SEZER AKSEL, M.D.
Psychogenic amenorrhea: Diagnosis by exclusion Nonphysiologic absence of menses among women in the reproductive age group may be caused by psychosocial stress factors as well as by disorders of the hypothalamic-pituitaryovarian axis. The diagnosis of psychogenic amenorrhea should not be entertained prior to exclusion of pathologic conditions of the uterus, ovaries, pituitary gland, and the central nervous system. Obtaining a thorough history, a complete physical examination, and selective laboratory tests is essential for evaluation of a patient with amenorrhea.
ABSTRACT:
Psychogenic disturbances that disrupt the mental and emotional state of women can easily influence their menstrual cycle. Absence of menses over a period of time without pregnancy becomes a cause of concern for the patient and usually prompts a visit to a gynecologist. If a specific disorder is not readily detectable, amenorrhea should not be attributed to a psychogenic cause without the benefit of a complete history, a careful physical examination, and selective laboratory
testing. The importance of following this logical sequence prior to reaching a definitive diagnosis cannot be overemphasized. The menstrual cycle Over the past decade, the neuroendocrine control of the sequence of events leading to cyclic menstruation has been generally accepted. The onset of menarche is attributed to the activation of the hypothalamic-pituitary axis by poorly understood mechanisms seemingly
Dr. Aksel is associate prOfessor in the division of reproductive endocrinology. department ofobstetrics and gynecology, at the University ofSouth Alabama College of Medicine. Reprint requests to Dr. Aksel at the College. 2451 Fillingim Street. Mobile, AL 36617.
MAY 1979· VOL 20· NO 5
mediated by the central nervous system. Prerequisites for menstrual function also include an intact outflow tract, normally developed MUllerian system, and gonads with follicles responsive to the circulating gonadotropin concentrations. There is now clear evidence that the hypothalamus synthesizes and emits a gonadotropin-releasing hormone that reaches the pituitary gland via the portal system, stimulating the synthesis and release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The secretion of this hypothalamic hormone is thought to be mediated by neurotransmitters, specifically norepinephrine. It has been demonstrated that via a feedback mechanism, sex steroids effectively suppress the norepinephrine content of the rat median eminence. When the source of sex steroids is removed by castration, a rise in circulating LH concentration is accompanied by a rise in hypothalamic norepinephrine values,1 demonstrating a positive correlation between gonadotropin and norepinephrine levels. There is no 357
Amenorrhea
direct proof that the catecholamine synthesis and turnover in the human central nervous system is involved in normal gonadal function. 2 Based on clinical and laboratory studies, however, adrenergic control of the neurosecretory processes in the hypothalamus has been hypothesized. 3 In general, there is agreement among reproductive endocrinologists that the feedback processes between the neuroendocrine system and gonadal function appear to involve the interaction between sex steroid and catecholaminergic pathways. Amenorrhea-psychogenic or not? Psychic stress or trauma can cause menstrual irregularities such as amenorrhea or anovulation associated with dysfunctional uterine bleeding. It is hypothesized that acute or chronic stress is associated with an accumulation of dopamine in the central nervous system that disrupts cyclic menstrual function, seemingly because of inadequate concentrations of other neurotransmitters.3.4 It would be ideal to be able to measure the concentration of these neurohormones in patients with amenorrhea to determine the psychogenic origins. Unfortunately, the diagnostic value of such assays is questionable because the neurotransmitter activities are intracellular and the circulating levels may not reflect either the acute or chronic tissue changes. 5 Therefore, the definitive diagnosis of psychogenic amenorrhea remains a diagnosis of exclusion. Factors influencing amenorrhea Unless there is utilization of psychotropic drugs, the mere presence of nervous symptoms or a neurotic character does not precipitate cessation of menses. Amenorrhea in358
duced by long-term usage of these compounds, such as phenothiazine derivatives and tricyclics, is reversible and frequently associated with galactorrhea. Depressed women tend to be more prone to psychogenic amenorrhea, as do those undergoing psychotherapy. Intellectual women, women who frequently travel abroad or are in the process of changing domiciles, and those who have oligomenorrhea or irregular menses may present with psychogenic amenorrhea. Lifethreatening or catastrophic events may also cause an abrupt cessation of menses. Nutritional amenorrhea and anorexia Women on crash diets who succeed in losing weight rapidly over a short period may become amenorrheic. Patients with weight-loss-associated amenorrhea have direct evidence of hypothalamic dysfunction demonstrated by abnormal thermoregulation in the heat and cold, laCK of a shivering response to hypothermia, and partial diabetes insipidus. Inadequate response to stimulation by thyrotropin-releasing and gonadotropin-releasing hormones is also indirect evidence of hypothalamic dysfunction. The pituitary-ovarian axis appears to function normally and so the mechanism of this dysfunction is unclear. 6 Once the phase of starvation is over and the patient has reached her optimum weight, normal caloric intake is resumed and menses may return. If chronic starvation and weight loss without a systemic disease continues, a very serious disorder of the adolescent and young woman has to be considered-anorexia nervosa. This syndrome is associated more with regressive behavior compatible
with the prepubertal age of the patient. Amenorrhea may develop before, during, or after the weight loss. Hormone abnormalities associated with hypothalamic dysfunction are more accentuated in this disorder than in other nutritional amenorrheas. Low circulating gonadotropin concentrations are similar to values observed in prepubertal girls. Low triiodothyronine levels and lack of diurnal variation of cortisol are consistent with abnormal hypothalamic function. Pseudocyesis The role of the central nervous system in controlling the ovarian function is clearly demonstrated in this condition-a conscious and erroneous belief that one is pregnant. This is a complete expression of pregnancy fantasies, and although the situation may be stress-induced, it usually reveals a significant fear of pregnancy even though these patients demonstrate all the signs and symptoms of pregnancy. It is not uncommon even to obtain a positive pregnancy test. This is probably due to an elevated LH level,? which may cross-react with human chorionic gonadotropin. Evaluation and therapy The absence of menses that occurs following stressful sitlJations has been interpreted as a biologic defense mechanism to establish equilibrium during a particular type of stress.8 In view of no previously existing hypothalamic-pituitaryovarian dysfunction, amenorrhea should promptly resolve once the anxiety-producing condition has been alleviated. If spontaneous menses do not return within six months, even if the psychic stress has not been removed, a brief workup is necessary to rule out PSYCHOSOMATICS
serious disease. The Figure outlines a stepwise evaluation of patients with a provisional diagnosis of psychogenic amenorrhea. Although this is an efficient method for evaluating the patient, individualized, systemic workups may be required to establish a definitive diagnosis. Adequate screening may be provided on an outpatient basis. This includes a complete history and a physical examination with specific attention to signs and symptoms of thyroid, adrenal, and metabolic disease. A very careful pelvic examination performed by a physician competent in the evaluation of the pelvis and a pregnancy test are essential. It is quite simple to determine the estrogenic status of an amenorrheic patient. This is ac-
complished by administration of progesterone in oil or an oral progestin. Along with this withdrawal test, a serum prolactin assay is most helpful. If the patients respond to progesterone stimulation with withdrawal bleeding and· have normal prolactins, or if they have no bleeding but a normal FSH level, they may be safely included in the psychogenic amenorrhea group.K However, patients with or without withdrawal bleeding but with abnormal prolactin values must be screened by polytomography of the pituitary gland to rule out a microadenoma. Stress increases peripheral prolactin levels. Stress also appears to alter neurotransmitter ratios in the hypothalamus. Interaction between psychological
disease and amenorrhea with hyperprolactinemia has been observed.9 Once the diagnosis of psychogenic amenorrhea has been reached, the most reasonable approach to therapy would be relief from stress. In some situations, stressful conditions cannot easily be alleviated. Even in these conditions, reassurance to the patient that her amenorrheic state is not due to serious disease may result in restored menses. For example, in pseudocyesis, once the patient is assured that she is not pregnant, symptoms disappear, the abdomen returns to normal size, and the patient resumes her cyclic menses. In some problem cases, such as when a patient suffers from anorexia nervosa, psychotherapy is necessary for long-term treatment. 0
Evaluation of Suspected Psychogenic Amenorrhea REFERENCES
I
Progesterone withdrawal and serum prolactin level
I
Withdrawal bleeding
t
I
I
No bleeding
Withdrawal bleeding Normal prolactin
pr0'L:~;jtln Polytomography of the pituitary
. MAY 1979· VOL 20· NO 5
I
I
No bleeding Normal prolactin
~ ,---.,__NO~r EI~r AssJance Counseling
Gonadal failure
I
1. Chiocchio SR. Negro-Vilar A. Tramezzani JH: Acute changes in norepinephrine content in the median eminence induced by orchidectomy or testosterone replacement. Endocrinology 99:629-635.1976. 2. Fernstrom JD. Wurtman RJ: Brain monoamines and reproductive function, in Greep RO (ed): Reproductive Physiology. II. University Park Press. Baltimore, london. Tokyo. 1977. pp 23-55. 3. McCann SM, Moss Rl: Putative neurotransmitters involved in the discharging gonadotropin-releasing neurohormones and the action of lH-releasing hormone on the CNS. Life Sci 18:833-852.1975. 4. lachelin GCl. Yen SSC: Hypothalamic chronic anovulation. Am J Obstet Gynecol 130:825831,1978. 5. Noth RH, Mulrow PJ: Serum dopamine P-hydroxylase as an index of sympathetic nervous system activity in man. Circ Res 38:2-5, 1976. 6. Vigersky RA. Anderson AE. Thompson RH, et al: Hypothalamic dysfunction in secondary amenorrhea associated with simple weight loss. N Engl J Med 297:1141-1145, 1977. 7. Yen SSC. Rebar RW. Quesenberry W: Pituitary function in pseudocyesis. J Clin Endocrinol Metab42:132-136.1976. 8. Fries H. Nillius SJ. Petterson F: Epidemiology of secondary amenorrhea. Am J Obstet Gynecol 118:473-479, 1974. 9. Zacur HA. Chapanis NP. lake CR. et al: Galactorrhea-amenorrhea: Psychological interaction with neuroendocrine function. Am J Obstet Gyneco/12S:859-862. 1976.
359
Psychogenic amenorrhea: Diagnosis by exclusion Nonphysiologic absence of menses among women in the reproductive age group may be caused by psychosocial stress factors as well as by disorders of the hypothalamic-pituitaryovarian axis. The diagnosis of psychogenic amenorrhea should not be entertained prior to exclusion of pathologic conditions of the uterus, ovaries, pituitary gland, and the central nervous system. Obtaining a thorough history, a complete physical examination, and selective laboratory tests is essential for evaluation of a patient with amenorrhea.
ABSTRACT:
Psychogenic disturbances that disrupt the mental and emotional state of women can easily influence their menstrual cycle. Absence of menses over a period of time without pregnancy becomes a cause of concern for the patient and usually prompts a visit to a gynecologist. If a specific disorder is not readily detectable, amenorrhea should not be attributed to a psychogenic cause without the benefit of a complete history, a careful physical examination, and selective laboratory
testing. The importance of following this logical sequence prior to reaching a definitive diagnosis cannot be overemphasized. The menstrual cycle Over the past decade, the neuroendocrine control of the sequence of events leading to cyclic menstruation has been generally accepted. The onset of menarche is attributed to the activation of the hypothalamic-pituitary axis by poorly understood mechanisms seemingly
Dr. Aksel is associate prOfessor in the division of reproductive endocrinology. department ofobstetrics and gynecology, at the University ofSouth Alabama College of Medicine. Reprint requests to Dr. Aksel at the College. 2451 Fillingim Street. Mobile, AL 36617.
MAY 1979· VOL 20· NO 5
mediated by the central nervous system. Prerequisites for menstrual function also include an intact outflow tract, normally developed MUllerian system, and gonads with follicles responsive to the circulating gonadotropin concentrations. There is now clear evidence that the hypothalamus synthesizes and emits a gonadotropin-releasing hormone that reaches the pituitary gland via the portal system, stimulating the synthesis and release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The secretion of this hypothalamic hormone is thought to be mediated by neurotransmitters, specifically norepinephrine. It has been demonstrated that via a feedback mechanism, sex steroids effectively suppress the norepinephrine content of the rat median eminence. When the source of sex steroids is removed by castration, a rise in circulating LH concentration is accompanied by a rise in hypothalamic norepinephrine values,1 demonstrating a positive correlation between gonadotropin and norepinephrine levels. There is no 357
Amenorrhea
direct proof that the catecholamine synthesis and turnover in the human central nervous system is involved in normal gonadal function. 2 Based on clinical and laboratory studies, however, adrenergic control of the neurosecretory processes in the hypothalamus has been hypothesized. 3 In general, there is agreement among reproductive endocrinologists that the feedback processes between the neuroendocrine system and gonadal function appear to involve the interaction between sex steroid and catecholaminergic pathways. Amenorrhea-psychogenic or not? Psychic stress or trauma can cause menstrual irregularities such as amenorrhea or anovulation associated with dysfunctional uterine bleeding. It is hypothesized that acute or chronic stress is associated with an accumulation of dopamine in the central nervous system that disrupts cyclic menstrual function, seemingly because of inadequate concentrations of other neurotransmitters.3.4 It would be ideal to be able to measure the concentration of these neurohormones in patients with amenorrhea to determine the psychogenic origins. Unfortunately, the diagnostic value of such assays is questionable because the neurotransmitter activities are intracellular and the circulating levels may not reflect either the acute or chronic tissue changes. 5 Therefore, the definitive diagnosis of psychogenic amenorrhea remains a diagnosis of exclusion. Factors influencing amenorrhea Unless there is utilization of psychotropic drugs, the mere presence of nervous symptoms or a neurotic character does not precipitate cessation of menses. Amenorrhea in358
duced by long-term usage of these compounds, such as phenothiazine derivatives and tricyclics, is reversible and frequently associated with galactorrhea. Depressed women tend to be more prone to psychogenic amenorrhea, as do those undergoing psychotherapy. Intellectual women, women who frequently travel abroad or are in the process of changing domiciles, and those who have oligomenorrhea or irregular menses may present with psychogenic amenorrhea. Lifethreatening or catastrophic events may also cause an abrupt cessation of menses. Nutritional amenorrhea and anorexia Women on crash diets who succeed in losing weight rapidly over a short period may become amenorrheic. Patients with weight-loss-associated amenorrhea have direct evidence of hypothalamic dysfunction demonstrated by abnormal thermoregulation in the heat and cold, laCK of a shivering response to hypothermia, and partial diabetes insipidus. Inadequate response to stimulation by thyrotropin-releasing and gonadotropin-releasing hormones is also indirect evidence of hypothalamic dysfunction. The pituitary-ovarian axis appears to function normally and so the mechanism of this dysfunction is unclear. 6 Once the phase of starvation is over and the patient has reached her optimum weight, normal caloric intake is resumed and menses may return. If chronic starvation and weight loss without a systemic disease continues, a very serious disorder of the adolescent and young woman has to be considered-anorexia nervosa. This syndrome is associated more with regressive behavior compatible
with the prepubertal age of the patient. Amenorrhea may develop before, during, or after the weight loss. Hormone abnormalities associated with hypothalamic dysfunction are more accentuated in this disorder than in other nutritional amenorrheas. Low circulating gonadotropin concentrations are similar to values observed in prepubertal girls. Low triiodothyronine levels and lack of diurnal variation of cortisol are consistent with abnormal hypothalamic function. Pseudocyesis The role of the central nervous system in controlling the ovarian function is clearly demonstrated in this condition-a conscious and erroneous belief that one is pregnant. This is a complete expression of pregnancy fantasies, and although the situation may be stress-induced, it usually reveals a significant fear of pregnancy even though these patients demonstrate all the signs and symptoms of pregnancy. It is not uncommon even to obtain a positive pregnancy test. This is probably due to an elevated LH level,? which may cross-react with human chorionic gonadotropin. Evaluation and therapy The absence of menses that occurs following stressful sitlJations has been interpreted as a biologic defense mechanism to establish equilibrium during a particular type of stress.8 In view of no previously existing hypothalamic-pituitaryovarian dysfunction, amenorrhea should promptly resolve once the anxiety-producing condition has been alleviated. If spontaneous menses do not return within six months, even if the psychic stress has not been removed, a brief workup is necessary to rule out PSYCHOSOMATICS
serious disease. The Figure outlines a stepwise evaluation of patients with a provisional diagnosis of psychogenic amenorrhea. Although this is an efficient method for evaluating the patient, individualized, systemic workups may be required to establish a definitive diagnosis. Adequate screening may be provided on an outpatient basis. This includes a complete history and a physical examination with specific attention to signs and symptoms of thyroid, adrenal, and metabolic disease. A very careful pelvic examination performed by a physician competent in the evaluation of the pelvis and a pregnancy test are essential. It is quite simple to determine the estrogenic status of an amenorrheic patient. This is ac-
complished by administration of progesterone in oil or an oral progestin. Along with this withdrawal test, a serum prolactin assay is most helpful. If the patients respond to progesterone stimulation with withdrawal bleeding and· have normal prolactins, or if they have no bleeding but a normal FSH level, they may be safely included in the psychogenic amenorrhea group.K However, patients with or without withdrawal bleeding but with abnormal prolactin values must be screened by polytomography of the pituitary gland to rule out a microadenoma. Stress increases peripheral prolactin levels. Stress also appears to alter neurotransmitter ratios in the hypothalamus. Interaction between psychological
disease and amenorrhea with hyperprolactinemia has been observed.9 Once the diagnosis of psychogenic amenorrhea has been reached, the most reasonable approach to therapy would be relief from stress. In some situations, stressful conditions cannot easily be alleviated. Even in these conditions, reassurance to the patient that her amenorrheic state is not due to serious disease may result in restored menses. For example, in pseudocyesis, once the patient is assured that she is not pregnant, symptoms disappear, the abdomen returns to normal size, and the patient resumes her cyclic menses. In some problem cases, such as when a patient suffers from anorexia nervosa, psychotherapy is necessary for long-term treatment. 0
Evaluation of Suspected Psychogenic Amenorrhea REFERENCES
I
Progesterone withdrawal and serum prolactin level
I
Withdrawal bleeding
t
I
I
No bleeding
Withdrawal bleeding Normal prolactin
pr0'L:~;jtln Polytomography of the pituitary
. MAY 1979· VOL 20· NO 5
I
I
No bleeding Normal prolactin
~ ,---.,__NO~r EI~r AssJance Counseling
Gonadal failure
I
1. Chiocchio SR. Negro-Vilar A. Tramezzani JH: Acute changes in norepinephrine content in the median eminence induced by orchidectomy or testosterone replacement. Endocrinology 99:629-635.1976. 2. Fernstrom JD. Wurtman RJ: Brain monoamines and reproductive function, in Greep RO (ed): Reproductive Physiology. II. University Park Press. Baltimore, london. Tokyo. 1977. pp 23-55. 3. McCann SM, Moss Rl: Putative neurotransmitters involved in the discharging gonadotropin-releasing neurohormones and the action of lH-releasing hormone on the CNS. Life Sci 18:833-852.1975. 4. lachelin GCl. Yen SSC: Hypothalamic chronic anovulation. Am J Obstet Gynecol 130:825831,1978. 5. Noth RH, Mulrow PJ: Serum dopamine P-hydroxylase as an index of sympathetic nervous system activity in man. Circ Res 38:2-5, 1976. 6. Vigersky RA. Anderson AE. Thompson RH, et al: Hypothalamic dysfunction in secondary amenorrhea associated with simple weight loss. N Engl J Med 297:1141-1145, 1977. 7. Yen SSC. Rebar RW. Quesenberry W: Pituitary function in pseudocyesis. J Clin Endocrinol Metab42:132-136.1976. 8. Fries H. Nillius SJ. Petterson F: Epidemiology of secondary amenorrhea. Am J Obstet Gynecol 118:473-479, 1974. 9. Zacur HA. Chapanis NP. lake CR. et al: Galactorrhea-amenorrhea: Psychological interaction with neuroendocrine function. Am J Obstet Gyneco/12S:859-862. 1976.
359
