estrogens coming in from the environment or diet or from having a high body percentage of fat.

The liver is responsible for metabolising and getting rid of estrogen. Sometimes the liver might be slow at getting rid of estrogen; this is because it does not have the right vitamins to do the job, there could be unhelpful bacteria living in the gut which slow down the process that gets rid of estrogen or a similar problem. Slow excretion of estrogen will cause high estrogen.

(Picture of the liver metabolising estrogen)

. Sometimes an estrogen like effect comes from our diet such as too much alcohol. Many chemicals in food or cosmetics will block the breakdown of estrogen in the liver or in fact act as estrogen in the body.

Being overweight will cause more estrogen as fat cells turn testosterone into estrogen. Certain environmental factors also lead to more estrogen such as mold.

To read more about the causes of extra estrogen, please click here (Estrogen and progesterone balance).

To read more about how the wrong bacteria living in our gut influence our health and hormones please click here (Dysbiosis)

How does extra estrogen change the period?

In general, if a woman has more oestrogen, it will take longer for the estrogen to be cleared from the body. This means that there are higher estrogen levels for longer.

(Picture of the menstrual cycle with the first half of the cycle enlarged to demonstrate the swelling of the first half of the cycle compared with the second. A normal menstrual calendar with hormones B: enlarge the first half to show the high estrogen)

The period only starts when oestrogen levels fall low enough for the uterus to shed its lining and thus cause the monthly bleed. Similarly, the brain will not ‘reset’ the cycle and start development and release of a new egg until estrogen levels are low enough to release FSH and LH from the brain.

 Women with estrogen dominance tend to have delayed periods.

Sometimes this is regularly delayed, such as 30-38 days, or sometimes the amount of estrogen any given month can change so dramatically that one period is 4 weeks, another is 6 weeks and anywhere in between.

Often, these women have very painful periods, heavy bleeding, headaches, breast pain and mood changes because of the extra estrogen. These are called Premenstrual syndrome and goes hand in hand with the idea of estrogen dominance. estrogen dominance simply describes the symptoms a woman gets when there is more oestrogen relative to progesterone.

(Repeat the picture of estrogen dominance) 

In general, high estrogen alone will delay the period but not cause it to be completely missed for months on end. When the period isn’t coming for a really long time, this is because the egg development cycle is not happening for reasons other than just higher estrogen for a really long time. This is called ‘anovulation’ and we must start to think of other causes of it.

What can cause the cycle to stop for a while?

There are many reasons that the cycle may not start for a while. In extreme cases where there are no periods at all, a person should speak to their doctor to look for bigger problems such as genetic issues or serious health issues.

More commonly, the ovulation cycle stops because of a problem with the body that tells the brain not to have a cycle. Classic examples of this are anorexia nervosa, starvation, serious illness or sometimes in athletes with high pressure on their body, the cycle will stop.

(Picture from google: Anovulation causes)

PCOS is a major cause of unpredictable and very delayed cycles.

What hormones get deranged in PCOS?

Poly cystic ovarian syndrome is a problem of hormone balance.

Usually, LH and FSH are released from the brain early in the cycle and tell the ovary to make estrogen and start developing an egg.

(Image showing LH and FSH coming from the brain to the ovary)

In PCOS, the amounts of LH and FSH become deranged. Normally, LH and FSH are in a ratio of 1-2 of each other; pretty similar amounts. In PCOS, the LH is much higher and so the ratio is 2:1 or 3:1.

FSH is involved in egg development whilst LH is involved in hormone production in the ovary; the higher ‘push’ from that greater amount of LH distorts the hormone production line in the ovary.

(Picture: upper picture A shows normal LH and FSH to the ovary. The second picture enlarges the LH and shows testosterone resulting)

In PCOS, the ovary will respond to the LH:FSH ratio by producing estrogen and more testosterone. Meanwhile, the egg is still being developed as the cycle goes along, but with the higher LH:FSH ratio and higher testosterone, the egg does not release.

Normally, when an egg gets released, it starts to make progesterone. In PCOS, the egg gets stuck in the ovary and there is less or no progesterone.

This means that in PCOS, the derangements stack up as follows:

• A higher ratio of LH:FSH from the brain
• Eggs are not properly released; so low progesterone
• A higher testosterone

There is one more important hormone in the PCOS story to talk about; insulin.

What is the cause of PCOS?

In broad terms, insulin resistance is the cause of PCOS.

Insulin is a major hormone in the body that helps glucose, sugar, get into cells to be used as energy. Insulin is released by the pancreas after we eat.

Type 1 Diabetes is a disease where somebody cannot make insulin themselves anymore. It is fatal if not treated as the body cannot cope without the insulin helping the glucose get into cells. These people need to inject insulin to stay alive.

Type 2 Diabetes is a condition of the insulin being too high and not working properly but they do not necessarily need to inject insulin.

PCOS has similarities with Type 2 Diabetes.

What is insulin resistance?

When there is higher insulin in the body, cells do not respond to insulin in a predictable way.

In a healthy person, if you gave them insulin, more glucose would enter their cells and the blood glucose would fall. However, in some people, this does not happen and they will have higher insulin and glucose over time.

Basically, the insulin just isn’t working as well as in a healthy person. These people have high glucose, a smaller response to giving insulin and over time start to have all the complications from higher glucose swimming in the blood; kidney disease, blood vessel damage to the eyes etc. that we find in diabetes.

We call this insulin resistance.

What is the cause of insulin resistance?

Insulin has more effects in the body than just pushing glucose into cells for energy. Insulin is also a stress hormone.

If somebody was stranded in the jungle and had no food, they would have very little calory intake and their body would not produce too much insulin.

However, if somebody was stranded in the jungle and given a lifetime supply of potato chips, they will have some calories and would release insulin; but eventually, they will run out of a heap of other important vitamins and minerals that the cells need to be properly nourished.

In this setting, the body gets distressed. It has one type of fuel, but not the others it needs. It will start to panic and try to conserve calories, lower the activity of other hormones in the body and enter a ‘starvation state’. The metabolic rate will go down, cells will be prevented from using too much glucose and the body will push that energy to be stored as fat for a rainy day. This is what insulin resistance does. This is the cause of type 2 diabetes.

Insulin is a stress hormone that helps survival calorie rich malnourishment states. It is almost like the body is predicting a famine that never comes and forces you to eat more, gain more fat and slow down despite your best efforts!

In the modern world, people are not stranded in jungles, but in supermarkets. Highly processed carbohydrate rich foods lack the vitamins, minerals and fibers needed to feed our good gut bacteria and provide a full and complete nourishment of our cells.

Insulin resistance is thus a multifactorial end stage for any cell under stress. Nutrition plays a key part, but so do many other causes of stress to cells such as:

• Toxic foods
• Toxic chemicals
• Lack of sleep
• Lack of exercise
• Lack of antioxidants (read more about antioxidants here)

To read more on this broad topic please see the following articles

• Oxidative damage
• Mitochondrial function and antiaging
• Insulin resistance
• Environmental Toxicity

How does insulin resistance cause PCOS?

When somebody has insulin resistance, the ovary will respond to the higher LH and FSH and make testosterone instead of progesterone.

Also, the same things that cause insulin resistance are capable of slowing the metabolism of estrogen.

PCOS sufferers will have higher estrogen and higher tesosterone which will delay the period.

What are the symptoms of PCOS?

In general, PCOS is a hormone disorder characterised by:

• Anovulation: the eggs is not released and so the periods can be very delayed or very irregular. It can be hard to fall pregnant.
• High testosterone: excess male type hormones.This can cause hair loss, hair growth on the face, pimples, oily skin and mood changes.
• Polycystic appearance of the ovary; this might show up on an ultrasound of the ovary
• AND insulin resistance, an excess of insulin; this may cause weight gain, high glucose, or even type 2 diabetes
• Estrogen dominance: if PCOS sufferers have this too, they may have bad menstrual symptoms, breast tenderness, heavy periods, heavy bleeding, migraines before the period and substantial mood changes.

What are the relevant genetics of PCOS?

The internet has multiple references to genetic testing and there is an increased uptake of this testing in the community. Multiple commercially available tests include testing for genes which impact PCOS.

It is thought that polymorphisms in a family of CYP genes play a role in PCOS. These genes influences the metabolism of estrogen. There are some theories that there is an epigenetic (gene changes that take places due to environmental exposure in utero or early life) component to the genetic basis of PCOS.

Epigenetic theories include a higher androgen exposure in utero influencing PCOS. Cyp11 gene regulates the conversion of cholesterol into progesterone. Cyp11a1 with tttta repeats was associated with higher androgens;

interestingly Han Chinese who have this altered gene have higher androgen but not hirsuitism.

Cyp 17 and Cyp 19 are also implicated in PCOS.

Routine genetic testing for PCOS is not recommended and the results of a genetic test regarding PCOS and estrogens should be discussed with your healthcare provider for context.

How is PCOS diagnosed?

Any woman with a suspicion of PCOS should have blood tests to look at the hormones.

• Estrogen-to see if it is high
• Progesterone- to see if the egg is releasing progesterone
• LH:FSH ratio to see if it is 1:1 or higher such as in PCOS
• Liver function tests – to see if the liver is ‘slow’ and not getting rid of estrogens properly
• Insulin: to see if it is high
• Testosterone and other androgens; to see if these are high

The blood tests are best taken 7 days before the next expected period. In PCOS, this can be very hard to time.

If there is evidence of delayed periods, high testosterone and especially high insulin then there is a high chance that this is PCOS.

How is PCOS treated?

There is no one clear treatment for PCOS.

The first thing to do is to treat the underlying cause of any insulin resistance:

• Nutritious diet
• High levels of dietary fiber
• Encourage estrogen metabolism by supporting the liver
• Plenty of sleep
• Exercise

All of this will make your cells happier and help with insulin resistance

It is also important to reduce estrogen; this can be helped by lowering body fat, reducing processed foods, minimising environmental chemicals which act like estrogen and encouraging estrogen metabolism. This is best achieved by eating leafy green vegetables and herbs.

Certain supplements are known to help with insulin resistance and reduce the symptoms of PCOS:

• Inositol
• Berberine
• Quercetin

Other supplements are used to support vitamins and healthy gut environment such as

• Probiotics
• Saccharomyces Boulardii a yeast probiotic
• DIM an extract from broccoli which helps metabolise estrogens
• B12 supplementation to help the liver
• Vitamin D if deficient
• Zinc, if deficient

After supporting the nutrition, medications can be used to help with PCOS

Treat androgen excess: this can be done with spironolactone, cyproterone acetate, finasteride or even some progesterones (drosperinone) that can block testosterone.

Insulin Resistance: Treating insulin resistance with weight loss, diet, exercise will all help with insulin resistance. Also, medications used to treat diabetes such as Metformin or Ozempic might be prescribed.

Manage the cycle: anovulation can expose a woman to prolonged estrogen. This is a risk for breast cancer and endometrial cancer (of the womb). It is advised to regulate the cycle either by using progesterone or the oral contraceptive pill. Insulin resistance impairs progesterone production and should be treated aggressively if present.

Manage deficient estrogen: if there has not been a period for a while, a woman may have symptoms of not enough estrogen and this should be considered

Manage Fertility: inducing ovulation, the release of the egg, is the goal of fertility management for PCOS. This should be referred to a specialist to monitor and oversee. This may involve drugs that promote ovulation such as clomiphene, Human Chorionic Gonadotropin and Human Menopausal gonadotropin (Menotropin) to stimulate the egg release. Letrozole is also used

How to go about getting treated for PCOS

PCOS is a complex multifactorial hormone disorder. It is best to form a relationship with your naturopath or doctor to discuss the options for you.

Many of the medications used to induce fertility, or manage testosterone, are toxic to babies. Therefore, all women are advised to be on contraception whilst managing higher androgens. If fertility is the goal, other methods will be advised.

Finally, PCOS is a disorder that has a huge impact on the wellbeing of any sufferer. Looking at the health holistically is useful to treat each domain of health. 

REFERENCES

Ashraf, S., Nabi, M., Rasool, S.u.A. et al. Hyperandrogenism in polycystic ovarian syndrome and role of CYP gene variants: a review. Egypt J Med Hum Genet 20, 25 (2019). https://doi.org/10.1186/s43042-019-0031-4

Guang HJ, Li F, Shi J. Letrozole for patients with polycystic ovary syndrome: A retrospective study. Medicine (Baltimore). 2018;97(44):e13038. doi:10.1097/MD.0000000000013038

Legro RS. Evaluation and Treatment of Polycystic Ovary Syndrome. [Updated 2017 Jan 11]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK278959/

Rasquin Leon LI, Anastasopoulou C, Mayrin JV. Polycystic Ovarian Disease. [Updated 2021 Jul 9]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-.

Rocha AL, Oliveira FR, Azevedo RC, et al. Recent advances in the understanding and management of polycystic ovary syndrome. F1000Res. 2019;8:F1000 Faculty Rev-565. Published 2019 Apr 26. doi:10.12688/f1000research.15318.1