Hot Flash Update – what’s new and on the horizon?

A hot flash is the signature symptom of menopause, affecting over 80% of women.  Most of the time hot flashes begin a few years before menopause and last for five to seven years.  In some cases, however, hot flashes can show up ten years before the final menstrual period and last twenty years afterward!  Some women have occasional hot flashes; others can have dozens per day.  Hot flashes can range from being a mild wave of warmth to being severe enough to require a change of clothes.

No one knows why there is so much variability in the way hot flashes occur, or why some women are more prone than others.  It appears to have a lot to do with genetics. Researchers have discovered several genes that may predispose women to be more at risk for hot flashes.  Other individual physical characteristics such as weight and ethnicity play a role.  Smokers are also more prone to getting hot flashes (another reason not to smoke!)

The exact mechanism causing hot flashes has been a mystery over the years.  It clearly has something to do with the loss of estrogen affecting how the body regulates temperature.  But how and why this happens remains uncertain.  Recent advances in medicine, however, are bringing us closer to unraveling this phenomenon.  We now realize that the mastermind behind the hot flash, not surprisingly, happens to be the brain.

A review of the physiology of the hot flash

First of all, let’s review what we know about the hot flash itself.  It is initiated when the body’s internal thermostat perceives a slight change in our core temperature.  This may be triggered by something very subtle, such as a warm drink or a slightly heavy sweater – factors that normally may not perturb the body’s temperature control system.  However, because it appears that the thermostat in midlife women is overly sensitive, alarms are set off and the brain responds by calling into play the body’s cooling mechanisms.  The blood vessels under the skin dilate, which allows more blood flow near the surface of the skin to dissipate heat.  This causes flushing.  In addition, tiny sweat glands are stimulated to produce moisture on the skin to create evaporative cooling.  With these measures the body’s thermostat is reset, and the hot flash can resolve as quickly as it started.

How the brain controls our body temperature

Scientists have pinpointed the area of the brain that is responsible for orchestrating the changes in the body that control temperature.  This thermoregulation center is in the hypothalamus.  The area that controls our temperature is a complex command center that receives and sends messages from all areas of the body via a network of nerves going to the heart, blood vessels, muscles, sweat glands, and the kidneys.  All of these organs are involved in moderating body temperature – by dilating and constricting blood vessels, adjusting fluid intake and output, and inducing sweating or shivering.  Sensors within the body constantly monitor our temperature in various areas, relay this information to the brain, and the thermoregulation center makes adjustments to conserve or discharge heat as needed.  This system has become highly refined because a person’s body temperature must be tightly controlled.  A few degrees change in core temperature for a number of minutes can cause brain cell damage.  That is why you see confusion, speech difficulties, and seizures in people with heat stroke.

The brain/ovary connection

The brain and ovaries are closely interconnected.  They communicate with each other by sending chemical messages back and forth in the form of hormones.  The main purpose of this partnership is to create a monthly cycle of ovulation.  Cells in the hypothalamus send chemical signals to the pituitary, which then makes follicle stimulating hormone (FSH) and luteinizing hormone (LH).  These two hormones travel to the ovaries to stimulate the maturation and release of an egg every month.  They also instruct the ovaries to make estrogen and progesterone.

If an egg gets fertilized, the developing placenta makes large amounts of female hormones.  The brain senses these and turns off FSH and LH since there is no need to trigger further ovulation.  If fertilization doesn’t occur, the levels of all the hormones get adjusted back to baseline and the cycle repeats itself a month later.

The ovaries’ production of estrogen and progesterone is tightly coupled to the status of the egg supply.  Once the supply of eggs is exhausted, the production of our female hormones greatly diminishes.  This is what happens at the time of menopause.  The hypothalamus senses this low estrogen level and instructs the pituitary to send out more FSH to the ovaries to get them to make more estrogen.  However, the ovary is unable to comply and so the estrogen level remains low.  In turn, the pituitary continues to produce increasingly higher amounts of FSH.

So, the hallmark of menopause is a condition where the FSH is very high, and the estrogen and progesterone levels are very low.  Sometimes doctors measure these levels to confirm that a woman has gone through menopause.

A fortuitous discovery helps solve the mystery

Until fairly recently, it was still unclear how the FSH/LH stimulating brain cells were connected to the brain cells that regulate temperature.  The answer became apparent somewhat by accident.  About ten years ago, researchers were investigating some families that were found to have genetic defects that prevented their children from going through puberty.  This was due to the fact that the children’s ovaries (and testes) were not producing estrogen or testosterone.  This was traced to a lack of FSH and LH.  Without these sex hormones, the children did not develop mature male and female characteristics.

In the process of examining this situation, it was discovered that the genetic mutation common to both families involved genes that regulated a chemical called neurokinin.  Neurokinin is produced by specialized cells in the hypothalamus which have been dubbed KNDy cells.  Neurokinin plays a role in regulating temperature.  In fact, if you inject neurokinin into a volunteer, he or she will get a hot flash!

It turns out, that these neurokinin-producing KNDy cells live close to the cells that stimulate the production of FSH and LH.  And these nerve cells apparently “talk” to each other through neural connections.  On further investigation it was discovered that the KNDy cells are sensitive to estrogen.  So, when the estrogen levels go down, the KNDy cells not only will release neurokinin, but will amplify the production of FSH and LH.  I’ve simplified the extensive neuroscience behind all of this, but the bottom line is that we have found the missing link between the parts of the brain that regulate the menstrual cycle and temperature.

 Why the connection?

The next question to answer is why the hormones involved in menstrual cycles and making babies would be so closely connected with the temperature regulation system.  One hypothesis is that the brain evolved in a way to make sure that body temperature was carefully controlled during pregnancy.  Once an egg is fertilized and nestles into the uterus, it is important to maintain a warm, but not too warm, environment.  This would also extend throughout the pregnancy – a favorable body temperature needs to be maintained to ensure the optimal growth and development of the fetus.  The thermoregulation center in the brain would need to stay in close contact to the part of the brain monitoring the hormones made by the placenta and fetus.  If a pregnant woman developed hyperthermia, such as from heat stroke, various cooling measures would be triggered to cool the mother’s body but not jeopardize blood flow to the uterus.

How does menopause fit into this picture?

The hypothesis linking temperature regulation to pregnancy status makes sense – but how do we explain the appearance of hot flashes in menopause?  The best answer that has been proposed is that the system really didn’t take into account that women would start living longer!  In ancient times, the life expectancy was barely 40.  Now a woman is outlasting her ovaries’ functional life, and at some point in her mid-40’s her estrogen level begins dropping in an erratic fashion.  This, coupled with the fluctuating levels of FSH that occur in perimenopause, may be sending “mixed up” signals to the thermoregulation center, which then releases bursts of neurokinin.  This creates the hot flash.  Eventually, when estrogen has descended to a low, stable level in postmenopause, the brain adjusts to the new “normal” and quits releasing the chemicals that lead to hot flashes.

The conclusion of this story is that this system is an example of a mechanism that evolved to be “good” for one thing but turns out to be “not-so-good” for another.  Having the body’s thermoregulatory system tied closely into estrogen levels would be important to ensure successful pregnancies.  However, this would be at the expense of making women past their reproductive primes miserable!

Implications for hot flash treatment – old and new

We have known for 70 years that taking estrogen as part of hormone replacement therapy is extremely effective for treating hot flashes.  Many, many studies attest to this.  It is approved by the FDA for this purpose and its effectiveness is over 75%.  Essentially all of the major menopause societies encourage estrogen for women with hot flashes, and there is general consensus that its benefits outweigh the risks for newly menopausal women.  Taking estrogen at the time of menopause clearly makes sense based on the current model that I have explained.  Research studies have shown that estrogen reduces the activity of the KNDy neurons and prevents the release of the hot flash-triggering chemical neurokinin.

However, estrogen therapy is not recommended for women with a history of breast cancer, and there are also some women who remain reluctant to take hormones.  Because of this there has been a push for other treatments.  Essentially all the current non-hormone options are considerably less effective than estrogen.  This has led to a search for other treatments – and the discovery of the KNDy system has opened up doors for novel hot flash drugs.

One such class of pharmaceuticals is called neurokinin B antagonists.  These are drugs that basically block neurokinin effects in the brain.  They are currently being tested in studies of menopausal women and appear to be very effective.  It is likely these new medicines may appear on the market in 2023 and I expect your will hear quite a bit of promotion in the media when these drugs come out.

Hot flash relief is the number one reason women opt for hormones.  When presented with these new drugs, women may believe they are the safer alternative.  And while it is encouraging that the safety profile of the neurokinin B antagonists appears to be good, like any other brand-new drug on the market, it may take many patients and many years to know with certainty if there are any long-term adverse effects.  So I am always cautious when a novel new treatment becomes available.

I also worry that these drugs may push more women away from considering estrogen.  Since these drugs work specifically only for hot flashes, choosing them over estrogen will not provide the additional benefits of estrogen.  Even though the current guidelines indicate that estrogen is only recommended for hot flash symptoms, there is overwhelming evidence that estrogen treatment at the time of menopause will decrease a woman’s risk of diabetes, heart disease, and osteoporosis and improve other perimenopausal symptoms of anxiety, sleep disturbance, depression and brain fog.