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Running head: HYPOTHALAMIC AMENORRHEA
Hypothalamic Amenorrhea
Cory Ruth
NTRS 521
Winter Quarter 2016
California State University, Los Angeles
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Background
Stress can play a positive role in a busy and constantly on-the-go life; high levels
of pressure can stimulate motivation to take on new and tougher challenges. On the
contrary, when taken to the extreme, stress can negatively affect wellbeing in a myriad of
ways. High stress levels have been correlated with health complications such as lowered
immunity, atherosclerosis, and psychiatric illness (Salleh, 2008). Stress affects every
individual differently, and women face unique challenges when compared to males in
terms of stress response. Palm-fischbacher and Ehlert (2014) have found that women who
have higher levels of this type of pressure are at an increased risk for endocrine
disruption, which may manifest itself in menstrual cycle irregularities.
Hypothalamic Amenorrhea (HA) is one type of menstrual cycle disruption that
has been defined as the absence or cessation of menses as an adaptive response to stress
so that the body can focus on other tasks essential to its survival (Palm-fischbacher &
Ehlert, 2014). It is mainly due to conditions that cause the body to wind up in a state of
energy deficit such as dieting, weight loss, extreme exercise, heavy lifting, intense
emotional events, and disordered eating (Beltsos, 2016). Klein and Poth (2013) have
described that this type of stress suppresses the hypothalamic-pituitary-ovarian axis,
temporarily shutting down reproductive function. This condition results from a deficiency
in gonadotropin-releasing hormone (GnRH), which in turn causes low levels of folliclestimulating hormone (FSH) and luteinizing hormone (LH). Additionally, cortisol levels
are often elevated in HA (Michopoulos, Mancini, Loucks, & Berga 2013) putting the
woman in a constant state of ‘fight or flight’. The final consequence of these hormonal
aberrations causes reduced estrogen production in the ovaries to the extent that ovulation
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ceases and the period stops (Meczekalski, Katulski, Czyzyk, Podfigurna-Stopa &
Maciejewska-Jeske, 2014).
HA can be extremely perplexing to doctors, specifically if the woman does not
appear malnourished or ill in any other form. Typically the diagnosis is one of exclusion,
as women with the disorder have no pre-existing endocrine or central nervous system
(CNS) disease, no tumors or trauma, and no systemic contributing factors (Genazzani,
Ricchieri, Lanzoni, Strucchi, & Jasonni, 2006). If HA is suspected, the clinician will
generally investigate recent weight loss or gain, an eating disorder, a low BMI (BMI <20
kg/m2), exercise patterns, reduced caloric intake, recent discontinuation of the
contraceptive pill, and past or present stressful life events (Beltsos, 2016).
Due to the complex and often elusive etiology of HA, frequently more than one
therapeutic approach to treatment is necessary. Behavior modification such as stress
reduction, reduced exercise, and an increase in weight and/or BMI has shown promising
reversals in the underlying causes of HA and normal patterns of menstruation and
ovulation may resume (Warren & Perlroth, 2001). Emerging research suggests that leptin
supplementation may be successful in the restoration of endocrine normality (Holtkamp,
et al., 2003). Furthermore, recent evidence suggests psychological interventions such as
cognitive behavioral therapy (CBT) may lower cortisol levels and improve metabolic and
neuroendocrine function in women presenting with HA (Michopoulos, Mancini, Loucks,
& Berga, 2013).
Importance of the Problem
HA can be a potentially devastating problem and severely impact a woman
physically, mentally, and emotionally. Because many women are taking birth control and
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receiving synthetic hormones, they are still bleeding every month and thus even if HA is
present, are likely unaware of its existence. Not only can it cause anovulation and an
inability to conceive, it may have lasting detrimental effects on bone mineral density
(BMD) (Beltsos, 2016). Once birth control is terminated, women with HA become attune
to the fact that normal ovulatory menstruation has ceased to resume and at that point in
time it may be too late to prevent permanent bone loss.
Furthermore, many women go off of birth control in order to become pregnant
and it may take many years before fertility returns in women currently experiencing HA
(Beltsos, 2016). It’s imperative to better understand the causes, symptoms, diagnosis, and
treatment of HA so that further education can be obtained in order to prevent women, as
well as their families, from suffering from the condition.
The purpose of this paper is to discuss potential treatments for HA beyond simple
behavioral modifications such as weight gain and an increase in BMI. This paper aims to
explore leptin supplementation and CBT as prospective therapies, identify gaps of
knowledge, and suggest where further research is needed. By giving readers this
information, this paper will provide clinicians, RDNs, and other non-medical persons
with a framework for treatment in a condition poorly studied.
Literature Review: Treatment with Leptin Supplementation
Circulating leptin levels have been demonstrated to be indicative of the amount of
energy fat stores in the body and highly correlated with even the smallest alterations in
energy intake (Chou et al., 2011). Because those with HA are continuously in an energy
deficit and are observed to have low levels of leptin, this population of women could
respond positively to leptin supplementation by resuming ovulatory menses and reaching
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normal levels of circulating reproductive hormones. Two studies in women diagnosed
with HA showed positive results when leptin was supplemented when compared to a
placebo.
In a randomized controlled trial (RCT) by Chou et al. (2011), 10 women received
metraleptin (a human recombinant leptin) and nine women received a placebo. After 36
weeks, seven of the women in the metraleptin group had resumed menses and four of
them were determined to be ovulating compared to the placebo group, in which only two
began menstruating. Levels of estrogen and progesterone increased during metraleptin
supplementation, while cortisol levels significantly decreased. Additionally, findings
from this study suggest long-term use of metraleptin may have beneficial effects on bone
metabolism.
In a study by Welt et al. (2004), eight women with HA were given leptin
supplementation in the form of r-metHuLeptin and six served as controls and received a
placebo. After three months, weekly blood samples demonstrated that three of the women
receiving r-metHuLeptin began ovulating while none of the controls resumed a cycle. LH
and estrogen levels increased in the women receiving r-metHuLeptin, while no changes
in reproductive hormone levels were found in the women who took the placebo.
This research suggests a threshold level of leptin may be required to restore and
maintain normal ovarian function. However, sample sizes of the studies discussed were
small and study durations were relatively short. Therefore, evidence for leptin
supplementation in the treatment for HA could be strengthened immensely by performing
RCTs over a longer period of time using a larger sample size. Additionally, neither study
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changed the dose of leptin and therefore future research could include dose-dependent
responses in order to test for improvements in changing the quantity of supplementation.
Literature Review: Treatment with CBT
HA is a disorder very closely linked to high stress levels and several studies have
shown positive results and the restoration of ovarian function after treatment with
psychotherapy. Along with hormonal aberrations in GnRH, LH, FSH, and cortisol,
Berga, et al. (2003) have reported that women with HA have higher levels of
perfectionism, altered attitudes surrounding eating, and an increased need for social
approval. CBT is a common type of psychotherapy that focuses on changing the
relationship between a person’s thoughts, actions, and feelings and has been shown to be
an effective treatment for anxiety, depression, and eating disorders (Michopoulos,
Mancini, Loucks, & Berga, 2013). Two studies found that women with HA showed
improvements in ovarian function and hormone levels when CBT was implemented as a
therapeutic approach.
Berga et al. (2003) performed an RCT where 16 women diagnosed with HA were
assigned to either CBT or observation for 20 weeks. The eight women assigned to CBT
received 16 session of CBT where they completed food diaries, received information on
healthy eating and exercise activities, and met with a dietitian to come up with a
nutritious eating plan. Additionally, behavioral interventions and coping mechanisms
were suggested in order to decrease levels of stress. Blood samples were taken each week
to test estrogen and progesterone levels. At the end of the study, the women receiving
CBT had higher levels of ovarian activity compared to the observation group. Among the
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eight women in the CBT group, six began to ovulate while only one of the women in the
observation group became ovulatory.
Michopoulos, Mancini, Loucks, & Berga (2013) took findings from the abovementioned study a step further. The researchers hypothesized that CBT would also
reverse other neuroendocrine and metabolic concomitants of HA such as elevated levels
of cortisol, decreased levels of leptin, and thyroid function. In an RCT, 17 women with
HA were randomized to CBT or observation for 20 weeks. Eight women in the CBT
group attended 16 sessions where they focused on evaluating nutrition and exercise
habits, identified maladaptive attitudes towards stressors and weight, and refined stress
management techniques. Blood samples were drawn weekly to test not only estrogen
progesterone concentrations, but also cortisol, leptin, and TSH levels. Results of the study
showed that among the eight women randomized to CBT, six began ovulating. Of the
nine women in observation group, only three resumed ovulation.
These studies suggest a powerful link between psychological stress and endocrine
function in women with HA. However, sample sizes were relatively small and study
durations were short. Further research on CBT as a treatment for HA could include RCTs
that have more subjects and are performed over a longer period of time. Additionally,
there are many types of psychotherapies such as Gestalt and Social Therapy that could be
used in the treatment of HA in order to reduce stress levels and improve reproductive
hormone levels.
Discussion
When it comes to healthy endocrine function and the restoration of menses and
ovulation, evidence in the success of both leptin supplementation and CBT in the
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treatment of HA is extremely encouraging. Though each study discussed had a rather
small sample size and relatively short study duration, the percentage of women who
responded well to the treatment was overwhelming compared to the control group. This
demonstrates that in many cases, HA is reversible in a moderately brief amount of time.
Furthermore, this evidence suggests that women with HA are highly sensitive to both
levels of stress and fluctuating leptin concentrations.
More research is needed to explore these treatments in depth. Future studies could
test the effects of varying doses of leptin supplementation over the long-term to obtain
dose-dependent responses on the condition. More research could be done on different
types of psychotherapy and its subsequent effects on stress levels. It would benefit
women with HA immensely if a larger-scale study could be done to test a combination of
these treatments in order to elevate hormone levels more quickly so that these women are
able to go on to achieve pregnancies faster. Furthermore, more studies could be
performed to test effects of different therapies over the course of a year or even longer to
obtain stronger evidence.
A future study that could be highly beneficial for those suffering from HA could
offer leptin supplementation in conjunction with CBT or another form of psychotherapy.
No studies to date have performed such a trial, but because HA can be due to so many
different factors, it would be most logical to approach treatment in a variety of ways.
Additionally, since HA is so closely tied to levels of stress, other stress-reducing
programs such as meditation and gentle yoga exercises could be combined with any of
the above-mentioned treatment strategies.
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References
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