Menopause — Its Triggers to Start a Complicated System.

Introduction

Just like in my previous blog titled “The Triggers That Start Puberty” demonstrated that puberty is a natural hormonal process that we all cannot escape… well… menopause is also a natural hormonal process that women cannot escape. It is the end cycle of fertility where puberty started, menopause will end it. But some questions arise. How does the body know when to start the process towards being menopausal? What starts it and what are the factors? What speeds it up or slows it down and can we escape from it?

There are many articles and blogs where writers (mostly women) talks about how to relieve menopause side effects or how to deal with the transition of this new process. This blog, however, will speak about how it starts at a hormonal level and cellular level. I will demonstrate histology slides of the ovaries to show how it changes over time from puberty to being menopausal and I will explain the normal hormone cycle vs the menopause hormone cycle. I will also touch on different treatments that alleviate the symptoms of becoming menopausal. It is a very interesting transition and an important one in a woman’s life where every woman deals with it differently physically and psychologically. I think, just like puberty, it should be embraced but maybe it is easy to say especially since I am not a woman.

What is menopause?

Menopause is clinically diagnosed after 12 months of amenorrhoea as it is the permanent cessation of the menstruation cycle as well as the inability to ovulate, hence the cessation of the ovarian cycle [1]. At the hormonal level, it is the withdrawal of Oestrogen over a long period of time [1]. The average year of a woman being menopausal is around 51 years old and the normal range is between 45 to 55 years old. It is found that maternal genetics predicts the daughter’s age when they are going to be menopausal [1]. Regarding smoking, there have been links towards being menopausal earlier than average but there are a lot of uncertainties none-of-the-less. The Cigarette Smoking and Risk of Early Natural Menopause by the American Journal of Epidemiology does highlight that smoking increases the chance of being menopausal earlier than non-smokers [2]. The peri-menopause which is the transition to menopause occurs around the mid-40s but can start as early as 35 years of age [1]. The peri-menopause transition is important regarding the changes in hormone levels and the changes in the ovaries structure.

At a non-menopausal hormonal level, what happens?

We need to know the normal hormonal level in a woman that is not menopausal and compare to a woman who is peri-menopausal and menopausal.

Figure 1. Displays the complex pathway of hormones in the body at a normal level.

Credit: Marieb EN, Hoehn K [3].

Figure 1 demonstrates the normal chain event in a woman who is not menopausal. The negative and positive feedback are working at their sensitive and normal range and the hormone concentrations should be normal. The surge centre should be sensitive to positive feedback and work as normal when ovulation occurs.

In short. When the Gonadotropin-Releasing Hormone (GnRH) is released from the hypothalamus it will act on the posterior pituitary gland. This will release the Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH). LH will act on the thecal cells to release androgens and FSH will work on the granulosa cells for the conversion of androgen to Oestrogen as well as releasing Inhibin (a hormone that inhibits the release of GnRH and FSH only). FSH recruits, stimulates and matures the ovarian follicles whereas LH helps in support from the thecal cells. In other words, FSH and LH are important in the growth and development of a mature follicle but FSH will be inhibited by both Oestrogen and Inhibin. Oestrogen concentration also inhibits the release of GnRH, FSH and LH.

Once the follicle reaches the mature tertiary states or antral state, there is a huge positive feedback on the surge centre created by a high amount of Oestrogen being released from the mature follicle [4]. What is interesting is that Oestrogen act in the negative feedback meaning that more Oestrogen, less Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) and hence less Oestrogen [5]. But that is not the case. Yes, there is negative feedback, however, the more the single dominant follicle grows and matures, the more Oestrogen it is releasing as more androgens are being released from the thecal cells and there is more androgen conversion to Oestrogen [5]. This will go on until there is a reached Oestrogen threshold, where suddenly a positive feedback is initiated and a huge LH surge is released. The pressure at the mature follicle, the increase in hormones (such as LH) and the weakened wall of the follicle will rupture and ovulation occurs. Meanwhile, even though FSH is inhibited “twice - from Oestrogen and Inhibin”, FSH also rises just like LH but far less in concentration.

Negative feedback: The diminution of an effect by its own influence, such as a high level a hormone A will cause a loop that will prevent further secretion of hormone A [6].

Positive feedback: The enhancing or amplification of an effect by its own influence, such as a baby suckling on its mother will cause the mother to release more milk [6].

Follicle: A follicle has a life cycle where it starts with a primary follicle and goes all the way to the tertiary follicle (mature antral follicle). At this stage, see in figure 1, you can see the antral follicle named as Mature Follicle. In the middle of the follicle notice the oocyte or “the egg”. The oocyte will meet with the sperm later on.

At a menopausal hormonal level, what happens?

Well before we get there, it is important to note that a woman is born with all her oocytes (follicles that has a potential to develop into a mature egg and then fertilize with a spermatozoid), which is about 1 000 000 to 2 000 000 oocytes at birth [6]. By puberty, there are about 300 000 oocytes and by menopause, it is almost completely depleted through atresia and natural breakdown.

Figure 2. Demonstrate throughout a woman’s life the number of oocytes available. Note that as a foetus it goes up to 6 000 000 oocytes!

Credit: Senger 2005 [7].

Menopause is the depletion of Oestrogen from a normal level to a really low level. Primarily it is due to the depletion of the finite pool of follicle (remember by puberty there are only 300 000 follicles). It is frustrating as there is nothing that can be done from depleting the oocyte reserves. Figure 3 below, shows the different concentration of Oestrogen and the peaks of Oestrogen release which is mainly from normal ovulation. At menopause, the Oestrogen level does not rise as high as it used to be and is a lot less frequent.

Figure 5. Shows the Oestrogen concentration in a woman’s life from puberty to menopause.

Credit: Melmed S, Polonsky K, Larsen PR, Kronenberg H [8].

In figure 6 below, it is the comparison of FSH and LH between a non-menopausal woman and a menopausal woman. Remember that follicles produce Inhibin that suppresses the release of FSH and also acts negatively on the hypothalamus. Oestrogen also has that effect hence why FSH in a non-menopausal woman is lower than LH. Removing Oestrogen and Inhibin will remove the double inhibition of FSH, hence that is what happens in a menopausal woman.

(a) - Low FSH and LH,

(b) - High FSH and LH with FSH being a lot higher than LH. There are almost 4 times more LH and almost 12 times more FSH than a non-menopausal woman.

Figure 6. The endocrine changes of FSH and LH before and after menopause.

Credit: Johnson MH [9].

Figure 7. The endocrine changes where FSH and LH are slowly increase and Oestrogen is decrease over time. This depicts years before and after menopause.

Credit: Jones and Lopez [10].

In figure 7, before being menopausal the Oestrogen (in yellow) is elevated and the FSH (in pink) and LH are low. However, do notice that FSH does increase before Oestrogen decrease. This is strange as FSH gets inhibited “twice” by the Oestrogen and Inhibin. Remember that FSH should not even be higher than LH levels at all.

What causes the FSH and LH to increase before Oestrogen decrease — since Oestrogen keeps that negative feedback (which is tightly regulated) and the FSH concentration in order. It is suggested that the hypothalamus is losing response to the negative feedback which is similar to puberty when it loses sensitivity to Oestrogen and Testosterone for the first time (which develops those secondary sex characteristics) [6]. Or the hypothalamus and anterior pituitary gland somehow gets more resistant to the FSH concentration and later to the LH concentration? What causes the hypothalamus to being less sensitive and what external factors can affect that sensitivity loss? Is genetics involved (most probably)? So many questions that we cannot answer. We just know that somehow a loss of sensitivity or resistance gain occurs and that different hormones are starting to increase.

An additional cause is the age-related changes in the central nervous system (CNS) and the hypothalamic-pituitary unit may also contribute to menopause [6]. Such as the circadian oscillator change where there is a decrease in melatonin secretion during the night and alters sleeps. This could decrease the sensitivity of the hypothalamic-pituitary axis to the steroids (FSH, LH and Oestrogen) negative feedback. This could be the reason for the gradual rise in FSH and LH prior to Oestrogen decline [6].

Circadian cycle: Your circadian rhythm is a 24-hour internal clock that is running in the background of your brain and cycles between sleepiness and alertness at regular intervals. It's also known as your sleep/wake cycle.

The ovaries at a histology level

Figure 8. This is an active ovary form a non-menopausal woman. There are several tertiary (antral) follicular stages at C and there are many small follicles that are present at the primary and secondary stages. M is the medulla which is richly vascularised.

Credit: Kerr J [11].

Figure 9. This is a peri-menopausal ovary showing the corpus luteum at CL from a previous cycle. The cortex at C is thin, there are no selective follicles and at A there are receding follicles remnants.

Credit: Kerr J [11].

Figure 10. This shows a menopausal ovary. Most of the medulla is filled with corpora ablicantia. There is atrophy of the ovaries, no tertiary follicles (antral stage) can be seen. There is no more recruitment of follicles and the follicle reserve should be completely depleted. Anovulation occurs (lack of ovulating).

Credit: Kerr J [11].

Symptoms of menopause

Now that we know which hormones are in constant excess (LH and FSH) and which hormones are in constant deficit (Oestrogen, Inhibin and Progesterone) we can link it to the side effects menopause creates on the human body. Most women will definitely relate to these symptoms and try to adjust their lifestyle to decrease some common side effects and live-on their lives. Others might use medications or supplements to prevent some symptoms or to decrease the current symptoms.

Figure 11. The unfortunate risks and symptoms that occurs once menopause starts.

Credit: Norwitz E, Schorge JO [12].

Figure 12. Risks and symptoms of menopause.

Credit: Norwitz E, Schorge JO [12].

The symptoms of being in the menopausal transition are (these are mainly due to the less than normal Oestrogen concentration) [6]:

• Menstrual irregularities

• Hot flushes

• Mood disturbance

• Atrophy of the reproductive tract and breasts

• Bone change

• Cardiovascular change

The concerning ones are the increased risk of osteoporosis (50% vertebrae and 25% hip fractures) and the increasing risk of cardiovascular disease [6].

This vicious cycle that starts the menopause transition

I will try to make it as simple as possible because even for me I got confused when reading about this. It starts at the peri-menopausal transition which can last to 2-8 years [13]. The 5 to 10 years before menopause, 90% of women will experience variability in frequency and variability of their menstrual flows [13]. The symptoms usually begin with the shortening of the menstrual cycle, which means shorter follicular phase (the making of that dominant follicle) which follows by unpredictable ovulation and lengthened menstrual cycle [13].

Around 37 to 38 years of age which is about 10-15 years before menstruation completely ceases, a woman will experience an accelerated follicular loss that begins with about 25 000 follicles (each potentially can ovulate) to complete depletion of the follicles [13]. Remember, the less you have follicles (they create lots of Oestrogen for that positive LH surge) the less Oestrogen and the less the negative feedback will occur, which will eventually start that FSH and LH rise we saw earlier. The loss of these follicles will start that subtle rise in FSH and decrease in Inhibin (the hormone that suppresses FSH). FSH accelerates the follicular loss process and Inhibin (since it is decreasing) disrupts the negative feedback system [13].

This is vicious part. Initially, there is a significantly high level of FSH and later LH. Normally Inhibin is supposed to suppress FSH. Remember FSH recruits, stimulates and mature the ovarian follicles so FSH accelerates the process of recruitment. If the process is accelerated, there is more ovulation and the follicle reserve will eventually deplete faster making the levels of Oestrogen drop. However, during the peri-menopausal transition, the high FSH causes an increase in follicular recruitment which are bad in quality and partially developed [13]. The net effect is irregular ovulation, lower progesterone levels and will deplete the follicle reserve. Now, due to an increase in recruitment and follicular development, this leads to an increase in Oestrogen (as follicles create lots of Oestrogen). Having lots of Oestrogen causes vasomotor symptoms like hot flushes and many other symptoms that a woman might experience during her menopausal transition. The cycle accelerates on itself until there are no more follicles to recruit. Figure 13 summarises nicely the cycle toward the depletion of the follicle reserve. It is a vicious cycle that accelerates on itself to follicle depletion.

Figure 13. The vicious cycle to ensure menopause and make the body infertile.

Credit: McCance KL, Huether SE [13].

Can we slow and prevent menopause? What are our treatment options?

This got me thinking. Why does a woman go into a menopausal stage? Why can’t they stay fertile for their whole lives? I think it is because the body is trying to help itself by not falling into pregnancy as after 40 years of age there is an increase in many genetic diseases (such as Down Syndrome) and other complications that could be lethal. Maybe an increase in danger by becoming pregnant in an ageing body could be the reason as pregnancy is a harsh and dangerous cycle. Remember that pregnancy does change many metabolic and physical states of the body.

So, can we prevent or slow down menopause? We need to find a way to slow down the follicular recruitment and decrease the loss of follicles from its reserve. Hence should we find a way for FSH to be suppressed? Maybe a monthly injection of Inhibin? Menopause is a natural part of life and it should be ill-advised to start tempering the delicate balance of hormones in the body. Preventing or slowing down menopause is an interesting concept none-of-the-less.

The treatment options are wiser. We are treating the symptoms from the high FSH and LH and the low Oestrogen, Inhibin and Progesterone. Hormone replacement therapy such as treating the low-level Oestrogen side effects is generally the way to go. There are other options such as supplements, natural or herbal therapy, exercise and avoiding risks that would cause or exacerbate the symptoms would be ideal.

Treatment

Oestrogen therapy

The benefits are: treats effectively some symptoms such as hot flush, osteoporosis, genital atrophy and possible mood disturbance [6]. Alzheimer’s, colon cancer, osteoarthritis, tooth loss and skin ageing may also be decreased. However, there is no reduction in cardiovascular disease [6].

Risks: increase risk of endometrial cancer unless combined with progestagen and there could be other potential serious side effects [6].

Side effects: there could be an increase in breast cancer, heart attack, stroke and blood clot particularly in long term treatment and in older women (such as 65 years old) [6].

Recommendation: hormone therapy should be used wisely and only during the peri-menopause period to alleviate symptoms, particularly for hot flushes. The shortest dose for the shortest amount of time is recommended [6].

Raloxifene

Is a selective Oestrogen receptor modulator (SERM). It treats and prevents osteoporosis, positively alters lipid ratio alleviate hot flushes, reduce breast cancer and does not stimulate endometrial proliferation [6]. This could be a good medication and a wiser option.

Figure 14. Most of the time it is not necessary to start hormone therapy especially while being menopausal for some time. Studies have shown that there is a battle between benefits and risks as when there is an increase in benefits there is always an increase in risks. It is safer to use hormone therapy during the peri-menopause stage and at a short dose for a short amount of time.

Natural or Herbal therapy

If hormone therapy is not for you there are also botanicals such as phytoestrogen from soybeans, chickpeas and wild yam. Evening primrose oil, Saint John’s wort and black cohosh [6] can also be used. These may provide short term alleviation for hot flushes but has limited scientific proof and may interact with other medications. Be careful falling into fake and scam-looking pseudoscientific products that make ridiculous claims and may harm you (as well as your wallet).

How can a woman help herself?

• Hot flushes: avoid trigger factors and do regular exercises. Maybe have a plan of action whenever you get hot flushes and find the best way to reduce it. Ask how your mother managed to control her hot flush (it is worth a shot).

• Sleep disturbance: develop a sleep routine, avoid caffeine or tea at night and start regular exercise. Having the body exercising helps in falling asleep faster compare to being immobile all day.

• Bone loss fracture: avoid active lifestyle that may increase a fracture such as roof building or other risky professions that could involve falling. Soft and caution exercise can still be done. Calcium supplements, vitamin D from the sunshine (or supplements) and fortified milk can be taken to help the bone formation. A regular check for bone mineral with the GP can be done. Most importantly, avoid falls or decrease risks that could cause them (add rails near the stairs for example) [6].

• Heart: Avoid smoking, reduce risk factor such as excess weight, high-fat diet and do some exercise [6].

From the author

Menopause is a natural process of life and should be embraced. The side effects due to the hormone level change can be alleviated by hormone therapy during the peri-menopausal stage but I believe a woman going through the transition is mostly about adapting to a better and healthier lifestyle.

These are:

1. Having a healthier eating habit. Eating vegetables and fruits are really important! That is where you get all your vitamins and minerals.

2. To have a planned exercise routine that is safe and customize for each person.

3. Avoid smoking which has many other health benefits.

4. Limit alcohol intake (I said limit, drinking alcohol responsibly is reasonable).

5. Having regular pap smear and mammograms checks are always important. Do have a regular check-up to investigate any cancerous growth.

6. Pelvic floor muscle exercises such as kegel exercises (invented by Dr Henry Kegel - a gynaecologist) is recommended to strengthen the deep and superficial muscle fascia. Having a strong pelvic floor will help in coping after giving birth, prolapse of the vagina wall or rectum and helps in urinary incontinence. Not to mention but it also strengthens the vagina wall which you and your husband might enjoy sex more ;)

7. The use of vaginal lubricant can always be an alternative for your sex life.

I hope this wasn’t too long and that you have learned something about menopause. Good luck to any women entering their menopausal transition (or peri-menopausal) and are coping in their own ways!

Published 15h March 2019. Last reviewed 30th December 2021.

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Reference

1. Drake RL, Vogl AW, Mitchell AWM. Gray’s Anatomy for Student. 3rd ed. Philadelphia: Churchill Livingston Elsevier; 2015. ISBN: 978-0-7020-5131-9.

2. Whitcomb B, et al. Cigarette Smoking and Risk of Early Natural Menopause. Am J Epidemiol. 2017;187(4):696-704. doi: https://doi.org/10.1093/aje/kwx292.

3. Marieb EN, Hoehn K. The Reproductive System. In: Beauparlant S, ed. Human Anatomy & Physiology. 9th ed.  Boston, USA. Pearson Education, Inc; 2013;1018-1094.

4. Dr. Damien Paris, 2018. Female Reproductive Pathophysiology. Lecture given at James Cook University. Friday, 19 October 2018.

5. Dr. Damien Paris, 2018. Puberty. Lecture given at James Cook University. Friday, 5 October 2018.

6. Dr. Damien Paris, 2018. Menopause & Hormone Replacement Therapy. Lecture given at James Cook University. Tuesday, 9 October 2018.

7. Senger PL. Pathways to Pregnancy and Parturition. 3rd ed. Current Conceptions Inc. ISBN: 0965764834.

8. Melmed S, Polonsky K, Larsen PR, Kronenberg H. Williams Textbook of Endocrinology. 12th ed. Philadelphia: Elsevier/Saunders, c2011. eBook ISBN: 9781437736007.

9. Johnson MH. Puberty and the Maturation of the Hypothalamic-Pituitary-Gonadal Axis. Essential Reproduction. 6th ed. Malden, Massachusetts. Blackwell Publishing, Inc; 2007;133-145.

10. Jones RE, Lopez KH. Human Reproductive Biology. 4th ed. Academic Press, 2013. eBook ISBN: 9780123821850.

11. Kerr J. Functional Histology. 2nd ed. Melbourne, Australia. Elsevier Mosby, 2010. ISBN 9780729538374.

12. Norwitz E, Schorge JO. Obstetrics and Gynecology at a Glance. 2 ed. Wiley-Blackwell. ISBN-10: 9781405131865.

13. McCance KL, Huether SE. Structure and Function of the Reproductive System. In: Dennison B, ed. Pathophysiology: The Biologic Basis for Disease in Adults and Children. 5th ed. St Louis, Missouri. Elsevier Mosby; 2006;735-770.

Additional source of information:

Husvéth F, Egyetem D, Egyetem N, Egyetem P. Physiological and reproductional aspects of animal production. Digitalis Textbook Library. https://www.tankonyvtar.hu/en/tartalom/tamop425/0010_1A_Book_angol_05_termeleselettan/ch12s03.html. Updated 2011. Accessed December 3, 2018.

VIVO Pathophysiology. Gonadotropins: Luteinizing and Follicle Stimulating Hormones. http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/hypopit/lhfsh.html. Accessed February 20, 2019.

Wikipedia. Follicle-stimulating hormone. https://en.wikipedia.org/wiki/Follicle-stimulating_hormone#Effects_in_females. Accessed February 20, 2019.

Wikipedia. Luteinizing hormone. https://en.wikipedia.org/wiki/Luteinizing_hormone#Effects_in_females. Accessed February 20, 2019.