Amenorrhea. A Case-Based, Clinical Guide

8. The Role of Body Weight in Menstrual Disturbances and Amenorrhea

Alex J. Polotsky  and Nanette Santoro

(1)

Department of Obstetrics and Gynecology, University of Colorado Denver School of Medicine, Aurora, CO, USA

Alex J. Polotsky

Email: Alex.Polotsky@ucdenver.edu

Abstarct

In normal weight women, a 10–15% reduction from ideal body weight (IBW) is associated with amenorrhea [12]. There is considerable interindividual variation in the menstrual cycle manifestations that may occur in association with low body weight. It is likely that the key element involved in eating disorders or low weight related amenorrhea is stress. It appears that the adaptation to the chronic stress involved in food restriction plays a major role. Additives to the low body weight are excessive exercise and a somewhat “driven” personality style. These attributes lead to chronic activation of the adrenocorticotrophic axis and elevated cortisol and corticotrophin releasing factor (CRF) [3]. The end result is functional hypothalamic amenorrhea (FHA), although less severe conditions appear to exist. For example, women who undergo rapid, intense exercise training, and mild dietary restriction will develop a luteal phase defect cycle phenotype, with lengthening of the menstrual cycle, but eventual folliculogenesis and ovulation (albeit with low levels of luteal progesterone secretion and a shortened luteal phase [4]). In many clinical scenarios, it is impossible to separate the relative contributions of body weight, body fat, perceived stress, and exercise to the amenorrhea or menstrual disturbances. This chapter focuses primarily on body weight and body fat as determinants of normal reproductive function.

Low Body Weight and Menstrual Disturbances

In normal weight women, a 10–15% reduction from ideal body weight (IBW) is associated with amenorrhea [12]. There is considerable interindividual variation in the menstrual cycle manifestations that may occur in association with low body weight. It is likely that the key element involved in eating disorders or low weight related amenorrhea is stress. It appears that the adaptation to the chronic stress involved in food restriction plays a major role. Additives to the low body weight are excessive exercise and a somewhat “driven” personality style. These attributes lead to chronic activation of the adrenocorticotrophic axis and elevated cortisol and corticotrophin releasing factor (CRF) [3]. The end result is functional hypothalamic amenorrhea (FHA), although less severe conditions appear to exist. For example, women who undergo rapid, intense exercise training, and mild dietary restriction will develop a luteal phase defect cycle phenotype, with lengthening of the menstrual cycle, but eventual folliculogenesis and ovulation (albeit with low levels of luteal progesterone secretion and a shortened luteal phase [4]). In many clinical scenarios, it is impossible to separate the relative contributions of body weight, body fat, perceived stress, and exercise to the amenorrhea or menstrual disturbances. This chapter focuses primarily on body weight and body fat as determinants of normal reproductive function.

Case 1

Your next patient is L.G., a 21-year-old college student, who has not had any menstrual bleeding for the last 6 months. She admits to “issues” with eating in the past but denies any active food restriction or excessive exercise. Her weight is 99 pounds; height is 5 ft. 2 in. A pregnancy test is negative.

Eating Disorders – Definition

Body mass below 15% of IBW is one of the diagnostic criteria for anorexia nervosa as defined by the DSM-IV [5]. While the concept of IBW originally came from actuarial life insurance tables and represents the presumably healthiest body mass for given weight [6], BMI) is the most practical and widely acceptable way to assess the degree of deviation from normal, as it is indexed to height and thus the normal BMI range is the same for adults of any size. BMI is easily calculated as the ratio of the body mass in kilograms and square of height in meters. A voluntary BMI threshold below 17.5 kg/m2 is one of the defining characteristics of anorexia nervosa based upon the ICD-10 diagnostic criteria [7]. Other mandatory diagnostic criteria include distorted body image, menstrual dysfunction and fear of weight gain (Table 8.1). Whereas, DSM-IV defines two additional eating disorders such as bulimia nervosa and “eating disorder not otherwise specified,” anorexia is the only entity that is associated with abnormally low body weight and menstrual dysfunction.

Table 8.1

DSM-IV diagnostic criteria for anorexia nervosa

Failure to maintain body weight around a minimally normal age- and height-adjusted weight (i.e., body weight less than 85% of that expected for age and height)

Fear of gaining weight or becoming fat, even if inconsistent with current weight

Distorted body image

Absence of three or more spontaneous consecutive menstrual cycles in postmenarcheal females

Adapted from American Psychiatric Association [5]

Epidemiology of Eating Disorders and Weight-Related Amenorrhea

It has been estimated that up to 1% of the population suffers from restrictive eating disorders [8]. However, the true prevalence of these conditions is probably underestimated as the data are notoriously fraught with methodological problems related to the changing diagnostic criteria and inherent difficulties of self-report [9]. These disorders can take several forms, and appear to have varying relationships to amenorrhea. Common features of eating disorders include an array of attitudes about food, fear of certain foods (because they are believed to cause fatness), body image distortion, and fear of fatness.

The long-term sequelae of FHA and, more broadly, amenorrhea caused by low body weight are only recently beginning to be recognized. Data from the Women’s Ischemia Syndrome Evaluation (WISE) study revealed that women with FHA had a 69% prevalence of coronary heart disease as compared to 29% in those without this condition [10]. This profoundly detrimental impact of menstrual irregularities on overall health is not well appreciated by patients and practitioners alike. More effort is needed to understand the mechanisms underlying the pathophysiology of this association as well as increasing the public awareness of this entity and some potential remedies designed to reverse the pathological chain of events.

Clinical Presentation

The clinical appearance of women with anorexia nervosa includes the following features: lanugo hair; orange-tinted skin (due to elevated circulating carotenoids), a low resting pulse rate, often in the 50s or even 40s (bpm); brittle nails, thinning hair, and an absence of the patient’s concern about her emaciated state. Such patients often come to the office accompanied by a concerned relative, usually a parent, and appear to lack an understanding of the fact that they are a cause of concern. The clinical history typically consists of an initial attempt at voluntary weight loss that has now become uncontrollable. The patient is frequently in denial of her behaviors, but family members will often describe extreme food restriction, with consumption of as little as 400 calories a day. To make matters worse, many such women will exercise compulsively out of a worry that they will become overweight if there are any lapses in their vigilance. If queried about their appearance, women in the throes of anorexia nervosa fail to recognize that they are excessively and even dangerously thin. They will express a belief that their body size is “normal” or even a little bit overweight. More savvy patients, who may wish to avoid confrontation, will sometimes conceal this striking body image distortion.

Hypothalamic–pituitary function in anorexia nervosa is similar to that observed in any state of starvation, involuntary or voluntary. It is helpful to conceptualize it as a reaction to the lack of nutrient availability. Thyroid hormone is typically low, with elevated reverse T3, to reduce the metabolic rate. TSH, however, remains in the normal range. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are often abnormally low, although they may be within the normal range, due to their inherent pulsatility. Estradiol is typically undetectable. Unlike patients with panhypopituitarism, the somatotrophic and adrenocorticotrophic axes are constitutively activated in women with anorexia. Dynamic pituitary testing is rarely necessary, as the diagnosis is often obvious based on the constellation of signs, symptoms and behaviors.

Women with bulimia are less likely to be underweight and may manifest some, but not all of the features of anorectics. Additional clinical signs of bulimia include erosion of tooth enamel from self-induced vomiting and esophageal damage.

Pathophysiology

Classically, anovulation associated with abnormally low body mass has been linked with WHO anovulation Class I or hypogonadotropic hypogonadism [11]. The mechanisms for impairment of the hypothalamic discharge of GnRH in these cases have been partially elucidated. Caloric restriction or intensive physical activity that exceeds intake produces a reduction in central neural drive of the GnRH pulse generator [212] that is tightly associated with reductions in circulating plasma glucose [13] and increased R (“reverse”)T3 [14]. In animal models, hypoglycemia rapidly induces GnRH inhibition, but this inhibition is much more easily elicited in men than in women [15]. Up to 72 h of starvation in normal weight women has not been shown to induce changes in the hypothalamic GnRH pulse generator, as assessed by the measurement of peripheral LH secretion [16]. However, a recently developed animal model of chronic stress [17] provides insight into the combination of mechanisms that contribute to hypothalamic amenorrhea and suggests that both a combination of stressors and an inherent vulnerability to such stressors are necessary to induce menstrual disturbances. In this model, cynomologus monkeys are subjected to mild caloric restriction that does not result in weight loss but reduces the metabolic rate (20% reduction in daily chow). In addition, to mimic the extra energy expenditure in many women with hypothalamic amenorrhea and anorexia nervosa, the animals are trained to run on treadmills for a specified period of time each day. Finally, to create chronic psychogenic stress, the animals are subjected to frequent changes of their cage location, such that unfamiliar animals often surround them. This latter series of experiments highlights in an elegant fashion that the combination of stressors and the susceptibility of the individual help create the amenorrheic phenotype. In the case of restrictive eating, the primary stress may be low body weight and body fat, but the additional components of psychic stress and further energy drainage through exercise are also often present.

Leptin deficiency has been shown to play an important role in hypothalamic amenorrhea. Welt et al. [18] administered recombinant leptin to women with FHA and was able to restore gonadotropin pulsatility (8/8 women) and menstrual cyclicity (3/8 women) along with restoration of normal free T3 and T4. Thus, the low leptin levels in women with weight-loss associated amenorrhea or menstrual disturbances appear to provide the metabolic communication to the central hypothalamic–pituitary axis that reproduction should be switched off, due to a lack of available nutrients. Although the aforementioned experiment provides great insight into the pathophysiology and mechanisms responsible for hypothalamic amenorrhea, leptin does not constitute a credible treatment for the disorder, as its provision of a satiety signal leads to further weight loss if given over a prolonged period of time.

Diagnostic Workup

Women suspected of restrictive eating disorders should undergo a thorough evaluation to exclude other alternative etiologies that may account for extreme thinness. Hyperthyroidism, malabsorption from ulcerative colitis, Crohn’s disease, or celiac disease can be ruled out by clinical history, physical examination, and laboratory testing as appropriate. As prudent for any evaluation of secondary amenorrhea, pregnancy must be excluded.

A major goal of the laboratory evaluation of a woman with anorexia nervosa is to rule out a potentially life-threatening emergency. The tragic case of Terry Schiavo was thrust in the public arena because of her family’s end-of-life issues. However, little attention was paid to the fact that the patient had reportedly suffered a cardiac arrest due to hypokalemia that was caused by an eating disorder [19]. This underscores the need to evaluate women with anorexia nervosa for electrolyte imbalances. An individual with a potentially life-threatening eating disorder may present to a primary care doctor for the treatment of menstrual irregularity and be reluctant to disclose her eating habits. Sadly, this appears to be exactly what transpired in Ms. Schiavo’s case and subsequently led to a $1 million settlement [20].

Once the diagnosis is established, the evaluation for associated comorbidities should be considered. Specifically, the measurement of bone density with dual X-ray absorptiometry may reveal important clinical information useful for the treatment and counseling [21].

Therapeutic Algorithms

Overcoming restrictive eating disorders should involve an approach directed at behavioral modification (Fig. 8.1). It is not sufficient to correct the sex steroid deficiency, although in some cases it may serve as a temporizing measure [22]. The long-term consequences of continuing to live in a state of chronic stress is likely related to the increased risk of heart disease in women with hypothalamic amenorrhea. Moreover, the bone density losses that such women often display may be related to chronic activation of their HPA axis and may not be amenable to estrogen replacement alone. Since eating disorders are often initially detected in the teenage years, cognitive behavioral therapy is recommended to lead to permanent change and true healing [23]. Hospitalization may become necessary if out-patient management fails to correct electrolyte imbalance and/or other serious medical or psychiatric complication are present [24]. Among outpatient measures, antidepressants have been found to be more efficacious for patients suffering from bulimia [25]. For anorexia nervosa, American Psychiatric Association recommends antidepressants solely for the prevention of relapse in weight restored patients or psychiatric comorbidities [26].

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Fig. 8.1

Evaluation of amenorrhea in women with low body mass

Obesity and Menstrual Disturbances

Case 2

Your next patient is B.G, a 34-year-old nulligravida, who has been trying to get pregnant for the past 2 years. She does not have any significant past medical or surgical history. Her husband’s semen analysis is normal. Hysterosalpingogram reveals bilaterally patent fallopian tubes. Her weight is 205; height is 5 ft. 2 in. She reports infrequent menstrual periods (3–4 per year); menstrual irregularity seems to have started after she gained about 100 pounds in college. She denies any excessive hair growth, has a normal ovarian appearance on ultrasound and does not have any biochemical evidence of hyperandrogenism. A pregnancy test is negative.

Defining Excess Body Mass

The World Health Organization (WHO) categorizes body mass by BMI into the following categories [27]:

·               Underweight – less than 18.5 kg/m2

·               Normal weight – 18.5–24.9 kg/m2

·               Overweight – 25.0–29.9 kg/m2

·               Class I obesity – 30.0–34.9 kg/m2

·               Class II obesity – 35.0–39.9 kg/m2

·               Class III obesity – greater than 40 kg/m2. This category is also sometimes referred to as severe, extreme, or morbid

Epidemiology of Obesity and Menstrual Dysregulation

The obesity epidemic in the United Sates is advancing at an ever-accelerating pace. Currently, 32% of U.S. adults are obese as defined by a BMI of greater than 30 kg/m2, according to the latest National Health and Nutrition Examination Survey [28]. It is estimated that by 2015, 75% of U.S. adults will be overweight or obese (BMI of greater than 25 kg/m2) and 41% will be obese [29]. Female adult obesity is associated with a variety of reproductive disturbances, including menstrual cycle irregularities, anovulation and a higher risk of obstetrical complications [30]. Recent data from the Study of Women’s Health Across the Nation (SWAN) indicate that increasing high school BMI is consistently and independently associated with reduced lifetime parity [31]. The relative risk of ovulatory infertility is tripled in women with BMI of greater than 27 kg/m2 compared to women with a normal BMI [32]. When compared with normal weight women, spontaneous abortion rates are higher in obese patients who conceive via either natural or assisted conception [3334]. Detrimental effects of obesity on performance in assisted reproductive technology are manifested by higher cycle cancellation, greater requirement for exogenous gonadotropins, and lower birth rates [3536]. Menstrual cycle irregularities are significantly more common with increasing body mass, a phenomenon that is often, but not exclusively, ascribed to anovulation [37].

Traditionally, reproductive effects of female adult obesity were attributed to increases in anovulation, amenorrhea, and hyperandrogenism [38]. Most of the existing body of literature concerning obesity and reproduction involves women with polycystic ovary syndrome (PCOS), a condition characterized by hyperandrogenemia and oligomenorrhea and, frequently, accompanying obesity [3941]. In obese women without PCOS, an influence of adiposity on reproductive outcomes has only recently attracted investigative attention. Obesity is detrimental to fertility even in women who are ovulatory. Obesity prolongs the time to pregnancy and is associated with decreased fecundity in women with regular menstrual cycles [4244]. An increase in waist-hip ratio of as little as 0.1 U was associated with a 30% decrease in the per cycle probability of conception in presumably reproductively normal women undergoing donor sperm insemination [45]. In a cohort of over 3,000 subfertile couples in whom the female partner was confirmed to be ovulatory, the probability of spontaneous conception declined with a BMI over 29 kg/m2 [46]. Multivariable analysis from the same study indicated that an increase in BMI by 1 unit resulted in a 4% reduction in the likelihood of conception [46].

Clinical Presentation

A typical presentation for obesity-related menstrual irregularity is a woman in her 30s who has been steadily gaining weight since adolescence. It is not uncommon that obesity is the only abnormal finding in an otherwise healthy individual. Prior conceptions and live births may have been attained, depending on the reproductive choice exercised by the patient. While long-standing hirsutism and oligoamenorrhea may be coincident with obesity and suggest the diagnosis of PCOS, the absence of such signs and symptoms may be indicative of so-called simple or nonsyndromic obesity [47].

Pathophysiology

Decreased central reproductive drive has been demonstrated in regularly cycling obese women. In the 1970s, when radioimmunoassay became widely available and was used to study day to day reproductive hormone secretion across the human menstrual cycle, obesity was first reported to be associated with long (>14 day) follicular phases and decreased serum gonadotropins and luteal progesterone [48]. In 1986, Grenman et al. examined the reproductive hormonal profile of a group of 25 obese women, and reported lower SHBG, estradiol, androstenedione, and LH in obese compared to normal weight women [49]. Notably, 24 of the 25 obese women reported were cycling regularly. In a large, community-based sample of midlife women from the SWAN study, increasing body size was associated with a greater prevalence of irregular and long menstrual cycles [50]. The latter study, a detailed evaluation of daily hormone patterns from 836 ovulatory cycles, indicated that overweight women (BMI >25 kg/m2) excreted significantly less urinary LH, FSH, and luteal progesterone metabolites; the association was weight dependent, with women in higher weight centiles excreting progressively less hormone. This relative hypogonadism of obesity may be potentially explained by either central (hypothalamic or pituitary) or peripheral (corpus luteum) defects within the hypothalamic–pituitary–ovarian (HPO) axis. In the studies of ovulatory, morbidly obese women indicate a significant reduction in LH pulse amplitude yet no change in LH pulse frequency compared to normal weight controls [51]. After bariatric surgery induced weight loss, a partial recovery of hypogonadotropic hypogonadism was observed [52].

While there are several potential molecules (reviewed in [53]) that communicate metabolic signals to the HPO axis, leptin has been studied most extensively. Leptin, initially described as a satiety factor [54], conveys an afferent signal to the CNS on the body’s fat status – a long-term indicator of nutrient availability. In humans, leptin levels are markedly elevated in obesity [55] and pregnancy [56], and are higher in women than in men [57]. The actions of leptin on the HPO axis are thought to have differential effects on the central and peripheral components of the reproductive system. In the CNS, leptin has been shown to modulate GnRH pulse frequency in vitro [58]. It does not act directly on GnRH neurons, but rather via indirect mechanisms through interneurons secreting hypothalamic neuropeptides, such as neuropeptide Y, galanin-like protein, MSH, and endogenous opioids (reviewed in [59]). In humans, leptin may interrupt normal oocyte maturation [60] and has been correlated with poor implantation potential [61]. The dual low-leptin/high-leptin mechanism has been proposed to take into account the complex nature of leptin-HPG axis interactions [62]. According to this theory, the predominant effect of leptin’s action on the HPG axis is determined by its concentration, whereby low leptin exerts a negative influence centrally and elevated leptin yields a negative effect peripherally at the gonadal and/or embryo level.

In 1970, Frisch and Revelle noted a direct relationship between body weight and age at the onset of puberty and concluded that a critical amount of body fat was needed for the onset of puberty [63]. While the original concept was based on the notion that a critical amount of body fatness is needed for menarche, it is not clear whether the degree of fatness causes menarche or whether an increase in body fat is the consequence of the onset of puberty, and the two findings may be coincidentally and independently related to endocrine or genetic factors. The exciting discovery of leptin as an indicator of fat mass gave rise to a speculation that it may represent the missing link in the Frisch hypothesis and thus serve as a trigger of pubertal development.

Leptin administration results in the reversal of pubertal arrest in leptin-deficient mice [64]. When given to normal prepubertal animals, leptin hastens sexual development as manifested by the advancement of vaginal opening [65]. Cheung et al. assessed the temporal sequence of pubertal events in rodents [6667] and showed that a rise in serum leptin did not precede pubertal development in rats. Similarly, the expression of leptin mRNA receptor in the hypothalamic of female mouse did not increase with pubertal development. Finally, the administration of leptin to starved animals advanced estrus as compared to food-restricted untreated controls, but first estrus occurred at the same time as mice fed ad libitum. Taken together, these results imply that leptin appears to provide a necessary input of adequacy of energy stores to the brain, and is capable of authorizing but not initiating progression to puberty. Thus, both animal and human data support the notion that leptin is necessary but not sufficient metabolic signal for the reproductive axis.

Diagnostic Workup

It is prudent to exclude other causes for menstrual irregularities before assigning the cause to obesity per se. Evaluation should be targeted to common etiologies, such as premature ovarian insufficiency, PCOS, prolactin, and thyroid abnormalities. Once the diagnosis is confirmed, attention should be paid to proper counseling. It is important to exercise care in avoiding punitive attitudes toward obesity that may discourage the patient and hinder compliance. Patients should be educated on the increased risk obesity poses for congenital anomalies, including neural tube defects and cardiovascular anomalies [68] as well spontaneous abortion [69] and obstetrical complications such as gestational diabetes, cesarean section, preeclampsia, and fetal macrosomia [70].

Therapeutic Algorithms

While exogenous gonadotropins and assisted reproductive technologies are the efficient ways to achieve ovulation and conception in many women, the first line of therapy should be directed at the root of the problem, i.e., large body mass, rather than its consequences (Fig. 8.2). Several investigators have addressed the beneficial effects of weight loss on fertility [7173]. Few of these studies included long-term follow-up or large numbers of subjects, yet it seems reasonable to support even modest weight reduction in the obese due to the indisputable benefits for overall health. The precise amount of the recommended weight loss that may result in the reversal of menstrual irregularities is unknown and is likely subject to wide intrapersonal variance. However, some studies suggest that as little as 5% weight loss may lead to an increased likelihood of conception. One uncontrolled study of a diet and exercise program in infertile women found that approximately 6% weight loss over 36 months resulted in pregnancy in 29 out of 37 subjects [72]. A recent systematic review of pregnancies after bariatric surgery revealed a decrease in prenatal complications and improved neonatal outcomes [74]. While bariatric surgery is understandably limited to the more extreme excesses of body mass, the decreased perinatal morbidity of women who lose weight prior to conception deserves further scientific scrutiny. More research is needed on the effects of modest weight reduction on fertility, as obesity represents one of the few modifiable factors that may be amenable to conservative management.

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Fig. 8.2

Evaluation of amenorrhea in women with high body mass

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