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The Premenstrual Tension Syndrome
The Premenstrual Tension Syndrome A. SEYMOUR PARKER, JR., M.D.
tension can be described as the cyclic occurrence of a wide variety of many nervous or emotional symptoms and somatic complaints which tend to occur about seven to ten days before the onset of menses.
PREMENSTRUAL
INCIDENCE
When a careful history is obtained, regardless of their primary complaint the majority of women will admit to some change in their disposition; they state that they have one or more distressing symptoms at the time of menses which they have learned to accept as a normal occurrence. Since these symptoms are of only minor to moderate degree in the average woman seeking medical and gynecologic advice, Greenhill and Freed4 have suggested the term "premenstrual distress" to distinguish this large group of patients from those who have the severe and more disabling symptoms of premenstrual tension-the subject under consideration. Although only a relatively small proportion of women suffer from distress of sufficient magnitude to seek medical attention, symptoms of a psychosomatic nature occurring during the later phase of the menstrual cycle-and thus consistent with premenstrual tension-should be evaluated with this diagnosis in mind. Premenstrual nervous and somatic complaints should be of concern to the physician, since this syndrome not only interferes with the domestic tranquility and social activity of the patient and her household, but also has been shown to be an important factor in industrial efficiency and national economy. In large factories employing 1500 or more women, as many as one-third have been found to take sedatives, analgesics or both premenstrually.! Absenteeism in women, largely because of premenstrual symptoms, has been estimated to cause a yearly loss of about five billion dollars. rr PATTERN OF SYMPTOMS
The great majority of women with premenstrual tension have essentially regular menses with the interval varying by only a few days. This syndrome may occur in single or married women, usually before age 35; it has no relationship to pregnancy. Married women with premenstrual
339
340
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SEYMOUR PARKER, JR.
tension tend to have a recurrence of the same symptoms after pregnancy, and in some these symptoms may be more severe. Although the number, type and intensity of the symptoms may vary considerably in different women, patients with this syndrome tend to have a characteristic pattern of premenstrual complaints; symptoms usually start about seven to ten days before a period and terminate rather abruptly at the onset of the menstrual cycle. An occasional patient will complain of the same pattern of symptoms for a day or so at the time of ovulation, with more intense discomfort four to seven days before her period. Very rarely a woman will insist that she has a cyclic recurrence of symptoms identical to thosc of premenstrual tension which are related to some other phase of the menstrual cycle. Nervous Symptoms
As the term "premenstrual tension" implies, the more constant and predominant features of this syndrome are nervous or psychic. Marked tension, irritability, apprehension or anxiety in one form or another is present in all patients. Many complain of fretfulness, fatigue, lethargy, sluggishness and moodiness or more severe depressive symptoms with a desire to be left alone. Others have sudden outbursts of emotionalism during which they become irascible or tend to weep at the slightest provocation. Some women seek advice solely because of these emotional episodes or because their premenstrual antisocial behavior seriously interferes with their work, household or social activities. Somatic Symptoms
Commonly encountered somatic symptoms include diffuse headaches of a pressure or tension type and-less often-unilateral headaches which may be consistent with or suggestive of migraine; painful swelling and tenderness of the breasts; abdominal bloating, nausea, gastrointestinal cramps and distress with some change of bowel function consistent with an irritable colon, and a gain in basal body weight of 2 to 6 or more pounds (this may be evident on physical examination as pitting edema). Patients with evidence of severe water retention and edema are prone to have a more severe and dramatic recurrence of nervous manifestations associated with painful turgidity of the breasts and more severe degrees of abdominal distention; a sense of fullness or painful distress in the pelvis; puffiness or swelling of the hands; ankle edema, and a history of increased frequency of urination associated with the onset of the menstrual flow. Vague, rheumatic-like pains are common. More rarely, a patient will complain of urticaria, marked thirst and a craving for food or sweets during the premenstrual phase. Although dermatoses, aphthous ulcers and psychosexual aberrations are listed among the less common accompaniments of this syndrome,2 these findings are rare in our experi-
The Premenstrual Tension Syndrome
341
ence. An occasional patient with acne may show a definite and consistent aggravation of her skin problem premenstrually. ETIOLOGY
The cause of the premenstrual tension syndrome is unknown. Many causal mechanisms have been suggested, including allergy, menstrual toxin, a disturbance of the autonomic nervous system, deep-seated psychologic problems, vitamin B deficiency and a temporary imbalance of ovarian and interrelated hormonal systems. Because of the wide variety of nervous and somatic complaints and the different mechanisms involved, there are many gaps in our knowledge of these mechanisms and their interrelationships which must be filled to establish the etiology. Current understanding of this syndrome has been obtained largely by the empirical administration of different drugs of known pharmacologic action and by observing the therapeutic results. Response to drugs has provided a clearer concept of some possible mechanisms involved in premenstrual tension. The preponderance of evidence indicates that the fundamental disturbance is transitory fluid retention, since relief is obtained by measures that produce diuresis. Some symptoms apparently result from proliferative changes in the breasts and uterus; some appear to be manifestations of autonomic imbalance, and others have been attributed to changes in carbohydrate metabolism with hypoglycemia. 6 Subjective factors, such as the emotional stability and attitude of the patient, and environmental factors influence the intensity and degree of incapacity.
Fluid Retention In a syndrome with very few objective manifestations, the most common finding is the occasional occurrence of edema of the subcutaneous tissues, present only in the premenstrual phase. Visible edema, however, is only one site of fluid retention and only one phase of a more generalized process. The internal organs may undergo a similar change and the increased water content of any segment of the body is then manifested by the development of premenstrual symptoms attributable to the site involved. When this occurs in the gastrointestinal tract, the patient complains of abdominal bloating, distention, and tightness of her clothing, or she may have nausea, painful cramps and altered bowel function, Intracranial fluid retention produces diffuse or unilateral headaches. With pelvic congestion, such symptoms as heaviness or a sense of weight within the pelvis may be associated with nagging pains and an inability to find a comfortable sitting position. With the onset of menstruation secondary to the suppression of hormonal secretion from the ovaries, the various tissues lose their retained sodium and water and the symptoms disappear.
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Hormonal Imbalance
That the disturbed water metabolism is related to ovarian steroid secretion seems probable. Estradiol concentration is at a peak at ovulation and during the premenstrual phase, and it is well known that estrogen, and progesterone to a lesser degree, are capable of causing water retention. The etiologic role of a relative excess of estrogens or a high estrogen-progesterone ratio, resulting from a relative deficiency of progesterone in the presence of normal estrogen, has found many supporters. This concept postulates a cyclic change in sodium and water metabolism which is controlled by the levels of estrogen and progesterone in the tissues. Thus, a gain in basal body weight before a period, followed by diuresis, loss of weight and symptomatic relief soon after the onset of menstruation, is thought to result from a cyclic accumulation of sodium and water produced by an increase in the tissue concentration of estrogens or by a relative deficiency in the tissue concentration of progesterone. Possibly, some alteration in adrenal function could be induced by the cyclic release of ovarian steroids, since adrenal corticoids are known to increase premenstrually. Such symptoms as apprehension, anxiety and tension are manifestations of a stress reaction, and it can be theorized that an altered secretion of the ovarian steroids may be followed by a secondary release of adrenal corticoids, an electrolytic hormone, adrenal steroids, or possibly catechols such as adrenochrome. Another hypothesis states that the ovarian hormones may cause some alteration in posterior pituitary function, with a temporary hypersecretion of antidiuretic hormone. Additional concepts suggested are sensitivity of the patient to progesterone and vitamin B deficiency, with an inability of the liver to inactivate excess estrogens as a partial factor. Carbohydrate Metabolism and Hypoglycemia
Although there is little doubt that much of the premenstrual symptomatology is related to abnormal electrolyte and water metabolism, not all symptoms can be explained on this basis or alleviated merely by salt restriction and the administration of diuretics. In addition to water retention and epithelial proliferation, Morton 6 believes that the premenstrual estrogens, uninhibited by sufficient progesterone, cause an alteration of carbohydrate ,metabolism with increased sugar tolerance. Some of his patients were found to have hypoglycemic tendencies premenstrually, and he thinks that some of the nervous and psychic changes, such as heightened anxiety and fatigue, are the result of low blood sugar levels. Although a relationship exists between estrogen levels and carbohydrate metabolism, especially in diabetes, the insulin requirements of a diabetic patient are not appreciably reduced unless relatively large doses of cstrogens are admini"tered. In cases of premenstrual tension it
The Premenstrual Tension Syndrome
343
seems unlikely that a relative excess of estrogen resulting from a relative deficiency of progesterone should be an important factor in the production of marked anxiety and other nervous manifestations. Even though an occasional patient will complain of increased thirst or a craving for food or sweets during the premenstrual phase, our observations have failed to confirm the presence of chronic hypoglycemia as an important factor in producing nervous manifestations. Since these symptoms are not ameliorated by eating, and since the results of spot blood sugar tests before and after a period are normal in most cases, these eating habits often seem secondary to frustration and other psychic premenstrual phenomena. Psychologic Factors
Although the physiologic mechanism producing abnormal fluid retention cannot be specified, the cyclic elaboration of ovarian hormones is believed to be responsible for the capriciousness of disposition found in most women during the premenstrual phase. Psychologic manifestations are the most frequent and usually the most obvious findings, and a psychologic origin of the premenstrual tension syndrome has been suggested. Undoubtedly, the underlying personality pattern and the environmental setting figure importantly in the development of symptoms. Emotional disturbances and psychogenic trauma not only aggravate these symptoms but also tend to evoke additional ones. The largest proportion of major crimes committed by women are committed during the ten-day interval before periods, and premenstrual tension has also been found to be more common and more severe among the mentally ill. 9 Despite these suggestions, the premenstrual syndrome may occur in both stable and unstable women, regardless of the underlying personality pattern. In women with underlying emotional and nervous disorders, a periodic and often spectacular variety of premenstrual personality changes is superimposed on other nervous symptoms. Since the same symptoms of premenstrual tension occur in women who are stable in all other respects, most authors agree with Kroger and Freed, 5 who reviewed the psychologic and endocrine aspects of the problem and concluded that the somatic factors are primary and that the psychic factors appear following the physiologic, biochemical and anatomic changes resulting from hormonal influences. TREATMENT
Because of the wide variety of symptoms and the complex nature of the many mechanisms involved, obviously one form of therapy will not correct all the symptoms. Most patients can be helped, and with few exceptions most women can be relieved of the majority of the distressing symptoms. Treatment must be individualized, and an evaluation of the
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SEYMOUR PARKER, JR.
patient's symptoms and personality should suggest the best over-all approach to the correction of her problem. Psychotherapy
Premenstrual tension is not amenable to psychotherapy alone, but a simple explanation can be of considerable assistance in helping the patient understand her condition and can improve the patient's attitude and reaction of her symptoms. 7 A realization that there is an underlying physiologic basis for the cyclic occurrence of symptoms is helpful. The patient is relieved to learn that her symptoms are not imaginative and purely psychogenic, and is encouraged when she realizes that a basic program will relieve her symptoms. Diuretics, Tranquilizers and Stimulants
Measures designed to prevent fluid retention are a basic part of therapy for the premenstrual tension syndrome and are effective in relieving an appreciable number of nervous and somatic complaints. Although ammonium chloride in doses of 1 gm. three times daily and other oral diuretics are effective in the prevention of fluid accumulation, it is necessary to "treat the patient as a whole" and avoid the inconvenience of taking too many medications. I agree with other authors2 • 6 that a preparation with multiple ingredients is useful in alleviating or lessening many premenstrual symptoms, regardless of their severity. A useful preparation is Pre-Mens tablets which contain ammonium chloride to lessen water retention; homatropine methylbromide to lessen generalized tension and certain gastrointestinal complaints; caffeine for moodiness and minor depressive symptoms, and vitamin B complex as an aid in the metabolism of estrogens by the liver. Another useful agent is M-Minus 5, which contains Pamabrom and acetophenetidin for the control of fluid retention and the alleviation of pain. Although Pre-Mens tablets with 2.5 mg. of d-amphetamine and Pambromal tablets with carbromal containing the equivalent amount of d-amphetamine may be used, I prefer to prescribe two Pre-Mens tablets three times daily after meals, or one to two M-Minus 5 tablets four times daily and recommend amphetamine preparations in varying dosages depending upon the extent of the associated symptoms of lethargy, moodiness, disinterest or depression. Patients react differently to a fixed dose of an amphetamine preparation and the hyperreactive patient may do better on an equivalent dose of a less stimulating preparation, such as Dexamyl. Others who are listless and have diffuse headaches, vague pains or cramps obtain greater relief by the addition of Edrisal or Daprisal in proper dosages. In patients with definite premenstrual symptoms without edema, often fluid retention cannot be demonstrated clinically even by means of basal weight charts-50 to 70 per cent_of patients will show some weight gain
The Premenstrual Tension Syndrome
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before any specific therapy is begun. Because of the varied nature and severity of the complaints, it is wise to try the simplest procedures first and to have the patient return at monthly intervals, or every second month if she lives at a distance. In addition to a low sodium regimen and one of the multipurpose drugs mentioned, a prescription containing a little phenobarbital and tincture of belladonna for increased tension and anxiety, or a little amphetamine or Dexamyl for predominantly depressive symptoms, may prove helpful. In many women with symptoms of moderate severity this program will prove satisfactory. To determine the effectiveness of the initial therapeutic program, patients are instructed to record graphically the basal weight on arising two to three times a week during the postmenstrual phase and daily for the ten-day interval before each period and to note their predominant complaints. Patients with visible edema (such afi localized swelling of the ankles and puffiness of the hands), localized headaches which are not consistent with migraine, or abdominal distention and vague, rheumatic-like pains, are advised to take an oral diuretic (such as Diamox, Diuril, N eohydrin or Esidrex) on those mornings during the premenstrual phase of the second period if there has been a gain of more than 1 pound in basal weight, or a definite recurrence of their distressing premenstrual symptoms, or both. In a majority of women with the more severe forms of this syndrome, and even in patients referred by psychiatrists for relief of various psychosomatic complaints superimposed on a nervous disorder, the above measures will afford satisfactory relief. In our experience, patients with the classic manifestations of migraine which recur premenstrually are seldom relieved by the routine measures which lessen tension and prevent fluid retention. Although estrogen, progesterone, testosterone and the adrenocortical steroids with minimal salt-retaining properties may prevent the cyclic occurrence of migraine in an occasional patient, ergotamine preparations, such as Cafergot, must be taken at the onset of symptoms for satisfactory relief. Hormonal Therapy
Based on the concept that the symptoms of premenstrual tension are caused by a relative excess of estrogens or a deficiency of progesterone during the premenstrual phase, many attempts have been made to correct this hormonal imbalance-and thus relieve the symptoms-by the use of testosterone to suppress excess endogenous estrogens or by the supplementary administration of progesterone. Because of unavoidable variations in the appraisal of patients with predominantly subjective complaints and because of the differences in dosage and methods of administration of the hormone given, it is difficult to evaluate the effectiveness of hormonal therapy in this syndrome. When taken as the only form of therapy, oral testosterone and ethisterone preparations would appear to be of equal effectiveness; perhaps
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30 per cent of patients will obtain satisfactory relief. Although eithisterone must often be given in larger dosages than testosterone to be of equal value, the dose of testosterone must be restricted to prevent untoward effects. In selected cases of mild to moderate severity, testosterone and ethisterone have been reported as effective in up to 85 per cent of cases,7. 8 but this has not been our experience. Although the results with each method of hormonal administration vary from unsatisfactory to very good, depending on the series of cases reported, progesterone given intramuscularly is considered to be the most effective. In a large series of cases in which progesterone therapy was evaluated and found to be effective, about 80 per cent of the patients required intramuscular injections on alternate days during the premenstrual phase, or progesterone implantations, for satisfactory to effective relief.3 Obviously, the inconvenience and expense of any single form of therapy requiring multiple injections prohibit its use in clinical practice. A long-acting preparation such as Delalutin, * which shows some progestational effects within three days of the injection and lasts for approximately 14 days in most patients, is a more convenient form of therapy. Delalutin is worthy of more extensive trials, with and without other measures, in patients whose symptoms are of varying severity. Many patients treated by the cyclic administration of various hormones or by progesterone given intramuscularly or by implantations, whose course has been followed for prolonged intervals, no longer need therapy after variable periods of time; in some of these patients the symptoms may recur at a later date. Although this might imply that a specific type of hormonal therapy has corrected the endocrine imbalance, this mayor may not be true, but it is open to question. Since many patients whose symptoms have been controlled by diuretics and tranquilizers with or without hormones may be able to discontinue therapy or omit most of the premenstrual program in about six months (and yet relapse may occur), there is no reason to think that hormonal therapy is any more corrective than the symptomatic approach. When hormones are the only form of therapy, they usually have to be given in relatively large doses before satisfactory relief is obtained. Patients with moderately severe premenstrual complaints may require methyltestosterone in doses of 10 mg. twice daily for adequate control, and such doses tend to delay the menses and may intensify menstrual cramps or aggravate skin blemishes. When the symptoms are of mild to moderate severity, ethisterone tablets, 30 to 150 mg. daily from the fourteenth through the twenty-sixth day, have been satisfactory in a majority of cases. In the failures and in patients with severe symptoms, progesterone may be effective in doses of 25 to 50 mg. intramuscularly on alternate days from the fourteenth through the twenty-sixth day. The administration of 1.5 to 2.0 cc. of Delalutin may be tried on the
* Hydroxyprogesterone caproate dissolved in sesame oil with 30 per cent benzyl benzoate, 125 mg. per cubic centimeter.
The Premenstrual Tension Syndrome
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twelfth day of a 28 day cycle; the dosage may have to be altered the following month for adequate relief. Since there is no apparent advantage in the use of hormones, a better program seems to be treatment with the simpler procedures first, reserving hormonal therapy for patients whose symptoms are not adequa tely controlled by the usual measures. Methyltestosterone, given premenstrually in doses of 5 to 10 mg. daily, may be helpful in the further control of symptoms, especially when mastalgia is a prominent complaint. Ethisterone or progesterone buccal tablets, 10 mg. two to three times daily from the fifteenth through the twenty-sixth day of a 28 day cycle, may prevent the remaining symptoms resulting from hydration and relieve symptoms of tension, anxiety or fatigue. This therapy is especially helpful for women whose periods are prolonged or profuse and for patients with 26 to 35 day cycles, whose symptoms may occur prior to the institution of preventive therapy because of a short cycle. When patients are only partially relieved, an increase in dosage to one 25 mg. tablet two to three times a day may be necessary. Another effective treatment for married women is the intravaginal insertion of one 50 mg. Colprosterone tablet on alternate nights from the sixteenth through the twenty-sixth night. If the above dosages of oral or intravaginal tablets fail to produce the desired effects, a trial of progesterone intramuscularly for one to two months may be worth while. If patients still complain of anxiety and tension with periods of emotional instability before or after the addition of hormonal therapy to the program, tranquilizers may be effective. The dermatoses of the premenstrual tension syndrome are not readily explicable on the water-retention hypothesis. In the few patients we have seen with urticaria or a painful herpetiform stomatitis, the premenstrual administration of oral cortisone therapy has been helpful. CONCLUSION
With few exceptions in our experience, most patients benefit from measures designed to eliminate fluid retention and tailored to fit the individual problems. Although the etiology and the interrelated mechanisms of a possible endocrine imbalance are unknown, the addition of sedatives, tranquilizers, stimulants and hormonal therapy in addition to simple psychotherapy may be indicated for the individual patient. Most patients obtain satisfactory relief from the distressing symptoms of the premenstrual tension syndrome by an individualized program adjusted to the needs of the patient. REFERENCES 1. Ferguson, J. H.: La tensi6n pre-menstrual y SUB efectos Bobre el trabajo. Arch. mM. Cuba 7: 189-190 (July-Nov.) 1956. 2. Greenblatt. R. B.: Premenstrual ten8ion syndrome. GP 11: 66-68 (March) 1955.
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3. Greene, R. and Dalton, K.: Premenstrual syndrome. Brit. M. J. 1: 1007-1014 (May 9) 1953. 4. Greenhill and Freed: Quoted by Freed, S. C.: History and causation of premenstrual tension. Internat. Rec. Med. 166: 502-504 (Nov.) 1953. 5. Kroger and Freed: Quoted by Freed, S. C.: History and causation of premenstrual tension. Internat. Rec. Med. 166: 465--468 (Nov.) 1953. 6. Morton, J. H.: Treatment of premenstrual tension. Internat. Rec. Med. 166: 505510 (Nov.) 1953. 7. Rees, L.: Premenstrual ten8ion syndrome and its treatment. Brit. M. J. 1: 10141016 (May 9) 1953. 8. Simmons, R. J.: Premenstrual tension: review of 288 cases. Obst. & Gynec. 8: 99-102 (July) 1956. 9. Suarez-Murias, E. L.: Psychophysiologic syndrome of premenstrual tension with emphasis on psychiatric aspect. Internat. Ree. Med. 166: 475-486 (Nov.) 1953.
tension can be described as the cyclic occurrence of a wide variety of many nervous or emotional symptoms and somatic complaints which tend to occur about seven to ten days before the onset of menses.
PREMENSTRUAL
INCIDENCE
When a careful history is obtained, regardless of their primary complaint the majority of women will admit to some change in their disposition; they state that they have one or more distressing symptoms at the time of menses which they have learned to accept as a normal occurrence. Since these symptoms are of only minor to moderate degree in the average woman seeking medical and gynecologic advice, Greenhill and Freed4 have suggested the term "premenstrual distress" to distinguish this large group of patients from those who have the severe and more disabling symptoms of premenstrual tension-the subject under consideration. Although only a relatively small proportion of women suffer from distress of sufficient magnitude to seek medical attention, symptoms of a psychosomatic nature occurring during the later phase of the menstrual cycle-and thus consistent with premenstrual tension-should be evaluated with this diagnosis in mind. Premenstrual nervous and somatic complaints should be of concern to the physician, since this syndrome not only interferes with the domestic tranquility and social activity of the patient and her household, but also has been shown to be an important factor in industrial efficiency and national economy. In large factories employing 1500 or more women, as many as one-third have been found to take sedatives, analgesics or both premenstrually.! Absenteeism in women, largely because of premenstrual symptoms, has been estimated to cause a yearly loss of about five billion dollars. rr PATTERN OF SYMPTOMS
The great majority of women with premenstrual tension have essentially regular menses with the interval varying by only a few days. This syndrome may occur in single or married women, usually before age 35; it has no relationship to pregnancy. Married women with premenstrual
339
340
A.
SEYMOUR PARKER, JR.
tension tend to have a recurrence of the same symptoms after pregnancy, and in some these symptoms may be more severe. Although the number, type and intensity of the symptoms may vary considerably in different women, patients with this syndrome tend to have a characteristic pattern of premenstrual complaints; symptoms usually start about seven to ten days before a period and terminate rather abruptly at the onset of the menstrual cycle. An occasional patient will complain of the same pattern of symptoms for a day or so at the time of ovulation, with more intense discomfort four to seven days before her period. Very rarely a woman will insist that she has a cyclic recurrence of symptoms identical to thosc of premenstrual tension which are related to some other phase of the menstrual cycle. Nervous Symptoms
As the term "premenstrual tension" implies, the more constant and predominant features of this syndrome are nervous or psychic. Marked tension, irritability, apprehension or anxiety in one form or another is present in all patients. Many complain of fretfulness, fatigue, lethargy, sluggishness and moodiness or more severe depressive symptoms with a desire to be left alone. Others have sudden outbursts of emotionalism during which they become irascible or tend to weep at the slightest provocation. Some women seek advice solely because of these emotional episodes or because their premenstrual antisocial behavior seriously interferes with their work, household or social activities. Somatic Symptoms
Commonly encountered somatic symptoms include diffuse headaches of a pressure or tension type and-less often-unilateral headaches which may be consistent with or suggestive of migraine; painful swelling and tenderness of the breasts; abdominal bloating, nausea, gastrointestinal cramps and distress with some change of bowel function consistent with an irritable colon, and a gain in basal body weight of 2 to 6 or more pounds (this may be evident on physical examination as pitting edema). Patients with evidence of severe water retention and edema are prone to have a more severe and dramatic recurrence of nervous manifestations associated with painful turgidity of the breasts and more severe degrees of abdominal distention; a sense of fullness or painful distress in the pelvis; puffiness or swelling of the hands; ankle edema, and a history of increased frequency of urination associated with the onset of the menstrual flow. Vague, rheumatic-like pains are common. More rarely, a patient will complain of urticaria, marked thirst and a craving for food or sweets during the premenstrual phase. Although dermatoses, aphthous ulcers and psychosexual aberrations are listed among the less common accompaniments of this syndrome,2 these findings are rare in our experi-
The Premenstrual Tension Syndrome
341
ence. An occasional patient with acne may show a definite and consistent aggravation of her skin problem premenstrually. ETIOLOGY
The cause of the premenstrual tension syndrome is unknown. Many causal mechanisms have been suggested, including allergy, menstrual toxin, a disturbance of the autonomic nervous system, deep-seated psychologic problems, vitamin B deficiency and a temporary imbalance of ovarian and interrelated hormonal systems. Because of the wide variety of nervous and somatic complaints and the different mechanisms involved, there are many gaps in our knowledge of these mechanisms and their interrelationships which must be filled to establish the etiology. Current understanding of this syndrome has been obtained largely by the empirical administration of different drugs of known pharmacologic action and by observing the therapeutic results. Response to drugs has provided a clearer concept of some possible mechanisms involved in premenstrual tension. The preponderance of evidence indicates that the fundamental disturbance is transitory fluid retention, since relief is obtained by measures that produce diuresis. Some symptoms apparently result from proliferative changes in the breasts and uterus; some appear to be manifestations of autonomic imbalance, and others have been attributed to changes in carbohydrate metabolism with hypoglycemia. 6 Subjective factors, such as the emotional stability and attitude of the patient, and environmental factors influence the intensity and degree of incapacity.
Fluid Retention In a syndrome with very few objective manifestations, the most common finding is the occasional occurrence of edema of the subcutaneous tissues, present only in the premenstrual phase. Visible edema, however, is only one site of fluid retention and only one phase of a more generalized process. The internal organs may undergo a similar change and the increased water content of any segment of the body is then manifested by the development of premenstrual symptoms attributable to the site involved. When this occurs in the gastrointestinal tract, the patient complains of abdominal bloating, distention, and tightness of her clothing, or she may have nausea, painful cramps and altered bowel function, Intracranial fluid retention produces diffuse or unilateral headaches. With pelvic congestion, such symptoms as heaviness or a sense of weight within the pelvis may be associated with nagging pains and an inability to find a comfortable sitting position. With the onset of menstruation secondary to the suppression of hormonal secretion from the ovaries, the various tissues lose their retained sodium and water and the symptoms disappear.
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SEYMOUR PARKER, JR.
Hormonal Imbalance
That the disturbed water metabolism is related to ovarian steroid secretion seems probable. Estradiol concentration is at a peak at ovulation and during the premenstrual phase, and it is well known that estrogen, and progesterone to a lesser degree, are capable of causing water retention. The etiologic role of a relative excess of estrogens or a high estrogen-progesterone ratio, resulting from a relative deficiency of progesterone in the presence of normal estrogen, has found many supporters. This concept postulates a cyclic change in sodium and water metabolism which is controlled by the levels of estrogen and progesterone in the tissues. Thus, a gain in basal body weight before a period, followed by diuresis, loss of weight and symptomatic relief soon after the onset of menstruation, is thought to result from a cyclic accumulation of sodium and water produced by an increase in the tissue concentration of estrogens or by a relative deficiency in the tissue concentration of progesterone. Possibly, some alteration in adrenal function could be induced by the cyclic release of ovarian steroids, since adrenal corticoids are known to increase premenstrually. Such symptoms as apprehension, anxiety and tension are manifestations of a stress reaction, and it can be theorized that an altered secretion of the ovarian steroids may be followed by a secondary release of adrenal corticoids, an electrolytic hormone, adrenal steroids, or possibly catechols such as adrenochrome. Another hypothesis states that the ovarian hormones may cause some alteration in posterior pituitary function, with a temporary hypersecretion of antidiuretic hormone. Additional concepts suggested are sensitivity of the patient to progesterone and vitamin B deficiency, with an inability of the liver to inactivate excess estrogens as a partial factor. Carbohydrate Metabolism and Hypoglycemia
Although there is little doubt that much of the premenstrual symptomatology is related to abnormal electrolyte and water metabolism, not all symptoms can be explained on this basis or alleviated merely by salt restriction and the administration of diuretics. In addition to water retention and epithelial proliferation, Morton 6 believes that the premenstrual estrogens, uninhibited by sufficient progesterone, cause an alteration of carbohydrate ,metabolism with increased sugar tolerance. Some of his patients were found to have hypoglycemic tendencies premenstrually, and he thinks that some of the nervous and psychic changes, such as heightened anxiety and fatigue, are the result of low blood sugar levels. Although a relationship exists between estrogen levels and carbohydrate metabolism, especially in diabetes, the insulin requirements of a diabetic patient are not appreciably reduced unless relatively large doses of cstrogens are admini"tered. In cases of premenstrual tension it
The Premenstrual Tension Syndrome
343
seems unlikely that a relative excess of estrogen resulting from a relative deficiency of progesterone should be an important factor in the production of marked anxiety and other nervous manifestations. Even though an occasional patient will complain of increased thirst or a craving for food or sweets during the premenstrual phase, our observations have failed to confirm the presence of chronic hypoglycemia as an important factor in producing nervous manifestations. Since these symptoms are not ameliorated by eating, and since the results of spot blood sugar tests before and after a period are normal in most cases, these eating habits often seem secondary to frustration and other psychic premenstrual phenomena. Psychologic Factors
Although the physiologic mechanism producing abnormal fluid retention cannot be specified, the cyclic elaboration of ovarian hormones is believed to be responsible for the capriciousness of disposition found in most women during the premenstrual phase. Psychologic manifestations are the most frequent and usually the most obvious findings, and a psychologic origin of the premenstrual tension syndrome has been suggested. Undoubtedly, the underlying personality pattern and the environmental setting figure importantly in the development of symptoms. Emotional disturbances and psychogenic trauma not only aggravate these symptoms but also tend to evoke additional ones. The largest proportion of major crimes committed by women are committed during the ten-day interval before periods, and premenstrual tension has also been found to be more common and more severe among the mentally ill. 9 Despite these suggestions, the premenstrual syndrome may occur in both stable and unstable women, regardless of the underlying personality pattern. In women with underlying emotional and nervous disorders, a periodic and often spectacular variety of premenstrual personality changes is superimposed on other nervous symptoms. Since the same symptoms of premenstrual tension occur in women who are stable in all other respects, most authors agree with Kroger and Freed, 5 who reviewed the psychologic and endocrine aspects of the problem and concluded that the somatic factors are primary and that the psychic factors appear following the physiologic, biochemical and anatomic changes resulting from hormonal influences. TREATMENT
Because of the wide variety of symptoms and the complex nature of the many mechanisms involved, obviously one form of therapy will not correct all the symptoms. Most patients can be helped, and with few exceptions most women can be relieved of the majority of the distressing symptoms. Treatment must be individualized, and an evaluation of the
344
A.
SEYMOUR PARKER, JR.
patient's symptoms and personality should suggest the best over-all approach to the correction of her problem. Psychotherapy
Premenstrual tension is not amenable to psychotherapy alone, but a simple explanation can be of considerable assistance in helping the patient understand her condition and can improve the patient's attitude and reaction of her symptoms. 7 A realization that there is an underlying physiologic basis for the cyclic occurrence of symptoms is helpful. The patient is relieved to learn that her symptoms are not imaginative and purely psychogenic, and is encouraged when she realizes that a basic program will relieve her symptoms. Diuretics, Tranquilizers and Stimulants
Measures designed to prevent fluid retention are a basic part of therapy for the premenstrual tension syndrome and are effective in relieving an appreciable number of nervous and somatic complaints. Although ammonium chloride in doses of 1 gm. three times daily and other oral diuretics are effective in the prevention of fluid accumulation, it is necessary to "treat the patient as a whole" and avoid the inconvenience of taking too many medications. I agree with other authors2 • 6 that a preparation with multiple ingredients is useful in alleviating or lessening many premenstrual symptoms, regardless of their severity. A useful preparation is Pre-Mens tablets which contain ammonium chloride to lessen water retention; homatropine methylbromide to lessen generalized tension and certain gastrointestinal complaints; caffeine for moodiness and minor depressive symptoms, and vitamin B complex as an aid in the metabolism of estrogens by the liver. Another useful agent is M-Minus 5, which contains Pamabrom and acetophenetidin for the control of fluid retention and the alleviation of pain. Although Pre-Mens tablets with 2.5 mg. of d-amphetamine and Pambromal tablets with carbromal containing the equivalent amount of d-amphetamine may be used, I prefer to prescribe two Pre-Mens tablets three times daily after meals, or one to two M-Minus 5 tablets four times daily and recommend amphetamine preparations in varying dosages depending upon the extent of the associated symptoms of lethargy, moodiness, disinterest or depression. Patients react differently to a fixed dose of an amphetamine preparation and the hyperreactive patient may do better on an equivalent dose of a less stimulating preparation, such as Dexamyl. Others who are listless and have diffuse headaches, vague pains or cramps obtain greater relief by the addition of Edrisal or Daprisal in proper dosages. In patients with definite premenstrual symptoms without edema, often fluid retention cannot be demonstrated clinically even by means of basal weight charts-50 to 70 per cent_of patients will show some weight gain
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before any specific therapy is begun. Because of the varied nature and severity of the complaints, it is wise to try the simplest procedures first and to have the patient return at monthly intervals, or every second month if she lives at a distance. In addition to a low sodium regimen and one of the multipurpose drugs mentioned, a prescription containing a little phenobarbital and tincture of belladonna for increased tension and anxiety, or a little amphetamine or Dexamyl for predominantly depressive symptoms, may prove helpful. In many women with symptoms of moderate severity this program will prove satisfactory. To determine the effectiveness of the initial therapeutic program, patients are instructed to record graphically the basal weight on arising two to three times a week during the postmenstrual phase and daily for the ten-day interval before each period and to note their predominant complaints. Patients with visible edema (such afi localized swelling of the ankles and puffiness of the hands), localized headaches which are not consistent with migraine, or abdominal distention and vague, rheumatic-like pains, are advised to take an oral diuretic (such as Diamox, Diuril, N eohydrin or Esidrex) on those mornings during the premenstrual phase of the second period if there has been a gain of more than 1 pound in basal weight, or a definite recurrence of their distressing premenstrual symptoms, or both. In a majority of women with the more severe forms of this syndrome, and even in patients referred by psychiatrists for relief of various psychosomatic complaints superimposed on a nervous disorder, the above measures will afford satisfactory relief. In our experience, patients with the classic manifestations of migraine which recur premenstrually are seldom relieved by the routine measures which lessen tension and prevent fluid retention. Although estrogen, progesterone, testosterone and the adrenocortical steroids with minimal salt-retaining properties may prevent the cyclic occurrence of migraine in an occasional patient, ergotamine preparations, such as Cafergot, must be taken at the onset of symptoms for satisfactory relief. Hormonal Therapy
Based on the concept that the symptoms of premenstrual tension are caused by a relative excess of estrogens or a deficiency of progesterone during the premenstrual phase, many attempts have been made to correct this hormonal imbalance-and thus relieve the symptoms-by the use of testosterone to suppress excess endogenous estrogens or by the supplementary administration of progesterone. Because of unavoidable variations in the appraisal of patients with predominantly subjective complaints and because of the differences in dosage and methods of administration of the hormone given, it is difficult to evaluate the effectiveness of hormonal therapy in this syndrome. When taken as the only form of therapy, oral testosterone and ethisterone preparations would appear to be of equal effectiveness; perhaps
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30 per cent of patients will obtain satisfactory relief. Although eithisterone must often be given in larger dosages than testosterone to be of equal value, the dose of testosterone must be restricted to prevent untoward effects. In selected cases of mild to moderate severity, testosterone and ethisterone have been reported as effective in up to 85 per cent of cases,7. 8 but this has not been our experience. Although the results with each method of hormonal administration vary from unsatisfactory to very good, depending on the series of cases reported, progesterone given intramuscularly is considered to be the most effective. In a large series of cases in which progesterone therapy was evaluated and found to be effective, about 80 per cent of the patients required intramuscular injections on alternate days during the premenstrual phase, or progesterone implantations, for satisfactory to effective relief.3 Obviously, the inconvenience and expense of any single form of therapy requiring multiple injections prohibit its use in clinical practice. A long-acting preparation such as Delalutin, * which shows some progestational effects within three days of the injection and lasts for approximately 14 days in most patients, is a more convenient form of therapy. Delalutin is worthy of more extensive trials, with and without other measures, in patients whose symptoms are of varying severity. Many patients treated by the cyclic administration of various hormones or by progesterone given intramuscularly or by implantations, whose course has been followed for prolonged intervals, no longer need therapy after variable periods of time; in some of these patients the symptoms may recur at a later date. Although this might imply that a specific type of hormonal therapy has corrected the endocrine imbalance, this mayor may not be true, but it is open to question. Since many patients whose symptoms have been controlled by diuretics and tranquilizers with or without hormones may be able to discontinue therapy or omit most of the premenstrual program in about six months (and yet relapse may occur), there is no reason to think that hormonal therapy is any more corrective than the symptomatic approach. When hormones are the only form of therapy, they usually have to be given in relatively large doses before satisfactory relief is obtained. Patients with moderately severe premenstrual complaints may require methyltestosterone in doses of 10 mg. twice daily for adequate control, and such doses tend to delay the menses and may intensify menstrual cramps or aggravate skin blemishes. When the symptoms are of mild to moderate severity, ethisterone tablets, 30 to 150 mg. daily from the fourteenth through the twenty-sixth day, have been satisfactory in a majority of cases. In the failures and in patients with severe symptoms, progesterone may be effective in doses of 25 to 50 mg. intramuscularly on alternate days from the fourteenth through the twenty-sixth day. The administration of 1.5 to 2.0 cc. of Delalutin may be tried on the
* Hydroxyprogesterone caproate dissolved in sesame oil with 30 per cent benzyl benzoate, 125 mg. per cubic centimeter.
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twelfth day of a 28 day cycle; the dosage may have to be altered the following month for adequate relief. Since there is no apparent advantage in the use of hormones, a better program seems to be treatment with the simpler procedures first, reserving hormonal therapy for patients whose symptoms are not adequa tely controlled by the usual measures. Methyltestosterone, given premenstrually in doses of 5 to 10 mg. daily, may be helpful in the further control of symptoms, especially when mastalgia is a prominent complaint. Ethisterone or progesterone buccal tablets, 10 mg. two to three times daily from the fifteenth through the twenty-sixth day of a 28 day cycle, may prevent the remaining symptoms resulting from hydration and relieve symptoms of tension, anxiety or fatigue. This therapy is especially helpful for women whose periods are prolonged or profuse and for patients with 26 to 35 day cycles, whose symptoms may occur prior to the institution of preventive therapy because of a short cycle. When patients are only partially relieved, an increase in dosage to one 25 mg. tablet two to three times a day may be necessary. Another effective treatment for married women is the intravaginal insertion of one 50 mg. Colprosterone tablet on alternate nights from the sixteenth through the twenty-sixth night. If the above dosages of oral or intravaginal tablets fail to produce the desired effects, a trial of progesterone intramuscularly for one to two months may be worth while. If patients still complain of anxiety and tension with periods of emotional instability before or after the addition of hormonal therapy to the program, tranquilizers may be effective. The dermatoses of the premenstrual tension syndrome are not readily explicable on the water-retention hypothesis. In the few patients we have seen with urticaria or a painful herpetiform stomatitis, the premenstrual administration of oral cortisone therapy has been helpful. CONCLUSION
With few exceptions in our experience, most patients benefit from measures designed to eliminate fluid retention and tailored to fit the individual problems. Although the etiology and the interrelated mechanisms of a possible endocrine imbalance are unknown, the addition of sedatives, tranquilizers, stimulants and hormonal therapy in addition to simple psychotherapy may be indicated for the individual patient. Most patients obtain satisfactory relief from the distressing symptoms of the premenstrual tension syndrome by an individualized program adjusted to the needs of the patient. REFERENCES 1. Ferguson, J. H.: La tensi6n pre-menstrual y SUB efectos Bobre el trabajo. Arch. mM. Cuba 7: 189-190 (July-Nov.) 1956. 2. Greenblatt. R. B.: Premenstrual ten8ion syndrome. GP 11: 66-68 (March) 1955.
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3. Greene, R. and Dalton, K.: Premenstrual syndrome. Brit. M. J. 1: 1007-1014 (May 9) 1953. 4. Greenhill and Freed: Quoted by Freed, S. C.: History and causation of premenstrual tension. Internat. Rec. Med. 166: 502-504 (Nov.) 1953. 5. Kroger and Freed: Quoted by Freed, S. C.: History and causation of premenstrual tension. Internat. Rec. Med. 166: 465--468 (Nov.) 1953. 6. Morton, J. H.: Treatment of premenstrual tension. Internat. Rec. Med. 166: 505510 (Nov.) 1953. 7. Rees, L.: Premenstrual ten8ion syndrome and its treatment. Brit. M. J. 1: 10141016 (May 9) 1953. 8. Simmons, R. J.: Premenstrual tension: review of 288 cases. Obst. & Gynec. 8: 99-102 (July) 1956. 9. Suarez-Murias, E. L.: Psychophysiologic syndrome of premenstrual tension with emphasis on psychiatric aspect. Internat. Ree. Med. 166: 475-486 (Nov.) 1953.