Hypothalamic amenorrhea: Clinical perspectives, pathophysiology, and management James H. Liu, MD Cincinnati, Ohio The development of functional hypothalamic amenorrhea reflects an individual's response to environmental stressors and life-style variables. In this disorder there are no detectable anatomic abnormalities with respect to the hypothalamic-pituitary-ovarian-endometrial axis. Current evidence suggests that the common underlying defect is a decrease in the activity of the hypothalamic gonadotropin-releasing hormone pulse generator. Of the neuroendocrine factors that appear to regulate gonadotropin-releasing hormone activity, the opiate and dopamine neuronal systems have been implicated as factors that are responsible in part for the decreased secretion of gonadotropin-releasing hormone. Because of the functional nature of this disorder, reactivation of the hypothalamic-pituitary unit would be expected to take place in most women after accommodation to environmental stressors or modification in life-style. For women with persistent anovulation, treatment with estrogen-replacement therapy should be offered. In those desiring fertility, ovulation induction with pulsatile gonadotropin-releasing hormone would be the most effective modality. (AM J OBSTET GVNECOL 1990;163:1732-6.)
Key words: Hypothalamic amenorrhea, gonadotropin-releasing hormone, environmental stressors, opiate, dopamine
Amenorrhea associated with hypoestrogenism, normal or low levels of follicle-stimulating hormone (FSH), and psychogenic factors was originally described by Klinefelter et aV in 1973. They were the first to coin the term "hypothalamic hypoestrinism" and postulated that this disorder was caused by the "failure of the hypothalamic-pituitary nervous pathways to release luteinizing hormone from the anterior pituitary." In recent years many studies have shown that individuals with hypothalamic amenorrhea have intact pituitaryovarian-endometrial function 2-4 and the common underlying defect in this disorder is a deficiency in pulsatile secretion of gonadotropin-releasing hormone (GnRH).5-7 Unfortunately, the neuroendocrine basis that can account for the decrease in GnRH-luteinizing hormone (LH) secretion remains unclear. An increasing number of studies have provided evidence that increased endogenous opiate activity plays a major role in suppressing pulsatile GnRH secretion. 6 . 8 In addition, other studies have suggested that there is a functionallink between environmentally and endogenously generated stress and onset of hypothalamic amenorrhea." 3. 9 With our alterations in life-style and the growing emphasis on exercise, nutrition, and slenderness, the incidence of hypothalamic amenorrhea can be expected to increase. From the Department of Obstetrics and Gynecology, University of Cincinnati. Reprint requests: James R. Liu, MD, Department of Obstetrics and Gynecology, University of Cincinnati. 231 Bethesda Ave., ML 526, Cincinnati, OR 45267-0526. 610124547 1732
Clinical and biochemical features of hypothalamic amenorrhea On a clinical basis it is difficult to provide a typical profile of the individual with hypothalamic amenorrhea because functional hypothalamic amenorrhea is considered a diagnosis of exclusion. There are several other related disorders that can be considered to be caused by dysfunction of the central nervoushypothalamic-pituitary system (Table I). One such disorder, isolated gonadotropin deficiency, shares many of the biochemical features with functional hypothalamic amenorrhea. Isolated gonadotropin deficiency is characterized by a decrease in the secretion of endogenous GnRH leading to hypogonadotropic hypogonadism, eunuchoid features, incomplete development of secondary sexual characteristics, primary amenorrhea, and, in some cases, anosmia. Because this defect is probably the result of a failure of GnRH neurons to develop completely or migrate from the olfactory bulb to the hypothalamus during embryogenesis, hypoplasia of the olfactory bulbs can be identified in some patients.!O In contrast, patients with a diagnosis of functional hypothalamic amenorrhea can be defined as those who have an absence of menstrual cycles for more than 6 months in which no anatomic or organic abnormalities can be identified. Most women with this disorder have a history of normal onset of menarche with regular menstrual cycles between 26 and 35 days. These patients tend to be highly motivated, intelligent, involved in high-stress occupations, and usually thin or of normal body weight. In some patients a variety of emo-
Volume 163 Number 5, Part 2
HA: Clinical views, pathophysiology, and management
Table I. Classification of anovulation caused by the central nervous-hypothalamic-pituitary system
Table II. Basal serum hormonal profiles in women with functional hypothalamic amenorrhea
Functional hypothalamic anovulation Psychogenic or stress factors Nutritional factors Exercise-related factors Physiologic anovulation Prepubertal period Postpartum period Pharmacologic-induced anovulation Dopaminergic antagonist Opiate agonist Psychiatric-associated disorders Anorexia nervosa Pseudocyesis Organic defects of the hypothalamic-pituitary unit Isolated gonadotropin deficiency Pituitary tumors Sheehan's syndrome Empty-sella syndrome Head trauma Inappropriate prolactin secretion
tional or stressful events (e,g., divorce) preceding the onset of amenorrhea can be identified during the initial interview. Other environmental and interpersonal factors that can be uncovered include academic pressure, social maladjustment, and psychosexual difficulties. Life-style factors that should be scrutinized include a history of weight fluctuations, dietary habits, type and intensity of exercise, and use of sedatives and hypnotics. A thorough physical examination should reveal normal secondary sexual development and fail to demonstrate abnormalities such as galactorrhea, thyroid enlargement, or signs of androgen excess. Despite findings of hypoestrogenic changes in the genital tract, these patients do not usually complain of hot flashes. Laboratory values including LH, FSH, prolactin, and thyroid-stimulating hormone levels are in the low or normal range (Table II).7 Estradiol levels are typically low or low normal. In general the progestin challenge test should confirm that there is a scant or absent estrogenic effect on the endometrium. To exclude an occult pituitary lesion, computerized tomographic scanning of the sella turcica should be performed.
Pulsatile GnRH-LH secretion in hypothalamic amenorrhea Findings from several laboratories have established that there is a slowing in frequency of hypothalamic GnRH-LH secretion that is the basic underlying cause of persistent anovulation in women with hypothalamic amenorrhea.5-7. II In these studies frequent peripheral blood samples were used to quantitate pulsatile LH secretion and provide an indirect assessment of GnRH secretion. These studies make the assumption that only
LH (units/L) FSH (units/L) Prolactin (j.Lg/L) Thyroid-stimulating hormone (mUlL) Growth hormone (j.Lg/L) Estradiol (pmoIlL)
8.5 9.3 12.2 1.05
± 1.1* ± 0.5* ± 0.8t ± 0.33
6.7 ± 1.3 142 ± 15
11.6 12.1 17.1 1.33
1733
± 1.2 ± 1.0
± 1.4
± 0.26
4.2 ± 0.7 156 ± IO
From Berga SL, Mortola JF, Girton L, et at. Neuroendocrine aberrations in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab 1989;68:301. Date are mean ± SE. *P < 0.05. tp < 0.01.
GnRH is capable of stimulating LH secretion and there is a close correlation between GnRH and LH secretion, as demonstrated previously in several animal models.12. 13 When exogenous GnRH is administered to women with hypothalamic amenorrhea, LH and FSH responses are either normal or exaggerated compared with women with eumenorrhea!' 14 These findings suggest that pituitary sensitivity and capacity are not impaired and the primary defect is at a central level. Examination of individual patterns of LH secretion demonstrates considerable variability in the pulsatile pattern (Fig. 1). Compared with the follicular phase of the cycle, these LH secretory patterns are characterized by alterations in LH frequency, amplitude, and, in some cases, a regression to a pubertal pattern. 5. 6 These LH patterns suggest that the activity of the GnRH pulse generator is not uniformly suppressed to the same degree in each individual. During recovery from hypothalamic amenorrhea, a reversal of the GnRH-LH secretory pattern, characterized by a sleep-associated increase in LH amplitude, is often evident.
Opioidergic and dopaminergic modulation of GnRH secretion A growing body of evidence indicates that endogenous opiates inhibit pulsatile GnRH and LH secretion. 15 . 16 In a subgroup of women with hypothalamic amenorrhea, blockade of endogenous opiate receptors by naloxone can increase LH pulse frequency and amplitude. 6. 8 In addition, long-term treatment with the opiate receptor antagonist naltrexone leads to a spontaneous return of gonadotropin secretion and ovulatory function. 17 Collectively these studies suggest that an increase in endogenous opiate activity plays a significant role in reducing pulsatile GnRH secretion in this disorder.
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Key words: Hypothalamic amenorrhea, gonadotropin-releasing hormone, environmental stressors, opiate, dopamine
Amenorrhea associated with hypoestrogenism, normal or low levels of follicle-stimulating hormone (FSH), and psychogenic factors was originally described by Klinefelter et aV in 1973. They were the first to coin the term "hypothalamic hypoestrinism" and postulated that this disorder was caused by the "failure of the hypothalamic-pituitary nervous pathways to release luteinizing hormone from the anterior pituitary." In recent years many studies have shown that individuals with hypothalamic amenorrhea have intact pituitaryovarian-endometrial function 2-4 and the common underlying defect in this disorder is a deficiency in pulsatile secretion of gonadotropin-releasing hormone (GnRH).5-7 Unfortunately, the neuroendocrine basis that can account for the decrease in GnRH-luteinizing hormone (LH) secretion remains unclear. An increasing number of studies have provided evidence that increased endogenous opiate activity plays a major role in suppressing pulsatile GnRH secretion. 6 . 8 In addition, other studies have suggested that there is a functionallink between environmentally and endogenously generated stress and onset of hypothalamic amenorrhea." 3. 9 With our alterations in life-style and the growing emphasis on exercise, nutrition, and slenderness, the incidence of hypothalamic amenorrhea can be expected to increase. From the Department of Obstetrics and Gynecology, University of Cincinnati. Reprint requests: James R. Liu, MD, Department of Obstetrics and Gynecology, University of Cincinnati. 231 Bethesda Ave., ML 526, Cincinnati, OR 45267-0526. 610124547 1732
Clinical and biochemical features of hypothalamic amenorrhea On a clinical basis it is difficult to provide a typical profile of the individual with hypothalamic amenorrhea because functional hypothalamic amenorrhea is considered a diagnosis of exclusion. There are several other related disorders that can be considered to be caused by dysfunction of the central nervoushypothalamic-pituitary system (Table I). One such disorder, isolated gonadotropin deficiency, shares many of the biochemical features with functional hypothalamic amenorrhea. Isolated gonadotropin deficiency is characterized by a decrease in the secretion of endogenous GnRH leading to hypogonadotropic hypogonadism, eunuchoid features, incomplete development of secondary sexual characteristics, primary amenorrhea, and, in some cases, anosmia. Because this defect is probably the result of a failure of GnRH neurons to develop completely or migrate from the olfactory bulb to the hypothalamus during embryogenesis, hypoplasia of the olfactory bulbs can be identified in some patients.!O In contrast, patients with a diagnosis of functional hypothalamic amenorrhea can be defined as those who have an absence of menstrual cycles for more than 6 months in which no anatomic or organic abnormalities can be identified. Most women with this disorder have a history of normal onset of menarche with regular menstrual cycles between 26 and 35 days. These patients tend to be highly motivated, intelligent, involved in high-stress occupations, and usually thin or of normal body weight. In some patients a variety of emo-
Volume 163 Number 5, Part 2
HA: Clinical views, pathophysiology, and management
Table I. Classification of anovulation caused by the central nervous-hypothalamic-pituitary system
Table II. Basal serum hormonal profiles in women with functional hypothalamic amenorrhea
Functional hypothalamic anovulation Psychogenic or stress factors Nutritional factors Exercise-related factors Physiologic anovulation Prepubertal period Postpartum period Pharmacologic-induced anovulation Dopaminergic antagonist Opiate agonist Psychiatric-associated disorders Anorexia nervosa Pseudocyesis Organic defects of the hypothalamic-pituitary unit Isolated gonadotropin deficiency Pituitary tumors Sheehan's syndrome Empty-sella syndrome Head trauma Inappropriate prolactin secretion
tional or stressful events (e,g., divorce) preceding the onset of amenorrhea can be identified during the initial interview. Other environmental and interpersonal factors that can be uncovered include academic pressure, social maladjustment, and psychosexual difficulties. Life-style factors that should be scrutinized include a history of weight fluctuations, dietary habits, type and intensity of exercise, and use of sedatives and hypnotics. A thorough physical examination should reveal normal secondary sexual development and fail to demonstrate abnormalities such as galactorrhea, thyroid enlargement, or signs of androgen excess. Despite findings of hypoestrogenic changes in the genital tract, these patients do not usually complain of hot flashes. Laboratory values including LH, FSH, prolactin, and thyroid-stimulating hormone levels are in the low or normal range (Table II).7 Estradiol levels are typically low or low normal. In general the progestin challenge test should confirm that there is a scant or absent estrogenic effect on the endometrium. To exclude an occult pituitary lesion, computerized tomographic scanning of the sella turcica should be performed.
Pulsatile GnRH-LH secretion in hypothalamic amenorrhea Findings from several laboratories have established that there is a slowing in frequency of hypothalamic GnRH-LH secretion that is the basic underlying cause of persistent anovulation in women with hypothalamic amenorrhea.5-7. II In these studies frequent peripheral blood samples were used to quantitate pulsatile LH secretion and provide an indirect assessment of GnRH secretion. These studies make the assumption that only
LH (units/L) FSH (units/L) Prolactin (j.Lg/L) Thyroid-stimulating hormone (mUlL) Growth hormone (j.Lg/L) Estradiol (pmoIlL)
8.5 9.3 12.2 1.05
± 1.1* ± 0.5* ± 0.8t ± 0.33
6.7 ± 1.3 142 ± 15
11.6 12.1 17.1 1.33
1733
± 1.2 ± 1.0
± 1.4
± 0.26
4.2 ± 0.7 156 ± IO
From Berga SL, Mortola JF, Girton L, et at. Neuroendocrine aberrations in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab 1989;68:301. Date are mean ± SE. *P < 0.05. tp < 0.01.
GnRH is capable of stimulating LH secretion and there is a close correlation between GnRH and LH secretion, as demonstrated previously in several animal models.12. 13 When exogenous GnRH is administered to women with hypothalamic amenorrhea, LH and FSH responses are either normal or exaggerated compared with women with eumenorrhea!' 14 These findings suggest that pituitary sensitivity and capacity are not impaired and the primary defect is at a central level. Examination of individual patterns of LH secretion demonstrates considerable variability in the pulsatile pattern (Fig. 1). Compared with the follicular phase of the cycle, these LH secretory patterns are characterized by alterations in LH frequency, amplitude, and, in some cases, a regression to a pubertal pattern. 5. 6 These LH patterns suggest that the activity of the GnRH pulse generator is not uniformly suppressed to the same degree in each individual. During recovery from hypothalamic amenorrhea, a reversal of the GnRH-LH secretory pattern, characterized by a sleep-associated increase in LH amplitude, is often evident.
Opioidergic and dopaminergic modulation of GnRH secretion A growing body of evidence indicates that endogenous opiates inhibit pulsatile GnRH and LH secretion. 15 . 16 In a subgroup of women with hypothalamic amenorrhea, blockade of endogenous opiate receptors by naloxone can increase LH pulse frequency and amplitude. 6. 8 In addition, long-term treatment with the opiate receptor antagonist naltrexone leads to a spontaneous return of gonadotropin secretion and ovulatory function. 17 Collectively these studies suggest that an increase in endogenous opiate activity plays a significant role in reducing pulsatile GnRH secretion in this disorder.
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