Leptin’s Surprising Role in Fertility – Part 1

How does leptin, a hormone talked almost exclusively in the context of appetite control affect fertility?

Leptin is rarely acknowledged for its importance in fertility despite many studies clearly showing its role in reproduction.  It signals your brain that enough fuel is available for a baby so releases the hormones needed for fertilization, implantation, and development of a healthy baby.

 

What is at the root of reproductive hormone production?

Looking at the big picture shows us one key hormone that your doctor may not be talking about.

When you zoom out and look at reproduction from a higher level, it’s obvious that pregnancy should only take place when conditions are right. Reproduction is an energy-intensive process - especially for mammals.

So one huge factor is having enough ‘fuel’ available. Not enough food means either baby or mom won’t be healthy. And thus conditions aren’t right for pregnancy.

Simple…  Enough nutrients = OK to have baby.

The key here is that your body produces a signaling molecule which tells your brain there is enough fuel. Kind of like a gas gauge on a car.  You wouldn’t start out on long road trip with no gas, and your body doesn’t want to start down the reproductive path without enough fuel.

The same signaling molecule is also involved in telling your body both that there is enough fuel (so you can stop eating) and that it is time to be fertile.

That signaling hormone is called leptin. Research studies on leptin explain why it is an integral part of fertility. The studies show exactly how it cues the body that the time is right for reproducing. (study)

Leptin: A Hormone Controlling Both Appetite and Fertility

Leptin is a hormone secreted by your adipose (fat) tissue. When leptin levels are low, it triggers your drive to eat more. When you have plenty of fat tissue, leptin levels are high, decreasing your appetite so you feel full..

In 1994, a geneticist name Jeffrey Friedman first discovered the gene that produced leptin. This hormone quickly became known as a major player in obesity. For people who don’t produce enough leptin, that signal that the body has enough stored fuel doesn’t reach the brain.

People and animals with a mutation that drastically reduced the amount of leptin are always hungry (hyperphagic) and obese. The low leptin levels tell their brain that they are starving. They are simply driven to eat more, starting as an infant.

But leptin deficiency is actually a really rare condition (unlike obesity!). Only a tiny percentage of people in the world have leptin deficiency due to a genetic mutation.

Looking at what happens with this extreme condition, though, explains a lot about leptin.

Babies with leptin deficiency start out normal weight, but they are constantly hungry and quickly gain weight. Children with leptin deficiency may horde food or fight over food -- they are reacting to extreme hunger.

But there is another sign of leptin deficiency that puzzled scientists for a long time: leptin deficiency also causes delayed puberty and infertility.  (study)

Leptin is more than just a hunger hormone -- it also signals to the reproductive systems that all is well and ready for baby. 

But if leptin deficiency is extremely rare, how does this apply to most people today?

Researchers find that almost all people who are overweight have higher leptin levels. So it isn’t a lack of leptin, but rather a lack of receiving the hormone’s signal that is playing a role in overeating. The fat cells are producing plenty of leptin, but that signal simply isn’t reaching the brain correctly.

And this inability to receive the leptin signal can also impair fertility.

Let’s dig into the details on how leptin signaling works and how it impacts your ability to get pregnant.

Step 1: You need enough fat cells to produce leptin.  Women who are underweight or extremely lean may not have enough leptin produced by their adipose tissue. (More on this in Part 3 of this series.)

Step 2: The leptin produced in the fat tissue must make it to the region of the brain called the hypothalamus. This area of the brain controls both appetite and reproductive hormone signaling.

Step 3: Leptin receptors on the cells in the hypothalamus must be able to bind to the leptin to transmit the signal into the cells.

Step 4: Cells within the brain that properly receive the signal from the leptin hormone can decrease your appetite and increase the amount of energy you burn. Other cells in the hypothalamus signal to your reproductive hormone system that your fuel stores are high and baby-making can ensue.

All of this works great when the signal from leptin is properly received.  But this pathway breaks down when the leptin signal isn’t getting through.

Leptin and Leptin Receptors: A big discovery

Researchers have known for quite a while that mice with leptin deficiency are both fat and infertile. The leptin-deficient mouse strain was developed in the 1950s and used as a model for obesity, although the actual cause (leptin) wasn’t discovered and named until the 1990s.

Researchers then discovered that giving those mice an infusion of leptin would restore their fertility and induce weight loss.

Another breakthrough was the discovery that a lack of leptin receptors also created an obese mouse that was infertile.

Like a lock and key, both the leptin hormone and leptin receptors are needed in the right amount and at the right location.

How does leptin influence reproductive hormones?

In the brain there is a small region called the hypothalamus. It is only about the size of an almond, but it controls a lot of important functions in your body. The hypothalamus controls your body temperature, appetites, circadian rhythm, sleep, and -- importantly here -- the regulation of reproductive hormones. (study)

Within the hypothalamus are different groups of neurons that perform the various functions.  One of these groups of neurons controls signaling for reproductive hormones, and leptin is a trigger for these neurons.

Gonadotropin-releasing hormone (GnRH) is controlled by the hypothalamus. GnRH is responsible for telling the pituitary to release follicle-stimulating hormone (FSH) and luteinizing hormone(LH).

FSH and LH are the hormones that control the maturation of the egg and ovulation. You have to have FHS and LH in the right amounts and at the right time for menstruation or pregnancy.

This pathway of signaling for the reproductive hormones is called the hypothalamic-pituitary-gonadal (HPG) axis.

RH

Leptin is the key here. It signals to the hypothalamus that you have enough nutrients and that your body should go ahead and release the hormones necessary for reproduction.

As one study puts it:  “Serum leptin levels are a critical link between sufficient nutrition and the function of the hypothalamic–pituitary–gonadal (HPG) axis.” (study)

Research studies on leptin and reproductive hormone levels:

Recent research using mice with the leptin receptors deleted from the brain has helped researchers narrow down the effects of leptin on reproduction.

One study found that specific neurons in the hypothalamus received the leptin signal and were responsible for both the normal onset of puberty and normal fertility.

And, importantly, this signaling action was completely independent of the way that leptin controls appetite and metabolism. (study)

In human studies, leptin levels are intertwined with fertility and reproductive hormones.

Girls who reach puberty very early (ages 7-9) have higher leptin levels. This was true for both normal weight and overweight girls, so being overweight wasn’t driving the increase in leptin and early puberty.(study)

A study of women with infertility found decreased leptin receptor function. (study) Another study of women with unexplained infertility found higher than normal leptin levels in the follicular fluid. (study)

A recent study found that leptin levels were “significantly higher in women with unexplained infertility than fertile control females”. The higher leptin levels correlated with higher BMI in the infertile women, while in the control group there was not a correlation between leptin and BMI. (study)

Women with PCOS and infertility were found to have higher serum and follicular fluid leptin levels than a control group of women who were infertile due to tubal blockage. (study)  (More on the links between PCOS and leptin in Part 2 of this series.)

A double-blind placebo controlled trial of prescription leptin was conducted on very lean women (BMI <20) who no longer had their periods. Giving them a prescription leptin medication restored menstruation for 70% of the women. (study)

Putting all of the research together:

  • Low amounts of leptin - either through lack of food or leptin deficiency - impairs fertility. This is a problem for women who have very low body fat.
  • More often, though, women have a problem with higher weight. Almost all overweight women are producing high amounts of leptin, but that signal isn’t being received correctly in the brain. The brain is resistant to the leptin hormone signal.
  • Leptin hormone resistance causes at least two issues:
    increased appetite and altered reproductive hormones
  • The increased appetite/weight and decreased fertility are actually two separate conditions. Fertility is impaired through changes in the hypothalamus-pituitary-gonadal (HPG) axis and subsequent changes to LH and FSH levels.
  • Whether through lack of leptin hormone or through leptin resistance, the impact on reproductive hormone signalling results in decreased fertility. (study)

What is leptin resistance?

The fact that overweight people have higher leptin levels has led scientists to conclude that the signal from leptin is just not getting through to the hypothalamus.  This is termed ‘leptin resistance’.

This same leptin resistance that causes people to gain weight may be causing problems when trying to conceive. If the hypothalamus isn’t receiving the leptin signal, your body may decrease reproductive hormones.

So what exactly is ‘leptin resistance’? It may surprise you to know that the term doesn’t really have a standard definition. For researchers, it means that leptin isn’t creating the outcome that is expected (i.e. weight management and appetite control).  But the actual mechanism that causes leptin resistance is still being debated. (study)

Sometimes researchers use the term leptin sensitivity instead of leptin resistance.  But whatever you call it -- leptin isn’t doing its job.

There are several theories of why people have leptin resistance.

One theory is that when leptin levels are too high in the bloodstream, it decreases the amount that can cross the blood brain barrier into the brain. The signal doesn’t reach the hypothalamus.

Another possibility is that low-grade, chronic inflammation in the hypothalamus decreases the leptin receptor function.(study)

Leptin's role in fertility and hormonal regulation

PCOS and leptin:

Women with PCOS often have problems with infertility due to altered hormone levels, which causes problems with ovulation.

An analysis of 19 different studies on PCOS showed that elevated leptin levels are a marker of the syndrome. (study)

Elevated leptin levels, along with altered hormones and a big tendency towards weight gain, go hand in hand with PCOS and infertility.

Genes involved in leptin:

 There are several genetic variants that change the way the leptin receptor functions.  These variants have all been linked to an increased risk of obesity, diabetes, and PCOS.

If you have your genetic data from 23andMe or AncestryDNA, you can check to see if you carry these leptin receptor variants.

Check your genetic data for rs1137101:

  • A/A: normal
  • A/G: increased risk of being overweight, diabetes
  • G/G: increased risk of being overweight, diabetes (study)(study)

Check your genetic data for rs1137100:

  • A/A: normal
  • A/G: increased risk of obesity, diabetes, PCOS
  • G/G: increased risk of obesity, diabetes, PCOS (study)(study)(study(study)

What can you do if you suspect that leptin resistance is sabotaging your ability to get pregnant?

In general, leptin sensitivity is a balancing act between the signal getting to your brain and the brain receiving the signal.

Sleep is absolutely vital for leptin sensitivity. Leptin levels are not only controlled by your body fat and eating, but they also vary according to your circadian rhythm.

Not getting enough sleep has been shown in studies to affect both leptin levels and BMI. And the amount of time spent in REM sleep is also associated with leptin levels. (study)(study)

A recent study showed that bright light in the morning can also help to restore leptin levels, especially when sleep deprived. The study used full spectrum light, so getting outside in the sunshine in the morning would be a great way to get your bright light. (study)