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The hypothalamic-pituitary-adrenal (HPA) axis (you can read an introduction to it here) is one of the leading contributors to poor reproductive health. The pituitary gland tells the reproductive organs what to do, and the hypothalamus tells the pituitary gland what to do. If the hypothalamus puts up a stop sign, then sex hormone levels fall.

Worse, when this stop sign is up, cortisol is usually being produced by the adrenals. This negatively influences the activity of both the hypothalamus and the pituitary glands.

Hypothalamic amenorrhea– or the loss of menstruation via disturbance to the HPA axis–affects 5 percent of women of reproductive age. Subclinical women (women who do not fully meet the requirements for the condition but nevertheless suffer from it in some way or another) I suspect double that number, at least. Many problems emerge as a result of HPA axis dysregulation that do not go as far as HA.

The HPA axis is dysregulated by all types of stress.  Acute stress is handled fairly easily, as the HPA axis is typically stable and in fact built to optimize an individual’s response to stress.  But chronic stress is– as we are all well aware– half of one of Satan’s eyelashes away from downright insidious.

Chronic stress itself is divisible into two distinct categories: psychological stress and metabolic stress.

Psychosocial stress is caused by mental, emotional, and social factors. Metabolic distress is caused by energy deficits–which are caused by restricted food intake and excessive exercise. Basically, anything that significantly deprives a woman’s body of caloric energy is a metabolic stress.

This post is going to focus on metabolic distress.  I treat the psychosocial and how these two are interrelated in the following post.

You can also read more on how to regain fertility through food and lifestyle by clicking here for my bestselling book, Sexy by Nature.

Hypothalamic Amenorrhea in general

The point of the HPA axis is to metabolically mobilize individuals in stressful circumstances.  It causes stress hormones to go up – which can energize you!

In stressful situations, stress hormone levels rise, and sex hormone levels fall.

In one study, the degree of ovarian compromise women suffered was in a precise inverse relationship with observed cortisol levels.  That’s pretty amazing.  Cortisol performs negative feedback on the hypothalamus, such that the hypothalamus releases GnRH (gonadotropin releasing hormone) in decreased quantities. Without GnRH, the pituitary doesn’t get the signal to more of its own hormones.  These include LH and FSH, hormones that in turn signal to the ovaries how much estrogen they should be producing according what time of the cycle it is. The Pituitary is also responsible for secreting thyroid stimulating hormone (TSH). Ordinarily, TSH levels rise or fall  in response to changes in T3 and T4 levels in the blood.  In HA, the pituitary never receives these signals, so TSH levels do not increase when they should. Additionally, due to HA, the secretory patterns of growth hormone, prolactin, and melatonin vary.  This is problematic for a wide variety of reasons, not  the least of which are sleep, tissue repair, and hormone development.

So that is stress and the hormone cascade in a nutshell. Hormones are produced like dominoes. If somethin goes wrong at the beginning of the set, then none of the dominoes are going to fall in the right way.

Exercise, weight loss, and metabolic stress

When compared with normally menstruating but sedentary women, amenorrheic athletes demonstrate less progesterone secretion, fewer LH pulses from the pituitary in a day, and higher cortisol levels.  Amenorrheic athletes that do not ovulate have the fewest LH pulses in a day of all groups of women and the highest cortisol levlesl despite comparable leves of exertion and fitness among these athletes and others.

This is all to say that athletes experience greater risk of amenorrhea.

Though both sorts of stress are important for the ovaries, there is no doubt that exercise and weight loss serve as stressors all their own:

In monkeys trained to run, it has been shown that caloric supplementation reversed the anovulation induced by training.  Interestingly, the monkeys did not spontaneously develop a compensatory increase in appetite and had to be bribed with colorful candy to consume more calories. The HPA axis was downregulating their drives to eat.  Studies in women also indicate that exercise and weight loss cause anovulation, probably through decreased GnRH release.

One team of researchers, Louks and Thurma, quantified the amount of energy restricted (absent of psychosocial stress*) needed to impact GnRH release in normally menstruating women. They fed the women an energy stasis of 45kcal/kg of mean body mass per day. This amounts to approximately 2200 calories for a woman weighing 110 pounds. They administered graded daily energy deficits of 10, 25, or 35 kcal/kg. This yields absolute values for the 110 pound woman of 1750 calories per day, 1000 calories per day, and then, 500 calories/day. An energy deficit of 33 percent showed no impact in LH pulse frequency after 5 days, and an energy deficit of 75 percent showed a 40 percent decrease in LH in 5 days.

I imagine that both of these numbers would be more signficiant with longer time periods. Much more significant.  For all energy deficits cortisol levels rose.  At the 75 percent reduction, cortisol levels rose by 30 percent. For the women who had the lowest progesterone levels at the start of the study, the cortisol levels and reductions in LH were impaced the most.

Most women, I’d imagine, who enter into such deficits do not have them imposed, but rather choose them. This indicates to me that they are under a great deal of stress as well, such that the “stressed” women tested in this study probably closer approximate the majority of real American women.

The question remains: Is it the stress of exercise or the energy deficit that alters LH pulsatility in exercising women?

This key question has been answered maybe by controlled studies in which women undergo dietary caloric restriction imposed in the face of increasing exercise demands. It would appear that LH pulsatility is not disrupted by the stress of exercise but rather by reduced energy availability.

With increased calories, the women don’t experience as much LH disturbance as when they don’t meet their caloric needs. Presumably, then, sufficient calorie ingestion would really help mitigate the problem for women suffering exercise-induced HA. According to this one spate of studies.

Honestly, I’m not sold.  Muscle tear down and growth, and any repair that occurs on joints and other tissues, involves the activation of inflammatory responses. Cortisol rides along with those. If the exercise and the resulting cortisol is significant enough, supplementation with calories cannot cure everything.  Additionally, the psychosocial stress that accompanies excess exercise plays a role. Additionally, thyroid function may be negative impacted by trying to make up for fluctuating caloric intake.  And finally, I find it implausible that women outside of controlled studies will know precisely how much they need to add to their diets in order to achieve the proper balance.

To read about healthy ways to lose weight as a woman, check out my book Weight Loss Unlocked.

Biochemical implications of excess energy expenditure

Metabolic imbalance occurs when energy expenditure exceeds energy intake. This is important for our bodies, so there are many different (and redundant) signals to the brain from metabolic systems. This makes it hard to suss out what system does precisely what, and which is the most important in studying these issues.  Signals reflecting energy stores, recent nutritional information, and specific classes of nutrients are integrated in the central nervous sytem, particularly the hypothalamus, to coordinate energy intake and expenditure. Chronic energy deficiency alters thyroidal function to slow metabolism and correct negative energy balance.

Putative appetite suppressing and satiety signals include cortisol, CRH, insulin, glucose, resistin, leptin, proopiomelanocortin POMC, cocain- and amphetamine-regulated transcript CART peptide, peptide YY, and glucagon=like peptide 1.

The hormones from fat cells implicated in energy regulation include leptin, adiponectin, and resistin. Leptin is the dominant long-term energy signal informing the brain of fat reserves– it is also a satiety signal.  It’s a big deal, and for women’s with HPA axis dysregulation, having lots of it, or at least good sensitivity to it, is helpful.

Adiponectin acts as an insulin-sensitizing agent by reducing liver glucose production. This one, contra leptin, is reduced in obesity. Resistin is linked to insulin tolerance and decreases glucose uptake by fat cells. Ghrelin is produced by the gastrointestinal tract.  Plasma ghrelin levels rise during fasting and immediately before anticipated mealtimes and then fall within an hour of food intake, suggesting that ghrelin is important for meal initiation.

Resistin levels correlate with free cortisol levels, indicating that in states of stress the body is trying to sensitize the body to insulin.  Adoponectin correlates with insulin sensitivity, too, particulalry in studies of depressed humans.  In women, ghrelin levels increase in both anorexia nervosa and exericise amenorrhea.  No surprise there. The greater the energy deficit, the more the body wants to eat.

Leptin is crucial. Importantly, women who primarily suffer from psychosocial stress and not metabolic distress recover from hypothalamic amenorrhea without changing weight or leptin levels.   What this tells us is that leptin is mostly a problem for women who suffer energy deficits.  Studies of rodents as well as of women indicate that increasing leptin and leptin sensitivity induces regularity. When mice are injected with leptin during a fast, for example, their cycles remain the proper length. Without leptin, however, their cycles become longer and irregular.

How to increase leptin levels

Leptin is produced by fat cells.  Some other tissue produces it as well, but not as significantly.  Low body fat is a very significant problem for hypothalamic amenorrhea.  This is indicated by the fact that while many athletic women experience HA, women who participate in sports that require thinner physiques have much greater rates of HA.
Depending on the type of sport and competition level, the incidence of amenorrhea varies from 5 to 25%.  The rates of HA in sports that require low body weight are as high as 6-43 percent in ballet and 24-26 percent in long distance running. In less stringent sports, such ad bicycling and swimming, the rates of HA are both 12 percent.

All that is to say that low body fat is a clear (leptin) signal that the body is running in an energy deficit. When this is the case–that is, when the body is running at a deficit– it thinks its starving.

No, I’m sorry, I mispoke. It doesn’t think it’s starving. It is starving. So all of the satiation hormones– in this case ghrelin, resistin, and leptin– they muster their collective powers and try to get the body to eat more.

If that does not happen, and if leptin levels are too low, the hypothalamus will not receive the signal to start the reproductive hormone cascade.


All that said, the factors that cause, respond to and mitigate metabolically induced hypothalamic amenorrhea are many and complex.  

In the end, they can almost be reduced to a leptin problem.  But leptin is an issue solely because of low body fat and energy deficits (*as well as any leptin insensitivity, which I will treat in another post).   There are also the issues of inflammation and stress that arises from exercise, as well as psychosocial stress–all of which build upon each other in the complex interactions between the HPA axis and the body at large.

The solution is to eat all the things. It is to err on the side of eating more rather than less. It is to reduce stress as much as possible. It is to refuel properly after workouts.

You can read about HA and psychological stress here.

You can read more about how to recover from HA (from all causes) here.

You can check out my best-selling book on how to get your natural swagger and fertility back at Amazon here and my healthy weight loss book here.



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