Amenorrhea. A Case-Based, Clinical Guide

10. Clinical Implications of Prolonged Hypothalamic Amenorrhea

Tammy L. Loucks and Sarah L. Berga 

(1)

Department of Gynecology and Obstetrics, Emory University, 1639 Pierce Drive, Suite 4208-WMB, Atlanta, GA 30322, USA

Sarah L. Berga

Email: sberga@emory.edu

Abstarct

History – A 26-year-old woman presents to the office with concerns about irregular menstrual periods. The patient reports normal developmental milestones, including menarche at age 13, and regular monthly periods until age 19. Her periods became irregular during college. The physician who saw her attributed the irregular cycles to the stress of college and prescribed oral contraceptive pills (OCPs) to regulate her cycles. The patient did not like the side effects from the OCPs, and so she stopped taking the pill after about 6 months. She reports no more than two episodes of very light vaginal bleeding per year in the past 3 years. She reports regular exercise and that she follows a heart-healthy diet. However, she often skips meals or grabs a piece of fruit for lunch because she is too busy and forgets to eat. She is concerned that her amenorrhea may be impacting her long-term health and in particular her bones. Her mother (age 58) was recently diagnosed with osteopenia and the patient has had two stress fractures in the last 4 years.

Case Scenario

History – A 26-year-old woman presents to the office with concerns about irregular menstrual periods. The patient reports normal developmental milestones, including menarche at age 13, and regular monthly periods until age 19. Her periods became irregular during college. The physician who saw her attributed the irregular cycles to the stress of college and prescribed oral contraceptive pills (OCPs) to regulate her cycles. The patient did not like the side effects from the OCPs, and so she stopped taking the pill after about 6 months. She reports no more than two episodes of very light vaginal bleeding per year in the past 3 years. She reports regular exercise and that she follows a heart-healthy diet. However, she often skips meals or grabs a piece of fruit for lunch because she is too busy and forgets to eat. She is concerned that her amenorrhea may be impacting her long-term health and in particular her bones. Her mother (age 58) was recently diagnosed with osteopenia and the patient has had two stress fractures in the last 4 years.

The patient reports that she regularly exercises to relieve stress. She began running in college while in an honors program with double major in political science and French literature. She is now enrolled in a JD program and is considering criminal law. She has friends, dates, is on good terms with family, and has no reports of abuse. She reports feeling overwhelmed and that she often says no to social functions because she has too much work and not enough time. She has always been at the top of her class and has always gotten nearly straight A’s.

On physical examination, the patient is 5′8² tall and 130 pounds (BMI 21.7 kg/m2) and is a nonsmoker. She is Tanner stage 5 for escutcheon and breasts, has a normal gynecoid habitus, and is not hirsute. Her sense of smell is intact. There is no acanthosis nigricans, no abdominal striae, and no areas of hyper- or hypopigmentation. The patient’s visual fields are normal to confrontation. There are no focal lateralizing neurological findings. She sustained a minor concussion 6 months ago while playing volleyball and an MRI obtained during her ER consult was normal. However, the amenorrhea began before the head injury. You suspect that the patient has functional hypothalamic amenorrhea (FHA).

Baseline Biochemical Evaluation

 

Systeme International d’Unites (SI)

Conventional (CI)

Urine βhCG

Negative

 

LH

1.2 IU/L (0.8–26)

1.2 mIU (0.8–26)

FSH

1.5 IU/L (1.4–9.6)

1.5 mIU/L (1.4–9.6)

E2

80.8 pmol/L (70–220)

22 pg/mL (20–60)

P4

0.8 nmol/L (6–64)

0.25 ng/mL (2–20)

Prl

5 μg/L (2–15)

5 ng/mL (2–15)

TSH

2.3 mU/L (0.5–5)

2.3 μU/mL (0.5–5)

T4

70.8 nmol/L (64–154)

5.5 μg/dL (5–12)

Androstenedione

3.8 nmol/L (3.5–7)

1.10 ng/mL (1–2)

Total testosterone

1.0 nmol/L (<3.5)

0.29 ng/mL (<1 ng/mL)

You offer the patient an opportunity to participate in a study of talk therapy and stress management for women with hypothalamic amenorrhea. The patient consents to participate and is enrolled in the 20 week program. Eight months later, the patient returns and reports that she has had regular menstrual bleeding pattern for 3 of the past 4 months. Her weight has not changed, and she continues to run 10–12 miles each week. With the help of nutrition counseling, she eats more regularly and no longer skips breakfast and plans a break in her day to eat lunch. She also had an opportunity to do a volunteer rotation with a nonprofit human rights foundation and feels less overwhelmed than before. The law school she attends has an excellent international human rights program, and she has changed her focus to this domain of law. She reports that she is now spending more time with friends and enjoys a busy social life and that she has also recently started a new relationship. Her last menstrual cycle was about 23 days ago, and the interval between cycles has been about 30 days.

Followup Biochemical Evaluation

 

Systeme International d’Unites (SI)

Conventional (CI)

Urine βhCG

Negative

LH

3.0 IU/L (0.8–26)

3 mIU/L (0.8–26)

FSH

4.0 IU/L (1.4–9.6)

4 mIU/L (1.4–9.6)

E2

367.1 pmol/L (70–220)

100 pg/mL (20–60)

P4

40.0 nmol/L (6–64)

12.6 ng/mL (2–20)

Prl

8 μg/L (2–15)

8 ng/mL (2–15)

TSH

4.0 mU/L (0.5–5)

4 μU/mL (0.5–5)

T4

96.5 nmol/L (64–154)

7.5 μg/dL (5–12)

Androstenedione

4.4 nmol/L (3.5–7.0 nmol/L)

1.25 ng/dL (1–2)

Total testosterone

0.9 nmol/L (<3.5 nmol/L)

0.26 ng/mL (<1 ng/mL)

You inform the patient that her biochemical evaluation indicates ovulation. You recommend a follow-up in 3 months or sooner should she decide that she needs a reliable form of hormonal contraception.

Overview

Secondary amenorrhea, or the cessation of menses unrelated to pregnancy in a ­previously eumenorrheic woman, may be the only overt indication of reproductive compromise. Frequently, amenorrhea has as its cause unrecognized metabolic and/or psychogenic stress. Reproductive “alignment” occurs when physiological responses elicited by the external milieu modulate reproductive processes. If the internal or external milieu is stressful, the biological systems mediating reproductive alignment act to halt or compromise gametogenesis or fertilization and effect relative reproductive quiescence until the stress ameliorates. Determinants and mediators of reproductive alignment are many and because factors interact, the independent impact of any one factor may be minimal and difficult to discern [1]. Indeed, a constellation of factors determines whether reproduction is favored or impaired. Stress-induced reproductive compromise is a diagnosis of exclusion. There are many organic, as opposed to functional, conditions that manifest as anovulation or amenorrhea. Congenital and anatomic causes, such as vaginal agenesis or other Muellerian abnormalities, must be excluded. Idiopathic hypothalamic hypogonadism due to Kallman’s syndrome is difficult to exclude unless there is anosmia. A careful evaluation is mandated to exclude organic brain, hypothalamic, pituitary, thyroidal, adrenal, or ovarian etiologies. Common organic etiologies include pituitary adenomas, ovarian failure, polycystic ovary syndrome (PCOS), and hypothyroidism. However, the most common cause of hypothalamic hypogonadism with amenorrhea is likely stress. This is important to recognize because stress-induced anovulation is theoretically reversible with appropriate intervention.

Stress may be the underlying cause in the majority of cases of secondary amenorrhea, yet it remains one of the most underappreciated causes of infertility in both women and in men. A clinically recognizable presentation of stress-induced hypothalamic hypogonadism in women is FHA. FHA affects roughly 5% of women of reproductive age but less severe forms of hypothalamic hypogonadism are far more common and occult (i.e., luteal insufficiency with eumenorrhea) and often only recognized clinically when fertility is desired [2]. Women with FHA typically have both subclinical metabolic compromise and psychogenic stress that interacts ­synergistically to compromise reproductive function. Neuroendocrine concomitants of FHA include activation of the hypothalamic–pituitary–adrenal (HPA) axis with resultant increased cortisol secretion and suppression of the hypothalamic–pituitary–thyroidal (HPT) axis with relatively decreased thyroxine release in the face of normal levels of thyroid stimulating hormone (TSH). Psychosocial correlates of FHA include unrealistic expectations of self and others, poor problem-solving skills, and cognitive distortions related to food and body image that do not meet criteria for an eating disorder. Women with FHA rarely meet criteria for depression or a bonafide syndromal psychiatric disorder. However, they typically report a higher need for social approval which generally reflects an external locus of control. Having an external locus of control heightens psychosocial stressors. Additionally, women with FHA report high degrees of perfectionistism, which may manifest behaviorally as excessive exercise, high achievement or good grades, and/or rigid dietary habits with imbalanced nutrient content or insufficient energy intake relative to expenditure [35].

Epidemiological data looking at long-term health of women with FHA are limited in part because most women are not given a concrete diagnosis before initiating treatment with oral contraceptives to regulate menstrual cycles or undergoing fertility procedures when pregnancy is desired. Because women with FHA do not display the same degree of undernutrition as women with anorexia nervosa and they do not meet criteria for depression, it is difficult to gauge the acute and chronic health risks of having untreated FHA by extrapolation from other similar conditions [6]. However, there is evidence to suggest direct negative health effects, including increased risk for osteoporosis, neurodegenerative diseases, and cardiovascular disease (CVD) in women with FHA. In addition, women with FHA who become pregnant are at increased risk for poorer pregnancy outcomes, including intrauterine growth restriction, preterm labor and low birth weight, and possibly congenital birth defects. Taken together, these observations support the notion that unresolved and untreated FHA and even less clinically obvious forms of hypothalamic hypogonadism may heighten acute and chronic health risk to the individual and through epigenetic mechanisms during gestation to future generations.

The conventional therapeutic options offered to women with FHA are oral contraceptives when fertility is not desired and ovulation induction or assisted reproductive interventions when fertility is sought. The rationale for these interventions is based on the view that FHA represents an isolated compromise of reproductive function and that only the reproductive manifestations need to be treated. Herein, we present evidence that challenges this perspective. We highlight the nonreproductive health consequences of stress-induced reproductive compromise in women and discuss nonpharmacological approaches, particularly cognitive behavior therapy (CBT), to ameliorate stress, restore fertility, and improve overall health.

Neuroendocrinology of FHA

Functional hypothalamic hypogonadism is present in about 35% of women seeking clinical evaluation of secondary amenorrhea [7]. The proximate cause of FHA is reduced in central GnRH drive. When sufficient in duration and magnitude, reduced GnRH drive results in anovulation and amenorrhea. Because decrements in central GnRH–LH/FSH drive exist on a continuum and vary from day to day [8], it follows that the associated ovarian compromise exists as a spectrum and manifests as amenorrhea, polymenorrhea, oligomenorrhea, or luteal insufficiency with preserved menstrual interval. The more occult forms of hypothalamic hypogonadism are estimated to be much more common [2] and likely come to clinical attention when fertility is compromised, see Fig. 10.1 [9].

A978-1-60327-864-5_10_Fig1_HTML.gif

Fig. 10.1

Representation of the spectrum of presentation of functional hypothalamic hypogonadism. Adapted from Berga and Loucks [9]

The purpose of the hypothalamus is to generate an “endocrine action plan” to preserve the organism in the face of challenge. Acutely, stress elicits homeostatic responses designed to restore hormonal equilibrium. When stressed chronically, the resultant adaptive hormonal alterations preserve the individual by conserving ­metabolic expenditure by limiting reproductive function and by dampening basal metabolic rate. Chronic adaptive responses are termed “allostatic.” Women with stress-induced anovulation or FHA show what might be termed neuroendocrine allostasis. Specifically, there is reduced GnRH drive in the face of reduced ovarian secretion of estradiol and progesterone, feedback resistance to the inhibition of corticotrophin-releasing hormone (CRH) release despite increased cortisol in both the circulation and cerebrospinal fluid [10], and lack of a rise in TSH levels despite a decline in thyronine and thyroxine levels. Using a monkey model of stress-induced reproductive compromise, we recently found enhanced sensitivity to the feedback suppression of the pituitary to estradiol [11].

The primary mediators of the stress response are the hypothalamic CRH and the locus coruleus-noradrenergic (LC-NE) neuronal networks and their respective effector systems, the pituitary–adrenal axis, and the autonomic pathways [12]. These systems are linked in a positive feedback loop so that activation of one system activates the other. There are innumerable animal studies demonstrating that the activation of the HPA axis using a variety of stress paradigms induces reproductive compromise. However, only a few studies have been performed to elucidate the mechanisms mediating the disruption of GnRH drive. The evidence that exists supports that hypothalamic GnRH secretion is influenced by both central and peripheral factors and putative regulators include CRH, β-endorphin, dopamine, vasopressin, neuropeptide Y, γ-aminobutyric acid (GABA), and serotonin. For a more extensive review of the neuroendocrine pathways regulating GnRH drive, please refer to Berga and Loucks [13] and Berga and Yen [14].

Evidence supporting the concept that stress impairs ovarian function in women is derived from the consistent demonstration that women with hypogonadotropic hypogonadism not due to defined organic conditions have higher cortisol levels than eumenorrheic, ovulatory women [1517]. Increased cortisol levels are evident in both the systemic [1518] and central [10] compartments. Further, the association between increased cortisol and functional hypothalamic hypogonadism holds in women with athletic amenorrhea [1920]. In their study, Loucks et al. found that eumenorrheic athletes had lower luteal progesterone secretion, fewer LH pulses in a day, and higher cortisol levels compared to eumenorrheic sedentary women. Furthermore, anovulatory amenorrheic athletes had the fewest LH pulses in a day and the highest cortisol levels despite comparable levels of exertion and fitness.

In addition to the activation of the HPA axis, women with FHA also display changes in the thyroidal axis. Specifically, women with FHA present with decrements in thyronine and thyroxine, yet TSH levels are preserved [151821]. This presentation suggests an altered hypothalamic set point akin to what is seen in hospitalized patients who develop what is referred to as “sick euthyroid syndrome.” [15] As was the case of HPA activation, athletic women who have reproductive compromise display hypothalamic hypothyroidism [22]. To summarize, the hypothalamic response to chronic stress causes metabolic mobilization, activation of the HPA axis, and hypothalamic hypothyroidism so as to reduce energy expenditure by lowering basal metabolic rate and reducing the energy spent on reproductive function.

Behavioral Correlates of FHA

Explicating the behaviors and psychosocial factors that promote and sustain the neuroendocrine allostasis of functional hypothalamic hypogonadism has been one of our primary research interests for more than two decades. We have characterized the psychosocial correlates of women with FHA using a wide variety of standardized psychometric inventories and have found that certain characteristics, including mild depressive symptoms, unrealistic expectations of self and others, maladaptive concepts centering on body image, drive for thinness, perfectionism, and need for social approval are more prevalent in women with FHA compared to ovulatory eumenorrheic women and women with other forms of anovulation [35].

Two contrasting schools of thought exist regarding the pathogenesis of FHA and the reduction in GnRH/LH drive. One school attributes the disruption of GnRH primarily to psychosocial stress and maladaptive cognitions engendering behaviors, such as undereating and overexercising, that alone or in combination induce mild chronic or intermittent energy deficiency [23]. The other school posits that FHA is primarily caused by volitional energy restriction or expenditure [24]. When subjected prospectively to the combination of running and weight loss, many, but not all women, developed transient anovulation [25]. Cameron et al. showed in monkeys that developed anovulation in response to running that caloric supplementation restored ovulatory function [26]. In unselected eumenorrheic women, GnRH/LH drive was resistant to the acute nutritional challenge of a 72 h fast [27] suggesting that acute caloric restriction alone was not a potent stressor. However, in a study that applied graded energy reductions in eumenorrheic women for a longer duration of 5 days, Loucks and Thuma observed a 40% decline in LH pulse frequency with a 75% reduction in energy availability. These same women displayed a compensatory increase in cortisol secretion and, at the highest level of energy restriction, the cortisol levels increased 30% [28]. Although the increase in cortisol levels observed in this group were comparable to that seen in women with FHA, the level of energy restriction in the experimental paradigm was far greater than that reported by women with FHA. What differs between the subjects in these studies and women with FHA is the psychological compartment. Thus, FHA is more likely to develop when there is both a psychosocial component and an energy deficiency [29]. To look at interactions, we employed a monkey model in which we applied an isolated energy challenge of exercising with mild calorie restriction, an isolated psychosocial challenge of moving to a new milieu, and then we combined both the metabolic and psychosocial challenges. We found that neither metabolic nor psychosocial challenge alone potently compromised menstrual cyclicity, whereas the combination elicited a marked impairment in most [1].

Another factor that differs between research subjects given an energy restriction and women with FHA is that women with FHA “voluntarily” restrict food and calorie intake. The restricted or irregular nutritional intake common in FHA likely indicates a disturbance in appetite and resistance to appetite signals. Ghrelin is a potent orexigenic signal secreted by the cells lining the gastric fundus. Ghrelin administration caused a negative energy balance that decreased GnRH/LH drive and increased cortisol in female rhesus monkeys. Vulliemoz and colleagues used this paradigm to assess the effects of CRH blockade on the effects of energetic challenge caused by ghrelin administration. Astressin B, a CRH receptor antagonist, blocked the reduction of GnRH/LH pulsatility and increased cortisol secretion when coadministered with ghrelin [30]. Interestingly, women with anorexia nervosa have elevated ghrelin levels elicited by chronic energy deprivation, yet they eat less when given ghrelin exogenously [31], indicating “appetite allostasis” or resistance to appetite signals. These results highlight the link between HPA activation and reproductive dysfunction and reinforce the concept that a combination of stressors more potently activates the HPA axis with concomitant neuroendocrine, including reproductive, consequences. These results invalidate the false dichotomy fostered by the question whether reproductive compromise is due to energy deficit vs. psychogenic challenge because in real life these types of stressors travel together [29].

The clinical significance of finding synergism between metabolic/energetic imbalance and psychosocial challenge is that recovery from FHA requires amelioration of energetic imbalance, but not necessarily weight gain, as well as psychosocial support and cognitive restructuring. Further, if FHA is an allostatic state attributable to psychophysiological and behavioral responses to stress that synergistically activate central neuroregulatory networks to concomitantly alter metabolism and suppress the central reproductive axis (GnRH/LH drive), then the neuroendocrine concomitants should reverse when the interaction between energy insufficiency and psychosocial challenge is interrupted. Given that sustained decrements in estradiol, increased cortisol, and subclinical hypothyroidism are likely to negatively impact long-term health for the individual and, through epigenetic mechanisms, fetal development if fertility is induced via reproductive technologies, we sought to determine if FHA could be reversed.

Potential Health Implications of FHA

Increased HPA axis activity is triggered by a variety of different stressors such as restraint or isolation stress, energy depletion, surgery, and psychosocial stress [3233]. When stress is defined as the anticipation of an adverse or dangerous situation that exceeds individual coping capacities [34], the ability to delay reproduction until conditions are more favorable makes sense. A decrease in GnRH drive results in a corresponding reduction of pituitary secretion of the gonadotropins LH and FSH and thus reduces the signals for follicle development and ovulation. Correspondingly, follicles make less estradiol and progesterone, which reduces endometrial stimulation and results in amenorrhea. When the HPA axis is chronically activated and results in FHA, the associated estrogen deficiency carries negative health consequences for nonreproductive tissues and heightens the risk for osteoporosis, CVD, and psychiatric syndromes, Table 10.1.

Table 10.1

Putative health consequences associated with functional hypothalamic hypogonadism

Systemic consequences

Reproductive consequences

Osteoporosis

Infertility

Psychiatric syndromes

Preterm labor

Neurodegenerative conditions

Intrauterine growth restriction

Cognitive impairment

Compromised fetal neurodevelopment

Cardiovascular disease (CVD)

Compromised parenting

Certainly, bone accretion is compromised in FHA [6], and bone accretion is not readily restored by oral contraceptive use in this context [3538]. The lack of effectiveness is likely a consequence of chronic or intermittent catabolism and/or hypercortisolism blocking the positive effect of sex steroids upon bone accretion. This topic is being addressed in greater detail in another section of this text, but suffice it to say that bone accretion is only possible when an individual is in an anabolic state and sex steroids alone will not reverse catabolism.

We recently found that CSF cortisol concentrations are significantly elevated in women with FHA [10], and this observation raises concern of heightened risk for neurodegenerative disease and dementia [39] as well as other potential health burdens [4041]. Further, premenopausal hypogonadism alone, independent of cause, has been linked to an increased late-life risk of depression, Parkinson disease, and dementia [4243]. In women with functional hypothalamic hypogonadism who conceive, hypothyroxinemia carries a risk of poor fetal neurodevelopment [4445]. Further, maternal stress [4648] and even brief undernutrition [49] increases the risk of preterm delivery and intrauterine growth restriction. For comprehensive reviews, please refer to Ditzen et al. [50]. What is less often appreciated is the impact of chronic hypoestrogenism coupled with increased cortisol on the cardiovascular system in women with FHA.

CVD is the leading cause of death in women in the USA and more women die from CVD than men. There are two forms of reproductive compromise that increase the risk of CVD, PCOS, and FHA. PCOS is a complex chronic condition associated with oligomenorrhea, hyperandrogenism, and metabolic syndrome, including dyslipidemia and insulin resistance. Women with PCOS display increased risk factors for CVD that are evident at younger age as compared to women with normal menstrual history [51], and these risk factors appear to be associated with the endocrine milieu rather than the appearance of polycystic ovaries on ultrasound evaluation [52]. Conversely, while women with FHA do not have the metabolic syndrome phenotype, they have chronic stress, undernutrition, and hypoestrogenism. Kaplan et al. have demonstrated that monkeys with mild subclinical ovarian compromise related to social subordination have an increased risk of CVD [253]. The monkey model raises concern that women with longstanding FHA may be at increased risk for premature or accelerated CVD.

Indeed, the Women’s Ischemia Syndrome Evaluation (WISE) study found a significant association between premenopausal angiographic coronary artery disease (CAD) and hypothalamic hypogonadism [54]. On further analysis, it was found that premenopausal women with both hypothalamic hypogonadism and diabetes had more extensive angiographic CAD than those with either diabetes or hypothalamic hypogonadism alone [55]. Low levels of gonadotropins in this study population argue against underlying PCOS as a contributor to the observed effect. Endothelial function has also been shown to be compromised in women with exercise amenorrhea [56]. O’Donnell et al. recently showed that women athletes with chronic hypoestrogenemia displayed impaired peripheral vascular function that was combined with lower resting blood pressures and heart rate and reduced ischemic responses to occlusion challenge compared to ovulatory exercising and ovulatory sedentary women [57]. These observations substantiate the importance of cyclic ovarian function as an indicator of overall health and wellbeing. When the internal and external environments are sufficiently stressful so as to disrupt systems mediating reproductive alignment, acute and chronic health risks accrue to the individual and future generations. Approaches that address the whole patient, identify and ameliorate stress, and promote balance are warranted as these will likely have the greatest impact on overall health.

Treatment Considerations

As depicted in Fig. 10.1, most functional hypothalamic hypogonadism in women is subclinical and may only come to clinical attention when there is unexplained infertility or when the menstrual interval is markedly short, long, very irregular, or absent. Similarly, luteal insufficiency due to decreased GnRH/LH drive may only be detected when infertility results. Even then, it is difficult using standard office techniques to document intermittent anovulation or luteal insufficiency. It is thus reasonable to say that the more clinically evident the ovarian compromise, the greater the hypothalamic challenge and the more profound the associated HPA, HPT derangements, and sex steroid deprivation. The diagnosis of FHA can be made only by the exclusion of all other organic forms of secondary anovulation, including PCOS, premature ovarian failure, hyperprolactinemia, organic adrenal and thyroidal dysfunction, autoimmune enteropathies, and psychiatric causes.

As mentioned previously, FHA is more than an isolated disruption in central GnRH/LH drive. There is direct evidence of HPA activation in the systemic [1518] and central compartments [10] and allostatic adjustments in the thyroidal axis, specifically normal TSH levels despite significantly lower T3 and T4 levels [151821]. In women who were in the process of spontaneously recovering from FHA, cortisol levels were comparable to eumenorrheic ovulatory women, but LH pulsatility was not fully restored, and TSH levels were markedly elevated in the face of persistent reductions in T3 and T4 levels [1821]. We recently compared metabolic variables in women who did and those who did not recover from FHA after a course of CBT [58]. Taken together, these findings suggest that the thyroidal axis remains restrained by an as yet uncharacterized factor(s) after HPA and HPO recovery or recovers more slowly than the HPA and HPO axes.

The conventional therapy for women with FHA is oral contraceptives when fertility is not desired and ovulation induction or assisted reproduction when it is. These approaches address the symptoms of amenorrhea and infertility but do not address the underlying allostatic adjustments of the adrenal and thyroidal axes. Thus, women with FHA treated with hormone replacement remain at increased risk for bone loss and cardiovascular effects related to chronic activation of the HPA, hypothalamic hypothryroidism and hypoestrogenism [6353659].

Alternatively, if a woman with functional hypothalamic hypogonadism is seeking to become pregnant, ovulation induction can be accomplished technically with exogenous administration of pulsatile GnRH therapy [6061] or exogenous administration of gonadotropins. The obvious advantage of exogenous GnRH therapy is that it diminishes the risk of ovarian hyperstimulation and multiple gestations associated with gonadotropins; however, it is no longer available. Clominphene citrate may not be an effective strategy because it has a hypothalamic site of action, and the ­hypothalamus is not normoresponsive to estrogen feedback [11]. There also is some concern that ovulation induction may place women with FHA at risk for premature labor and intrauterine growth retardation [62]. The parenting skills of women with FHA may be impaired because they are already overwhelmed and stressed prior to pregnancy and delivery and thus their children may be at risk for poor psychosocial development [63]. Further, children born to mothers with clinically occult autoimmune hypothyroidism had a mean full-scale intelligence quotient that was 7 points lower than the control population [44]. The women with clinically occult hypothyroidism had a 30% reduction in thyroxine, which is roughly what is observed in women with FHA. These findings are explained by the fact that maternal thyroxine is the only source of fetal thyroxine in the first trimester and the predominant fetal source in the second and third trimesters. Appropriate thyroxine is required for fetal neurogenesis and even small decrements may induce neurodevelopmental deficits. Increased maternal cortisol may also have independent effects upon fetal neurodevelopment and organogenesis. Recent evidence showed that severe stress such as that associated with the unexpected death of a child increased the risk of congenital anomalies of the cranial neural crest eightfold [47]. Further, stress and its endocrine concomitants have been implicated as a cause of preterm delivery. It is not known if the endocrine concomitants associated with FHA pose a similar risk, but this is clearly a potential hazard if ovulation induction is undertaken before amelioration of the allostatic changes in the adrenal and thyroidal axes.

Although psychopharmacologic approaches have not been well studied, they probably could be used on an interim basis in special circumstances. The study of Judd suggested that a short course of alprazolam might be effective in reducing HPA activation and permitting hypothalamic–pituitary–ovarian recovery [64]. However, this approach would not be the best for a woman hoping to conceive because of the risk of fetal exposure to benzodiazepines. The optimal intervention is to interdict the stress process so that the hypothalamus recovers and gonadal function resumes. An integral goal of the treatment plan for women with functional hypothalamic hypogonadism is to help them identify and ameliorate the sources of psychogenic and metabolic stress and to provide emotional support while coping mechanisms other than nutrient restriction or exercising are learned. Nonpharmacologic interventions, such as stress management, relaxation training, or psychoeducation, empower individuals by fostering self-care and competency. In this regard, nonpharmacologic therapies have the potential to produce long-term benefits upon psychological, and thereby, physical health. Behavioral therapies acknowledge the wisdom of the body and recognize that FHA represents an endocrine adaptation that can be reversed with appropriate psychogenic and behavioral modifications.

Given these considerations, we recently studied whether CBT aimed at ameliorating problematic attitudes and behaviors would permit reproductive recovery in normal weight women with FHA [65]. Women with FHA were randomized to observation vs. CBT. CBT focused on attitudes rather than behaviors. The program consisted of 16 individual sessions over 20 weeks. Participants met with a trained master’s level clinician, a research dietitian, and a reproductive endocrinologist. The sessions occurred in three overlapping stages intended to (1) define healthy eating and exercise patterns; (2) identify stress-enhancing behaviors and guide the participant in developing ­strategies and problem solving skills to reduce stress; and (3) reinforce strategies and plans for resolving stress and avoiding relapse once CBT concluded [65]. Women in both the observation and CBT groups were followed for the return of menses for up to 8 weeks following the intervention. Regardless of menstrual pattern, estradiol and progesterone levels were monitored at weekly intervals for 4 weeks before and after observation vs. CBT. About 88% of those who underwent CBT had evidence of ovulation, whereas only 25% of those who were observed did. Figure 10.2 shows sex steroid secretion in a woman treated with CBT who showed ovarian recovery contrasted with those in a woman randomized to observation who did not have the recovery of ovarian function. Interestingly, when it occurred, ovarian recovery was not associated with significant weight gain. This does not mean that subjects did not alter food intake or energy expenditure, however. Once stress and undernutrition are reduced, the thyroidal axis may increase basal metabolic rate, allowing greater food intake without weight gain.

A978-1-60327-864-5_10_Fig2_HTML.gif

Fig. 10.2

Serum levels of ovarian hormones (estradiol open circle) and (progesterone filled square) and episodes of vaginal bleeding (red filled circle) in a woman with functional hypothalamic amenorrhea (FHA) who was observed and did not recover (top) compared to a woman with FHA who was treated with cognitive behavior therapy (CBT) and recovered (lower). Adapted from Berga et al. (2003) [65]

Persistent HPA activation, which elevates CSF cortisol more than circulating cortisol levels, [10] carries long-term health risks for the woman and, should she conceive, for the fetus [4648]. Increased cortisol is one of the factors that suppresses the thyroidal axis. As the mother is the sole source of thyroxine for the fetus during the first and the predominant source during the second and third trimester, the clinician should consider that assisted reproduction presents an unrecognized fetal risk because persistent hypothalamic hypothyroidism may compromise fetal neurodevelopment [4445]. Further, psychosocial stress [4648] and even brief undernutrition [49] increases the risk of preterm delivery and intrauterine growth restriction. In contrast, CBT offers a focused therapeutic option that avoids medical risks and costs associated with ovulation induction and assisted reproduction while at least partially reversing neuroendocrine allostasis. Since the effect of CBT accrues with time while that of pharmacologic interventions does not, CBT should be a mainstay of intervention for stress-related infertility and FHA even if it is not the only therapy the patient receives.

Conclusion

While stress is generally categorized as psychogenic or metabolic, strictly speaking, these are not separable entities. Further, the impact of chronic stress is not limited to the reproductive axis. Adjustments in other systems, specifically HPA and HPT axes occur concomitantly. The health burden of chronic stress puts individuals at increased risk for osteoporosis, CVD, and mental health impairments such as mood disorders, migraines, and insomnia. Thus, when evaluating the patient with hypothalamic amenorrhea, consideration must be given to both long-term and short-term consequences. Behavioral treatments are directed toward amelioration of the underlying stress, are effective, and will likely have a greater positive impact on overall health than pharmacologic approaches.

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