Body Fat, Leptin, and Hypothalamic Amenorrhea
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《新英格兰医药杂志》
Hypothalamic amenorrhea can be defined as the cessation of menstruation due to a dysfunction of hypothalamic signals to the pituitary gland, resulting in a failure of ovulation. Typically, young women who are affected by the condition have no obvious structural abnormalities of the hypothalamus or the rest of the brain, pituitary gland, or ovaries. The common type of hypothalamic amenorrhea (also called functional amenorrhea) is a diagnosis of exclusion. Hyperprolactinemia, primary deficiency of gonadotropin-releasing hormone, and other hormonal abnormalities must be ruled out. Affected women are reportedly more likely to be underweight, athletic, engaged in "intellectual" professions, or exposed to social stress than women without the disorder.
Hypothalamic amenorrhea may be preceded by a history of irregular menses and may last several months to years. When it occurs in association with weight loss or intense exercise, hypothalamic amenorrhea is considered to result from energy deficiency. Deficits in nutrients, hormonal perturbations, or both may signal to the brain, leading to the disruption of the pulsatile secretion of gonadotropin-releasing hormone and luteinizing hormone as well as of the menstrual cycle. On the other hand, hypothalamic amenorrhea has also been described in nonathletic women of normal weight — a variant that may be associated with psychogenic factors such as stressful life events or adverse childhood experiences. Moreover, psychogenic amenorrhea, like exercise-related amenorrhea, has been associated with subtle deficits in calorie and macronutrient intake, as well as with neuroendocrine abnormalities. Thus, a central signal related to energy deficit may be the common factor underlying the two forms of hypothalamic amenorrhea (see Table).
Table. Comparison of Functional Amenorrhea with Psychogenic Amenorrhea and Anorexia Nervosa.
Hormonal evaluation in women with functional amenorrhea often reveals a reduction in the mean and pulsatile gonadotropin secretion and a diminished estradiol concentration during the early follicular phase of the menstrual cycle. Other hormonal abnormalities may include a slight increase in the cortisol level and a suppression of thyrotropin and thyroid hormone. Osteopenia may be present, though it is not clear whether it results from hormonal or nutritional deficiency.
Although chronic anovulation in anorexia nervosa may resemble an extreme form of functional amenorrhea, there are distinct differences. Functional amenorrhea is not associated with starvation, wasting, distorted attitudes toward food, or altered body image, as anorexia nervosa characteristically is (see Table). Moreover, anorexia nervosa is also associated with hormonal and metabolic features suggesting more severe hypothalamic dysfunction — for example, abnormal responses to heat and cold, bradycardia, suppression of triiodothyronine, increased levels of reverse triiodothyronine that are consistent with starvation, and mild diabetes insipidus. The basal cortisol level is typically elevated, although the diurnal secretory rhythm is preserved. Osteopenia is very common in anorexia nervosa.
Adequate nutrition has long been considered to be a critical determinant of normal reproductive function, given epidemiologic studies showing a close association between greater body weight or body fat and a younger age at menarche as well as increased fertility. These findings are supported by experiments showing close correlations of nutrition with estrous cycles, puberty, and fecundity in animals. Frisch proposed that a critical amount of body fat was essential for achieving and maintaining normal reproductive function; however, the nature of the signal or signals linking fat to the hypothalamic–pituitary–gonadal axis remained elusive.1 After the discovery of leptin, studies suggested that this adipocyte hormone was the long-sought factor linking energy stores to reproduction.2,3 The leptin concentration increases with obesity and decreases rapidly during fasting, making it an ideal sensor of energy deficiency. Leptin receptors are present on hypothalamic neurons that control energy balance and reproductive function. Leptin regulates the synthesis and secretion of gonadotropin-releasing hormone, gonadotropins, and sex steroids.
As predicted, congenital leptin deficiency results in voracious feeding and morbid obesity — effects that are consistent with a failure of negative-feedback regulation. Moreover, leptin deficiency results in hypothalamic hypogonadism and central hypothyroidism. In rodents, leptin deficiency elevates the levels of glucocorticoids. Leptin treatment reverses these abnormalities, confirming the crucial role of this hormone in energy homeostasis and neuroendocrine function. The decrease in leptin levels during fasting mediates the suppression of reproductive, thyroid, and growth hormones and the elevation in glucocorticoid levels, in addition to stimulating food intake and limiting energy expenditure. This leptin-mediated response to fasting may have evolved to provide a defense against the threat of starvation by limiting the high-energy cost of reproduction, growth, and thyroid thermogenesis, while stimulating food intake and energy storage.2 Further evidence of a link among energy stores, leptin, and reproduction has come from patients with lipodystrophy, a condition characterized by the loss and redistribution of body fat; low leptin levels; hypothalamic amenorrhea; the accumulation of triglycerides in liver, muscle, and other tissues (steatosis); hyperlipidemia; severe insulin resistance; and diabetes.4 In addition to reversing the metabolic derangements, leptin stimulates gonadotropin and estradiol secretion and normalizes menstrual cycles, despite a further decrease in body fat.4
This early work provided a rationale for examining the role of leptin in hypothalamic amenorrhea, and Welt et al. report the results of such a study in this issue of the Journal (pages 987–997). Patients with hypothalamic amenorrhea due to underweight or strenuous exercise were treated with recombinant human leptin twice daily for three months, with 40 percent of the dose taken at 8 a.m. and 60 percent taken at night, to mimic the diurnal variation in plasma leptin levels. Patients maintained their accustomed food intake, exercise habits, and lifestyle. Leptin treatment increased the mean and pulsatile luteinizing hormone levels, resulted in a concomitant enlargement of the ovaries, increased the number and size of dominant follicles, and raised the estradiol concentration. Three of the eight patients had ovulatory menstrual cycles with this therapy, and preovulatory follicles associated with withdrawal bleeding developed in two others. Furthermore, the levels of free triiodothyronine and thyroxine, insulin-like growth factor 1, insulin-like growth factor–binding protein 3, and bone alkaline phosphatase and osteocalcin were increased by leptin therapy. Body fat was substantially reduced by leptin therapy, although food intake and energy expenditure were not affected.
The study by Welt et al., though limited in size and duration, suggests that leptin is important in mediating the neuroendocrine abnormalities of hypothalamic amenorrhea. Leptin administration increased the levels of reproductive, thyroid, and growth hormones, without apparent adverse effects. The failure of leptin therapy to reverse amenorrhea in three subjects appeared to be influenced by low baseline leptin levels, rather than by a longer duration of amenorrhea. Although the levels of markers of bone formation were increased by leptin therapy, the relevance of these markers to the health of bone in patients with hypothalamic amenorrhea is unclear.
These results are consistent with findings in other leptin-deficient states, but questions remain. Does leptin mainly regulate the levels of gonadotropin-releasing hormone and luteinizing hormone, or does it affect ovarian steroids directly? Can the response to leptin be potentiated by improvement in nutrition and a decrease in exercise? Will pulsatile leptin treatment be more effective in reversing hypothalamic amenorrhea? Will leptin supplementation be effective in women of normal weight who have psychogenic amenorrhea? Can the link among body fat, leptin, and reproduction serve as a model for understanding the so-called thrifty genotype, which seems to be intended to maximize energy efficiency? How safe and effective will treatment with recombinant leptin be in the long term? Will the loss of body fat trigger adverse metabolic changes?
Basic science only occasionally reshapes our understanding of major biologic systems as quickly and profoundly as the discovery of leptin has done. The effect of leptin on reproduction was demonstrated in rodents two years after the discovery of the leptin gene and was subsequently confirmed in humans.2,3 The study by Welt and colleagues represents a further step in unraveling the role of leptin in reproduction and neuroendocrine regulation. In addition to storing triglycerides, adipose tissue produces and secretes various hormones that are actively involved in energy balance and diverse physiological systems. An understanding of this complex biology is crucial for elucidating the pathogenesis and potential treatment of diseases, such as obesity, that result from energy imbalance. Thanks to recent advances in the knowledge of the molecular biology of adipose tissue, patients with hypothalamic amenorrhea, a disease that was first described in the 1940s and was poorly understood for decades, may finally benefit from a rebirth of investigation leading to rational therapy.
Dr. Ahima reports having received a consulting fee from Procter & Gamble Pharmaceuticals.
Source Information
From the Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia.
References
Frisch RE. The right weight: body fat, menarche and ovulation. Baillieres Clin Obstet Gynaecol 1990;4:419-439.
Ahima RS, Prabakaran D, Mantzoros C, et al. Role of leptin in the neuroendocrine response to fasting. Nature 1996;382:250-252.
Chan JL, Heist K, DePaoli AM, Veldhuis JD, Mantzoros CS. The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. J Clin Invest 2003;111:1409-1421.
Oral EA, Ruiz E, Andewelt A, et al. Effect of leptin replacement on pituitary hormone regulation in patients with severe lipodystrophy. J Clin Endocrinol Metab 2002;87:3110-3117.(Rexford S. Ahima, M.D., P)
Hypothalamic amenorrhea may be preceded by a history of irregular menses and may last several months to years. When it occurs in association with weight loss or intense exercise, hypothalamic amenorrhea is considered to result from energy deficiency. Deficits in nutrients, hormonal perturbations, or both may signal to the brain, leading to the disruption of the pulsatile secretion of gonadotropin-releasing hormone and luteinizing hormone as well as of the menstrual cycle. On the other hand, hypothalamic amenorrhea has also been described in nonathletic women of normal weight — a variant that may be associated with psychogenic factors such as stressful life events or adverse childhood experiences. Moreover, psychogenic amenorrhea, like exercise-related amenorrhea, has been associated with subtle deficits in calorie and macronutrient intake, as well as with neuroendocrine abnormalities. Thus, a central signal related to energy deficit may be the common factor underlying the two forms of hypothalamic amenorrhea (see Table).
Table. Comparison of Functional Amenorrhea with Psychogenic Amenorrhea and Anorexia Nervosa.
Hormonal evaluation in women with functional amenorrhea often reveals a reduction in the mean and pulsatile gonadotropin secretion and a diminished estradiol concentration during the early follicular phase of the menstrual cycle. Other hormonal abnormalities may include a slight increase in the cortisol level and a suppression of thyrotropin and thyroid hormone. Osteopenia may be present, though it is not clear whether it results from hormonal or nutritional deficiency.
Although chronic anovulation in anorexia nervosa may resemble an extreme form of functional amenorrhea, there are distinct differences. Functional amenorrhea is not associated with starvation, wasting, distorted attitudes toward food, or altered body image, as anorexia nervosa characteristically is (see Table). Moreover, anorexia nervosa is also associated with hormonal and metabolic features suggesting more severe hypothalamic dysfunction — for example, abnormal responses to heat and cold, bradycardia, suppression of triiodothyronine, increased levels of reverse triiodothyronine that are consistent with starvation, and mild diabetes insipidus. The basal cortisol level is typically elevated, although the diurnal secretory rhythm is preserved. Osteopenia is very common in anorexia nervosa.
Adequate nutrition has long been considered to be a critical determinant of normal reproductive function, given epidemiologic studies showing a close association between greater body weight or body fat and a younger age at menarche as well as increased fertility. These findings are supported by experiments showing close correlations of nutrition with estrous cycles, puberty, and fecundity in animals. Frisch proposed that a critical amount of body fat was essential for achieving and maintaining normal reproductive function; however, the nature of the signal or signals linking fat to the hypothalamic–pituitary–gonadal axis remained elusive.1 After the discovery of leptin, studies suggested that this adipocyte hormone was the long-sought factor linking energy stores to reproduction.2,3 The leptin concentration increases with obesity and decreases rapidly during fasting, making it an ideal sensor of energy deficiency. Leptin receptors are present on hypothalamic neurons that control energy balance and reproductive function. Leptin regulates the synthesis and secretion of gonadotropin-releasing hormone, gonadotropins, and sex steroids.
As predicted, congenital leptin deficiency results in voracious feeding and morbid obesity — effects that are consistent with a failure of negative-feedback regulation. Moreover, leptin deficiency results in hypothalamic hypogonadism and central hypothyroidism. In rodents, leptin deficiency elevates the levels of glucocorticoids. Leptin treatment reverses these abnormalities, confirming the crucial role of this hormone in energy homeostasis and neuroendocrine function. The decrease in leptin levels during fasting mediates the suppression of reproductive, thyroid, and growth hormones and the elevation in glucocorticoid levels, in addition to stimulating food intake and limiting energy expenditure. This leptin-mediated response to fasting may have evolved to provide a defense against the threat of starvation by limiting the high-energy cost of reproduction, growth, and thyroid thermogenesis, while stimulating food intake and energy storage.2 Further evidence of a link among energy stores, leptin, and reproduction has come from patients with lipodystrophy, a condition characterized by the loss and redistribution of body fat; low leptin levels; hypothalamic amenorrhea; the accumulation of triglycerides in liver, muscle, and other tissues (steatosis); hyperlipidemia; severe insulin resistance; and diabetes.4 In addition to reversing the metabolic derangements, leptin stimulates gonadotropin and estradiol secretion and normalizes menstrual cycles, despite a further decrease in body fat.4
This early work provided a rationale for examining the role of leptin in hypothalamic amenorrhea, and Welt et al. report the results of such a study in this issue of the Journal (pages 987–997). Patients with hypothalamic amenorrhea due to underweight or strenuous exercise were treated with recombinant human leptin twice daily for three months, with 40 percent of the dose taken at 8 a.m. and 60 percent taken at night, to mimic the diurnal variation in plasma leptin levels. Patients maintained their accustomed food intake, exercise habits, and lifestyle. Leptin treatment increased the mean and pulsatile luteinizing hormone levels, resulted in a concomitant enlargement of the ovaries, increased the number and size of dominant follicles, and raised the estradiol concentration. Three of the eight patients had ovulatory menstrual cycles with this therapy, and preovulatory follicles associated with withdrawal bleeding developed in two others. Furthermore, the levels of free triiodothyronine and thyroxine, insulin-like growth factor 1, insulin-like growth factor–binding protein 3, and bone alkaline phosphatase and osteocalcin were increased by leptin therapy. Body fat was substantially reduced by leptin therapy, although food intake and energy expenditure were not affected.
The study by Welt et al., though limited in size and duration, suggests that leptin is important in mediating the neuroendocrine abnormalities of hypothalamic amenorrhea. Leptin administration increased the levels of reproductive, thyroid, and growth hormones, without apparent adverse effects. The failure of leptin therapy to reverse amenorrhea in three subjects appeared to be influenced by low baseline leptin levels, rather than by a longer duration of amenorrhea. Although the levels of markers of bone formation were increased by leptin therapy, the relevance of these markers to the health of bone in patients with hypothalamic amenorrhea is unclear.
These results are consistent with findings in other leptin-deficient states, but questions remain. Does leptin mainly regulate the levels of gonadotropin-releasing hormone and luteinizing hormone, or does it affect ovarian steroids directly? Can the response to leptin be potentiated by improvement in nutrition and a decrease in exercise? Will pulsatile leptin treatment be more effective in reversing hypothalamic amenorrhea? Will leptin supplementation be effective in women of normal weight who have psychogenic amenorrhea? Can the link among body fat, leptin, and reproduction serve as a model for understanding the so-called thrifty genotype, which seems to be intended to maximize energy efficiency? How safe and effective will treatment with recombinant leptin be in the long term? Will the loss of body fat trigger adverse metabolic changes?
Basic science only occasionally reshapes our understanding of major biologic systems as quickly and profoundly as the discovery of leptin has done. The effect of leptin on reproduction was demonstrated in rodents two years after the discovery of the leptin gene and was subsequently confirmed in humans.2,3 The study by Welt and colleagues represents a further step in unraveling the role of leptin in reproduction and neuroendocrine regulation. In addition to storing triglycerides, adipose tissue produces and secretes various hormones that are actively involved in energy balance and diverse physiological systems. An understanding of this complex biology is crucial for elucidating the pathogenesis and potential treatment of diseases, such as obesity, that result from energy imbalance. Thanks to recent advances in the knowledge of the molecular biology of adipose tissue, patients with hypothalamic amenorrhea, a disease that was first described in the 1940s and was poorly understood for decades, may finally benefit from a rebirth of investigation leading to rational therapy.
Dr. Ahima reports having received a consulting fee from Procter & Gamble Pharmaceuticals.
Source Information
From the Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia.
References
Frisch RE. The right weight: body fat, menarche and ovulation. Baillieres Clin Obstet Gynaecol 1990;4:419-439.
Ahima RS, Prabakaran D, Mantzoros C, et al. Role of leptin in the neuroendocrine response to fasting. Nature 1996;382:250-252.
Chan JL, Heist K, DePaoli AM, Veldhuis JD, Mantzoros CS. The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. J Clin Invest 2003;111:1409-1421.
Oral EA, Ruiz E, Andewelt A, et al. Effect of leptin replacement on pituitary hormone regulation in patients with severe lipodystrophy. J Clin Endocrinol Metab 2002;87:3110-3117.(Rexford S. Ahima, M.D., P)