- Email: [email protected]
Disorders of Menstruation
DISORDERS OF MENSTRUATION JOHN ROCK,
M.D.*
BLEEDING from the endometrium may be functional or dysfunctional, and either form may be pathologic in cause or in effect, or in both. Pathologic flow is most frequently induced by morbid changes in the uterus, usually metaplastic-occasionally inflammatory. Because the metaplastic changes which cause bleeding are usually neoplastic and often malignant, this possible cause of disturbed uterine flow must be kept constantly in mind. Cancer of the cervix is common enough in women in their twenties-and of the endometrium in those in their thirties-to require biopsy of the cervix or curettage of the endometrium, or both, when intermenstrual staining is recurrent or flow excessive and prolonged. Pelvic inflammatory disease should also be ruled out, as well as pathologic changes in the ovary, the pituitary and the thyroid. When disturbance of flow originates in diseased conditions of the latter two glands, it is usually only a part of a multiform disorder. Sometimes it is the one most evident to the patient; hence this constitutes her complaint. A general physical examination with careful bimanual pelvic palpation and x-rays or special tests, as indicated, are requisite in all cases. The following discussion is limited to nonpathologic forms of functional and dysfunctional uterine bleeding.
TYPES OF NONPATHOLOGIC DISORDERS
Menstruation, strictly speaking, is the "monthly" flow resulting from the normal functioning of the endometrium as a tissue which "proliferates," becomes "secretory," and finally "deciduates," in response to the cyclic production in the ovary, first of increasing amounts of estrogen, then of estrogen plus progesterone, and finally to the rapid decrease of both. This sequence is produced by activation of follicles, ovulation, and functioning of the corpus luteum, followed by its regression. In all cases where the ovarian hormones are thus cyclically elaborated, although their absolute amounts, as well as their relative proportions may vary, the flow from the endometrium responding to them is considered "functional. U If, on the other hand; the growth of follicles does not result in the rupture of at least one, and the formation of a corpus luteum, the flow resulting from such disturbed activity is considered "dysfunctional." • Visiting Surgeon and Director of Fertility, Endocrine and Rhythm Clinics, Free Hospital for \Vomen, Brookline, Massachusetts; Research Associate in Obstetrics and in Gynecology, Harvard University Medical School. 1217
1218
JOHN ROCK
Functional Disorders of Menstruation.-From the end of adolescence to the beginning of the climacteric, the healthy mature ovary completes the cycle of follicular growth, ovulation and luteal activity in about 28 days, arbitrarily expressed as (28 + 2) ± 2 days, and the endometrium responds with flow on the 25th to the Brd day.* vVithin these limits, the normal individual usually, not always, completes the ovarian cycle in x + 2 days, x representing a single number within the range (28 + 2). Often the sequence of maturation, ovulation and luteinization takes up more or less than x + 2 days in the normal woman. If so, it usually does this repeatedly, for many months or years at a time. For no woman, however, is x a constant. Many ;women have "short" cycles or "long" cycles. The resultant flow is in short or long cycles, but so long as ovulation occurs, bleeding is ,fairly cyclic. If this cyclic flow following ovulation takes place regularly within the limits: (28 ± 2) ± 2, it is still to be considered typical and thus in order. TEMPORAL DEVIATIONs.-An habitual deviation from such limits of cycle length, provided ovulation occurs, is a functional disorder of menstruation, since it is caused by change in the length, and not the completeness, of the ovarian cycle. In other words, fairly regular postovulatory flow occurring habitually at intervals shorter than 24 days, or longer than 32 days, is occasioned by the breakdown of a predecidua built up by the normal sequence of ovarian hormones, estrogen and progesterone. The shorter type is called polymenorrhea, because there are more periods in the year than the usual thirteen; the longer type, oligomenorrhea, since there are fewer than thirteen of them. QUALITATIVE AND QUANTITATIVE DEVIATIONS AND THE FACTORS CONDITIONING THESE.-I shall discuss the nature of these temporal deviations and their treatment later. First we must consider differences in the kind of flow. The duration, amount and quality of all periods of functional flow are essentially similar in the individual female throughout many years. The over-all characteristics of flow may vary in one woman during different phases of her mature life, such as before or after marriage, or after parturition, or in succeeding decades, or when domiciled in different geographic areas; but from month to month they are closely alike. The determinants of these characteristics of flow -duration, amount and quality-are but ill-understood; indeed, many are doubtless unknown as such. They are, however, fairly constant for long periods of time. The absolute amount of the estrogen which stimulates proliferation of the endometrium and establishes therein the bleeding potential is one of these factors; the amount of progesterone which conditions the metabolism of estrogen and its degradation, causes the proliferative endometrium to change into the predecidua, and enhances, .. rThe cycle begins on the first day of menstruation and extends up to, but does not include, the first day of the succeeding flow.
DISORDERS OF MENSTRUATION
1219
but also inhibits, the activation of the bleeding potential, is another one; the endometrial response in thickness and vascularity to the ovarian hormones is a third factor; the reaction of the myometrium, as manifested by contraction and relaxation, may be a fourth agent; the intrinsic individual quality of time-rep air-growth must also be involved; and finally, the peculiar chemical and physical characteristics of the blood itself must be a sixth and very important factor. These six factors, and doubtless others, which condition the kind and duration of flow, are fairly constant, not only in the individual healthy mature female, but also in most of her kind. And so there occurs in these women what we consider the standard or typical menstrual flow. This typical flow lasts for about 3 to 7 days, usually 4 or 5; it requires an average of about four napkins per day; and it consists of a fluid mixture of blood, tissue elements, and mucus, occasionally accompanied by a very few small clots. Any appreciable deviation from this type is properly diagnosed a disorder of menstruation. Whatever the type of flow, it is still functional if it is preceded by maturation and rupture of the follicle (ovulation) and corpus luteum formation, for in such a case it is brought about by the normal sequence of estrogen and progesterone secretion and the final decrease of both. When such functional flow persists for less than three days, or requires less than an average of three napkins a day, we call it hypomenorrhea-"less menstrual flow." If it lasts more than seven days, or requires more than an average of four napkins per day, it is called hypermenorrbea-"more menstrual flow." Something will be said later of the causes of such disturbances and their treatment. COMBINATIONS OF TEMPORAL AND QUALITATIVE-QUANTITATIVE ABNORMALITIES.-Of functional disorders, we have then four main types: oligo-, poly-, hypo-, and hypennenorrhea. Besides these simple forms, there mav occur combinations of either of the first two with either of the s~cond two types. The commonest is oligo-hypomenorrhea; the other three forms, poly-hypermenorrhea, oligo-hypermenorrhea and poly-hypomenorrhea do occur, however. It should be emphasized that these types of flow, whether simple or compound, are fairly constant in any individual over long periods; some one of them constitutes the habitual character of her flow. Ovulation and Menstruatiol1.-In ordinary menstruation, occurring in cycles of x ± 2 days, x being any single figure within the limits (28 -+- 2), ovulation takes place within the range of (x - 14) -+- 2, or on about the 14th day before the first day of menstruation. 1 In women who, as we say, menstruate about every 28 days, ovulation, then, occurs not only about 14 days before each period, but also about 14 days after the onset of flow. The first 2 weeks are consumed in the growth of follicles with the maturation and rupture of usually only one of them. The consequent corpus luteum of the ruptured follicle
1220
JOHN ROCK
then functions for 14 days. During the preovulatory phase, estrogen, which stimulates proliferation of the endometrium, is produced in increasing amounts. From a short time preceding and during the 2 weeks after ovulation, the corpus luteum secretes estrogen and progesterone, the latter evoking in the endometrium those cytologic qualities denoting "secretion" or "function." In oligomel1orrbea, when periods of flow closely resembling each other in quality and duration occur at longer intervals than every 32 days, as for instance every six weeks or only every few months, the prolongation of the intermenstrual phase, as far as I have been able to discern, is invariably due to delay in the rupture of the follicle (ovulation)-never to protracted functioning of the corpus luteum. For some unknown reason, either the pituitary hormones, which cause the follicles to grow, fail to appear, or, for equally obscure reasons, the ovaries remain insensitive to these hormones for variable periods. My observations indicate, however, that once ovulation is accomplished, the corpus luteum goes into action and completes its function in 2 weeks. Treatment of this delay in ovulation is discussed later. In po/ymeno1'fbea, postovulatory or functional catamenia habitually occurs in cycles of from 22 to 23 days; i.e., menstruation starts on the 23rd or 24th day of the cycle.* As in oligomenorrhea, the flow is uniform in duration and quality. The underlying disturbance is often to be found in a shortening of the time taken to achieve ovulation. A sufficient number of carefully studied cases has not been analyzed to permit statement of what proportion of the instances of polymenorrhea are due to the speeding-up of follicle-maturation. My guess is that this is so in not less than 50 per cent of the cases. In these, it is important to note that ovulation occurs-as in typical menstruation and in oligomenorrhea-about 14 days before the first day of flow. In these cases, however, it does not occur 2 weeks· after menstruation begins, but in less time than this; i.e., the follicular phase of the cycle is shortened, contrary to the situation in oligomenorrhea where, as mentioned above, this stage is lengthened. The disturbance in this form of polymenorrhea is one of follicular activation to which curative treatment, if any, should be directed. There are two other forms of polymenorrhea in which, although ovulation occurs at the more common interval of 14 days after flow, the succeeding period starts sooner than the 25th day. One form, in which there is flowing about every 2 weeks, is due, not to displacement of the time of ovulation, but apparently to a delay in the immediately postovulatory secretion of sufficient progesterone by the corpus luteum to suppress the bleeding potential, which, as has been stated previously, is established in the endometrium by the estrogen • Flow recurring at intervals of less than 22 days is almost never cyclic for more than 3 or 4 months and is practically always a form of aperiodomenorrhea (discussed later).
DISORDERS OF MENSTRUATION
1221
from the young follicles and released by a change in estrogen metabolism at ovulation time. In such cases, there occurs "ovulatory flow," as is normally seen in many subprimates; for example, the bitch and the cow. Slight bleeding into the uterus of this character doubtless takes place in many women, as Hartman 2 has shown to be the case frequently in the macaque monkey where the bleeding was usually found to be in microscopic amounts. In women, Papanicolaou3 noted that almost 24 per cent of vaginal smears taken on the 14th day contained microscopic traces of bood. This flow at ovulation time is sufficiently gross to attract the attention of probably less than 5 per cent of women. In some cases, it may require protection for several days. The affected patient usually complains of periods occurring about every 2 weeks; or, more commonly, she says that she has troublesome flow which starts about 1 week after her regular period is over. Diagnosis is usually easy: only alternate periods resemble each other in quality, quantity and duration of flow. The intermenstrual discharge is occasionally constant in these characteristics, but more often it is variable, and in most cases it does not occur to a troublesome degree in all cycles. I have not attempted to stop this kind of functional flow. One or two well-timed intramuscular injections of about 5 mg. of progesterone theoretically would do so. The last group of cases of polymenorrhea (where catamenia habitually recurs on the 23rd or 24th day) are those in which ovulation takes place in the standard time of about 14 days after the flow, but the corpus luteum does not function for the full 2 weeks following. In these cases, progesterone is thus prematurely withdrawn and menstruation is found to take place from an incompletely developed predecidua. This functional deviation undoubtedly contributes to many cases in which the so-called "rhythm" practice of contraception fails, depending, as it does, on the theory that ovulation invariably occurs about 14 days before t~ first day of flow. Except in the interest of relieving infertility, I do not attempt to influence this minor disturbance of menstrual frequency. Daily ingestion of 0.1 mg. of diethylstilbestrol or of ethinyl estradiol, beginning on the tenth day of the cycle, together with intramuscular injections on the 16th and 19th days, of 3 to 5 mg. of progesterone, will prolong the cycle in about half the cases. Dysfunctional Disorders of Menstruation.-Amenorrhea, the absence of menstruation, is a dysfunctional disorder. It is called primary, if flow has never occurred, and secondary, if previously recurrent catamenia has ceased. For how long must this freedom from flow prevail before the patient is considered amenorrheic? Convention has said 3 months. Many such cases were better termed "oligomenorrhea," for in them ovulation takes place normally, about 14 days before the flow. Insight acquired during the last decade into the hormonal basis of amenorrhea makes it advisable to limit such a diagnosis to an interval
1222
JOHN ROCK
without catamenia of, shall we say, at least 6 months. Accepting such a limitation of the diagnosis, we may consider that amenorrhea is always due to hypoestrinism, an amount of estrogen insufficient to cause proliferation of the endometrium and the establishment of the bleeding potential. I shall mention later the frequent cases where flow is absent, usually for less than 6 months, in which highly proliferated endometrium denotes prolonged secretion of appreciable amounts of estrogen. On the other hand, cases of amenorrhea for 6 months or more are probably always due to abnormally low secretion of estrogen, which is caused either by a failure of the ovarian follicles to respond to a normal or an increased amount of hormones from the anterior pituitary gland, or to lack of these substances because of pituitary dystrophy. Treatment, as described below, must be varied with due regard to different causes. Aperiodomenorrhea.-Other nonpathologic disorders of menstruation, which are not included in the categories mentioned-amenorrhea, oligo-, poly-, hypo- and hypermenorrhea-I have grouped under the diagnosis aperiodo-, or "immeasurable," menorrhea. Even this is somewhat of a misnomer, as all patients thus affiicted do not flow with any degree of "monthly" regularity; but this is also the case with the terms "oligo-" and "polymenorrhea," wherein the syllable "men," meaning "monthly," is also not invariably applicable. They are old and honored terms, however, so can safely engross this newcomer. Aperiodomenorrhea corresponds to the well known category of dysfunctional flow, menometrorrbagia, metropatbia haemorrhagica, or uterine insufficiency of the older clinicians. In this condition, the bloody uterine discharge is immeasurable in incidence, duration, quantity and quality; it may occur every few days or weeks or be absent for months and last for days or weeks, even months. From time to time it may vary in amount from staining to excessive flow. Clots of various sizes may often be passed along with the fluid discharge. Aperiodomenorrhea is due to failure of tny one of many growing follicles to ovulate. Thus, no corpus luteum is formed; no progesterone is secreted. The bleeding potential is established in the endometrium by the estrogen of many active follicles, but is inhibited, not by progesterone, but only by this estrogen and then only so long as that critical change in the quantity or quality of the estrogen that will activate the bleeding mechanism fails to occur. Experimentally, in castrates, the sudden withdrawal of prolonged doses of estrogen is followed by bleeding from a proliferated endometrium. Likewise, if administration is continued indefinitely for many months, bleeding also occurs, even during the treatment. Without digressing into a discussion of the metabolism of estrogen and the control exerted on its degradation by progesterone,4 we may infer from observation of ovaries in these cases, as well as from experimental work on monkeys,5 that the absence of progesterone is the primary cause of the aperiod-
DISORDERS OF MENSTRUATION
1223
lClty of flow. Therapeusis, discussed later, is therefore directed to inducing ovulation and subsequent formation of the corpus luteum, and, failing this, to substitution of a synthetic progesterone for that which the ovary fails to produce. DIAGNOSIS OF MENSTRUAL DISORDERS
Recognition of the form of menstruation, normal or abnormal, functional or dysfunctional, is easily made by biopsy of the endometrium. This has been discussed in detail elsewhere6 - s and criteria are given for differentiation between early and late proliferation (stages which indicate follicular growth) and for successive phases of secretory activity denoting the presence and the age of the corpus luteum. Frequently one may dispense with biopsy, although without it one can never be absolutely sure of the true nature of bleeding tissue or of the quality of ovarian activity. We clinici:llls will profitably keep in mind the following: (1) When periods of flow occur at widely varying intervals or differ markedly in quality, quantity or duration of flow, ovulation is almost surely absent. (2) The anovulatory female may spontaneously ovulate any time. TREATMENT OF MENSTRUAL DISORDERS
From the above discussion it is evident that the treatment of menstrual disorders must be directed to three objectives: (1) To diminish the amount of flow: in hypermenorrhea and aperiodomenorrhea. (2) To cause ovulation: in amenorrhea; oligomenorrhea; aperiodomenorrhea. (2a) Failing ovulation, at least to produce regular flow. (3) To prolong the life of the corpus luteum, as in some cases of pol ymenorrhea. Since we do not admit that the blood lost in menstruation relieves the body of noxious elements, we see no need of increasing the flow in most cases of hypomenorrhea. In a few instances, when hypomenorrhea appears first in the thirties after previous habitually more profuse catamenia, this scanty flow may be considered as the forerunner of amenorrhea, or of a phase of aperiodomenorrhea, which will usher in an early menopause. In these cases the therapeutic aim is to preserve or reestablish normal ovulation and function of the corpus luteum; i.e., objectives (2) and (3) mentioned above. I. Means of Limiting the Flow of Blood.-Six factors have been mentioned which probably condition the actual bleeding from the uterus. The first is the amount of estrogen and the duration and degree of its proliferative effect upon the endometrium and its vascular system. Progesterone and testosterone have been used clinically to restrain this factor, but I know of no biochemical or cytologic studies in humans that show the actual effect of these hormones. In hypermenorrhea, treatment theoretically should be given during the preovulatory
1224
JOHN ROCK
or proliferative phase of the cycle when either hormone may unfortunately inhibit ovulation. Except by the use of pellets, treatment must be repeated during each cycle, and the cost of solutions for injection or, in the case of testosterone, of tablets, is prohibitive. Until more extensive studies of the use of pellets are made, this method of decreasing the effect of estrogen in the endometrium without inhibiting ovulation is denied to clinicians. Greenblatt9 reported the helpful effect of pellets of testosterone propionate in cases of "functional menometrorrhagia" (what I call "dysfunctional aperiodomenorrhea," since ovulation is absent), as well as in some cases of functional hypermenorrhea. In discussing this paper, Salmon stated that he and Geist did not get such good results. There is hope that in the future we may decrease excessive estrogen stimulation of the endometrium by the male sex hormone. At present, other methods must be used to diminish excessive flow. Years ago, the beneficial effect of injections of chorio1lic hormone (Antuitrin-S; Follutein; A.P.L.; Korotrin, etc.) of the order of 1500 rat units, divided into about three doses, given daily, was recognized. Continued use has shown a beneficial effect in only about 30 per cent of the cases, and then only if the hormone is given during the flow. At present, I occasionally use it in functional hypermenorrhea, beginning on the second or third day of the profuse period. Theoretically, its influence is exerted on the bleeding potential. Its use is unsatisfactory, since the effect is limited to the single treated catamenia. The second factor in bleeding is the amount of progesterone which conditions the metabolism of estrogen. Progesterone should not be used in functional hypermenorrhea. Although progesterone may inhibit expression of the bleeding potential, the latter may be enhanced by this hormone, so that withdrawal of it increases the flow. On the other hand, in hyper-aperiodomenorrhea, progesterone is the hormone of choice, as will be discussed later. The other four factors in bleeding are the tissue response of the mucosa to estrogen stimulation, the reaction of the myometrium, the repair potential of the remaining mucosa, and the clotting power of the blood. In respect to these, we must depend on a normal basal metabolic rate, a normal blood picture, a normal position of the fundus, a normal diet of high vitamin content, and good hygiene. I have found styptics and oxytocics of no avail. Curettage will relieve the condition sometimes for several months, more often for only one. Radium in doses of 1000 mg.-hrs. will stop the bleeding for many months, but should be used only in those cases of aperiodomenorrhea occurring so late in the thirties or in the forties that a prolonged or perhaps permanent suppression of ovulation, a not uncommon effect of such treatment, is no great hardship. I believe the same can be said of the only slightly less drastic but more popular use of x-ray in three divided doses, each of 50 roentgens. Even though he is unwarrantably not fearful of preventing ovulation, the careful clinician will
DISORDERS OF MENSTRUATION
1225
take heed of the geneticist's warning that x-rays may permanently affect genes to the detriment of distant descendants. 1o Treatment by irradiation is supposed to destroy the secretory activity of those follicles which are upsetting the endocrine balance. The same end is sought by those who recommend resection of the ovaries with careful removal of all existing follicles. I have had no convincing experience with this method, so, while recommending caution and conservatism, will refer the reader to the report by Robinson.ll When reproductivity is of no concern, debilitating hypermenorrhea in women in their late thirties or older is often best treated by hysterectomy without castration. 2. Induction or Acceleration of Ovulation.-Two substances are needed to produce ovulation: the follicle-stimulating hormone and a critical proportion of luteinizing hormone.12 The former we have in various preparations. Some are derived from anterior pituitary glands of sheep or horses; some are obtained from the serum of pregnant mares; and some are extracted from the urine of pregnant women. They will all stimulate growth of follicles to a greater or less extent, but only very rarely, ·if at all, and then by inexplicable accident, is their use followed by ovulation. The necessary luteinizing hormone is present in some of these, notably Gonadophysin (Searle) from sheep's anterior pituitary gland, and in the chorionic hormone from the urine of pregnant women, and in Synapoidin (Parke, Davis), a combined pituitary and chorionic hormone, but unfortunately, the proportions are not physiologic, nor do we know how to adjust them. And so we are forced to utilize ill-defined empirical means to encourage ovulation in amenorrhea, severe oligomenorrhea, and in aperiodomenorrhea. In all these conditions, our first concern is for the patient's basic mental and physical health. Especially anemia, disorders of the thyroid gland, obesity, leanness, or dietary deficiency, and any emotional strain should receive thorough study and treatment. I believe our present therapeutic limitations make it undesirable to do much more than this in true oligomenorrhea, in which ovulation, however infrequent, is demonstrated by endometrial biopsy done on the first day of the delayed flow. Such patients often complain of lassitude and irritability during the long intervals between infrequent catamenia. Small daily doses of a combined estr6gen, such as 1000 international estrone units of Estrogenic Hormone (Reed and Carnrick), obtained from pregnant mares' urine, or of such synthetic products' as ethinyl estradiol (Schering), or of diethylstilbestrol, in doses of only 0.1 mg., will usually relieve those symptoms and may possibly stimulate the gonadotropic activity of the anterior pituitary gland. The dosage must be kept below the critical level, variable among individual patients, at which the gland is inhibited, instead of stimulated. Another and purely haphazard treatment, indulged in by many clini-
1226
JOHN ROCK
cians and occasionally followed by improvement, consists of intramuscular injections of any of several preparations of estradiol, such as Progynon-B or OP (Schering), or of the ketohydroxyestrin, such as Theelin (Parke, Oavis), in doses of about 5000 I.U., given at weekly or biweekly intervals. In cases without vasomotor or emotional disturbances, others try weekly injections of progesterone, such as Proluton, (Schering) in doses of 5 mg. given intramuscularly. Use in this manner of either estrogens or progesterone is unscientific; but, with the reservation made above regarding hypophyseal-inhibiting doses of the former, it is apparently quite harmless; and no one can say these hormones surely do not enhance the effectiveness of general health measures in those cases· improved after the combined treatment. Because the extracts from human pregnancy urine, from the anterior pituitary gland, and from pregnant mares' serum are all folliclestimulating in varying degrees, injections of one or the other are still prescribed by some clinicians in the hope of evoking ovulation. I have seen no good results from such treatment, although I have experimented with many of these gonadotropes extensively during the last ten years. Whereas to produce ovulation in amenorrhea and in aperiodomenorrhea is our main objective, to produce flow in the former and to regulate it in the latter is often quite satisfactory to the patient, especially if fertility is not an object. In aperiodomenorrhea, estrogen is present in variable amounts, and usually there is an established bleeding potential. When aperiodic flow is scanty, regularity and increase in amount may frequently be obtained by oral use of an estrogen for 21 days; e.g., 0.1 to 0.2 mg. of diethylstilbestrol, or 0.1 mg. of ethinyl estradiol (Schering). Withdrawal flow usually occurs within 10 days of cessation of dosage. This sequence may be kept up for many months, each 21-day period beginning with the onset of flow. When the irregular flow is profuse, biopsy will show the endometrium to be in full proliferation. Secreted estrogen is already excessive so its therapeutic use is contraindicated. Likewise, the folliclestimulating chorion or pituitary hormone should not be used, except, as has been mentioned above, when, during the flow, divided doses totaling about 1500 R.U. of chorionic hormone may be given for its theoretical hemostatic effect in tbe endometrium. To regulate the flow in aperiodomenorrhea, progesterone is necessary. This is best given by 5 daily intramuscular injections, each of 5 mg. If these are started during the flow, it will almost invariably cease before the series is completed and recur in moderate amount within 10 days after the last injection. With this flow, subsequent to injection. the surface of the endometrium is shed, as in menstruation. This is what Albright13 calls "medical o. and c." After usually not more than 7 days, flow ceases, not to recur for several weeks. It is my
DISORDERS OF MENSTRUATION
1227
custom to repeat the series of five injections three or more times at intervals of 28 days. Each series is followed by a semblance of normal catamenia. Successive periods of flow may become more scanty, indicating that estrogen is not present in sufficient quantity. This is easily remedied by adding 1 or 2 mg. to the first two or three injections of progesterone. I usually use Progynon-B or OP (Schering) for this purpose. A very small percentage of patients treated thus will ovulate. Many more will flow fairly regularly for several months following the last of three or more series of injections. To establish flow in amenorrhea, the same methods are used. Some patients, in whom there is already an appreciable secretion of estrogen, will respond to the 21-day treatment with only oral estrogen, mentioned above as of value in cases of hypo-aperiodomenorrhea. More troublesome and expensive, but also more certain, is the use of 5 daily intramuscular injections of 5 mg. (10 mg. in severe cases) of progesterone, together with 1 to 2 mg. of estradiol, in repeated series every 28 days. 3. Prolongation of Corpus Luteum Ac:tivity.-The third main objective in the treatment of menstrual disorders is to prolong the functional activity of the corpus luteum, as in some cases of polymenorrhea. I know of no way to do this. It might be thought, from the biologic experiments of several years ago,14 that moderate doses of estrogen would stimulate the anterior pituitary gland to pour fonh the luteinizing hormone, which would invigorate the failing corpus luteum. Endo cri no logic relations are not so simple as once they seemed to be. Limitations of space and my knowledge forbid detailed discussion of the probability that not one, but two hormones function in establishing and maintaining the integrity of the corpus luteum for the usual 14 days, and that not only the anterior pituitary gland is involved as the source of the ovarian stimulant, but that the adjacent hypothalamus, reacting to stimuli from both the central and the autonomic nervous systems, also plays a major roleP Attention to the general physical and mental well-being of patients with polymenorrhea, as with other disorders of the reproductive system, already empirically indicated, will be further justified by extended psychosomatic study. At the moment, we may try small doses of ingested estrogen, such as daily doses of 1000 international estrone units of Estrogenic Hormone (Reed and Carnrick), or of 0.1 mg. of either ethinyl estradiol (Schering), or diethylstilbestrol, during the last 18 days of the cycle. If treatment with estrogen is started, even in this dosage, much before 4 days prior to ovulation time, maturation and release of the ovum may be inhjbited, as was found to be so in all cases when larger doses were given. Hi One is tempted to prolong the luteal phase by substitution with synthetic progesterone for the secretion of the failing corpus luteum. In my experience, this does not help in polymenorrhea.
1228
JOHN ROCK
I have found that in cases of inexplicable infertility, associated with short cycles, an injection of 5 mg. of Proluton (Schering) on the second and again on the fifth day after the estimated ovulation date, is often effective for the relief of barrenness. I believe it is useless to attempt to prolong the luteal phase except in such cases where fertility is the object. In others, our ignorance of means to regulate the complexities involved, especially as the misery, when its cause is explained to the patient, is minimal, renders unjustifiable the expense and the uncertainties of treatment. SUMMARY
1. Nonpathologic disorders of uterine flow may be divided into
two categories: functio1lal, in which ovulation occurs; and dysfll11ctional, in which follicles, however closely they approach rupture, fail to complete this process. Dialectics demands somewhat arbitrary limits to what we should call normal menstruation. The author's criteria are stated below. 2. The ovarian cycle of follicular growth, maturation of the ovum in at least one follicle, rupture of this follicle, corpus luteum formation and regression takes place ordinarily and normally in (28 -+- 2) ±2 days. For months or years at a time, the cycle in most women remains as of x -+- 2 days, x being any number within the limits (28 ± 2). Almost all women will have several cycles in the course of a year which extend beyond their pattern-range. When the cycles are habitually in the lower range of from 22 to 23 days in length, the condition is termed polymenorrhea. \-Vhen menstruation frequently occurs at intervals of 21 days, ovulation is almost certain to have failed, and the condition is dysfunctional. When cycles are habitually of the longer variety and menstruation takes place at intervals longer than 32 days, even up to several weeks or months, the condition is called oligonzenorrhea. Ovulation, in such cases, may occur as infrequently as only two or three times a year . . Flow occurring at fairly regular intervals but persisting for longer than 7 days, or requiring more than an average of four napkins per day, is called hypernzenorrbea. If fairly cyclic flow lasts less than 4 days and requires less than an average of four napkins per day, it is called hypomenorrbea. Functional disorders may also appear as combinations of these four main t~Tpes; i.e., oligo-bypomenorrbea, poly-bype1711e1l0rrbea, and so forth. The significant characteristic of functional flow (always preceded by ovulation) is that it occurs in fairly constant cycles and that the bleeding is fairly similar in duration, quality and quantity in all . the periods of flow. 3. The regularity and similarity of periods in normal menstruation, as also in functional disorders thereof, are due to the fact that the
DISORDERS OF MENSTRUATION
1229
corpus luteum normally develops only after ovulation and is a gland of finite activity. It functions for about 14 days, secreting the progesterone which enhances and controls the bleeding potential already established by estrogen from preovulatory follicles. This potential, the ability and tendency to bleed, is expressed by flow when the gland finally regresses. (a) In oligomenorrhea, the delay in flow is due to prolongation of the preovulatory phase; the luteal or postovulatory phase remains at about 14 days. (b) In polymenorrhea, the shortening of the cycle is due usually to acceleration of ovular maturation and early rupture of the follicle, occasionally to premature regression of the corpus luteum. In the latter case, ovulation deceptively occurs in less than the expected 14 ± 2 days before the first day of the succeeding flow. (c) False polymenorrhea appears in those who flow appreciably, not only on regression of the corpus luteum, but also, as do many sub primate mammals, with ovulation. Such a condition is easily recognized: only alternate periods of flow resemble each other, and the intervals between flowing are of the order of 14 days. (d) In hypomenorrhea, there is no failure of ovulation, and the corpus luteum functions normally. The endometrium is thinner than is usual, and the bleeding potential is less. (e) In hypermenorrhea, the ovarian cycle is normal, but proliferation of the endometrium is excessive and the bleeding potential is enhanced. 4. There are two dysfunctional nonpathologic disorders of menstruation: namely, amenorrhea and aperiodo- (or immeasurable) menorrhea. In both conditions, ovulation fails to occur for many months or years. (a) The habitually anovulatory woman may ovulate any time. (b) The term amenorrhea is best used to characterize the absence of flow for 6 months or longer. (If the flow occurs more frequently than this, and if the condition is not oligomenorrhea, it were more accurately classified as aperiodomenorrhea.) Amenorrhea, as defined, is caused by a failure of follicular devel,opment, and thus an insufficiency of estrogen necessary to establish a bleeding potential. (c) In aperiod01nenor-rhea, follicles approach maturity in ever varying numbers and degree, but none achieves ovulation, and so no normal corpus luteum, which would -regulate follicular development and estrogen metabolism, is fornled. The intensity of the bleeding pote'ntial is now great, now small. For variable periods it is built up and inhibited by increasing supplies of estrogen only to be released aperiodically, as some follicles regress, causing so-called "estrogen withdrawal bleeding." This' will vary in amount, quality and duration, according to the extent of endometrial proliferation, the inten-
1230
JOHN ROCK
sity of the bleeding potential, and the promptness of the growth of new follicles, which will raise the concentration of estrogen up to a recurring inhibitory point. 5. The treatment of menstrual disorders requires, first of all, meticulous attention to mental and physical hygiene. In addition, there are three more specific objectives: (a) to diminish the amount of flow, as in hypermenorrhea and in aperiodomenorrhea; (b) to cause ovulation, as in amenorrhea, marked oligomenorrhea, and aperiodomenorrhea; or, failing in this, at least to produce flow at acceptable intervals; (c) to prolong the life of the corpus luteum, as in some cases of polymenorrhea. To accomplish these ends, we have, besides measures of general health, various hormones and stilbestrol derivatives. (a) Extracts of the anterior pituitary gland of sheep, which are clinically follicle stimulating in varying degrees. They do not, except rarely and apparently accidentally, cause ovulation, although they do sometimes evoke slight flow. (b) Serum gonadotropes, derived from the serum of pregnant mares, which are similar in origin and effect to the anterior pituitary extracts. (c) Chorionic hormones, derived from the urine of pregnant women, which are mildly luteinizing and in addition have a slight inhibitory effect on the bleeding potential. (d) The estrogens, including stilbestrol derivatives, which stimulate the endometrium to proliferate and establish therein the bleeding potential. These hold in restraint this tendency to bleed, only to precipitate "withdrawal flow" when they themselves are withdrawn or catabolized. In small amounts, they may sometimes stimulate anterior pituitary gonadotropic activity. (e) Progesterone, which enhances but, more strongly than estrogen, inhihits the hleeding potential during its use, and promptly precipitates flow from the estrogen-conditioned endometrium when it is withdrawn. BIBLIOGRAPHY
I. Rock, .l. and Hcrtig, A. T.: Information Regarding thc Time of HUlllan
Ovulation Derived from a Study of 3 Unfertilized and 11 Fertilized Ova. Am . .l. Ohst. & Gyncc., 47:343-356 (March) 1944. 2. Hartman, C. G.: The Homology of Menstruation. New Observations on Intermenstrual Bleeding in the Monkey. .l.A.M.A., 92:1992-1995 (June 15) 1929.
3. Papanicolaou, G. N.: The Sexual Cycle in the Human Female as Revealed by Vaginal Smears. Am. J. Anat., 52:519-637 (May) 1933. 4. Smith, O. W., Smith, G. V. and Schiller, S.: Clinical Experiments in Relation to the Excretion of the Estrogens. Ill. Urinary Estrogens in a Normal Menstrual Cycle and in a Case of Essential Dysmenorrhea. Am. J. Obst. & Gynec., 45:15-22 (Jan.) 1943.
DISORDERS OF MENSTRUATION
1231
5. Hisaw, F. L.: The Interaction of the Ovarian Hormones in Experimental Menstruation. Endocrinology, 30:301-308 (Feb.) 1942. 6. Rock, J. and Bardett, M. K.: Biopsy Studies of Human Endometrium: Criteria of Dating and Information About Amenorrhea, Menorrhagia and Time of Ovulation. J.A.M.A., 108:2022-2028 (June 12) 1937. 7. Rock, J., Barlett, M. K. and Matson, D. D.: The Incidence of Anovulatory Menstruation Among Patients of Low Fertility. Am. J. Obst. & Gynee., 37:3-13 (Jan.) 1939. 8. Rock, J.: The Role of Endometrial Biopsy in Diagnosis. Am. J. Surg., 48:228237 (April) 1940. 9. Greenblatt, R. B.: Implantation of Testosterone Propionate Pellets in Gynecic Disorders. ].A.M.A., 121:17-24 (Jan. 2) 1943. 10. Little, C. C. and Bagg, H. J.: The Occurrence of Two Heritable Types of Abnormality Among the Descendants of X-rayed Mice. Am. J. Roentgenol., 10:975-989 (Dec.) 1923. 11. Robinson, M. R.: The Surgical Treatment of Ovarian Dysfunctions. A Clinical and Pathological Study. Am. J. Obstet. & Gynec., 30:18-36 (July) 1935. 12. Fevold, H. L.: The Follicle Stimulating and Luteinizing Hormones of the Anterior Pituitary. In Sex and Internal Secretions, 2nd ed., edited by AlIen, E., Danforth, C. H. and Doisy, E. A. Baltimore, Williams & Wilkins Co., 1939, pp. 966-1002. 13. Klinefelter, H. F., ]r., Albright, F. and Griswold, G. C.: Experience with a Quantitative Test for Normal or Decreased Amounts of Follicle Stimulating Hormone in the Urine in Endocrinological Diagnosis. J. Clin. Endocrinol., 3:529-544 (Oct.) 1943. 14. Fevold, H. L., Hisaw, F. L. and Greep, R.: Effect of Oestrin on the Activity of the Anterior Lobe of the Pituitary. Am. ]. Physiol., 114:508-513 (Jan.) 1936. 15. Sturgis, S. H.: The Use of Stilbestrol in the Relief of Essential Dysmenorrhea. New England J. Med., 226:371-376 (March 5) 1942.
M.D.*
BLEEDING from the endometrium may be functional or dysfunctional, and either form may be pathologic in cause or in effect, or in both. Pathologic flow is most frequently induced by morbid changes in the uterus, usually metaplastic-occasionally inflammatory. Because the metaplastic changes which cause bleeding are usually neoplastic and often malignant, this possible cause of disturbed uterine flow must be kept constantly in mind. Cancer of the cervix is common enough in women in their twenties-and of the endometrium in those in their thirties-to require biopsy of the cervix or curettage of the endometrium, or both, when intermenstrual staining is recurrent or flow excessive and prolonged. Pelvic inflammatory disease should also be ruled out, as well as pathologic changes in the ovary, the pituitary and the thyroid. When disturbance of flow originates in diseased conditions of the latter two glands, it is usually only a part of a multiform disorder. Sometimes it is the one most evident to the patient; hence this constitutes her complaint. A general physical examination with careful bimanual pelvic palpation and x-rays or special tests, as indicated, are requisite in all cases. The following discussion is limited to nonpathologic forms of functional and dysfunctional uterine bleeding.
TYPES OF NONPATHOLOGIC DISORDERS
Menstruation, strictly speaking, is the "monthly" flow resulting from the normal functioning of the endometrium as a tissue which "proliferates," becomes "secretory," and finally "deciduates," in response to the cyclic production in the ovary, first of increasing amounts of estrogen, then of estrogen plus progesterone, and finally to the rapid decrease of both. This sequence is produced by activation of follicles, ovulation, and functioning of the corpus luteum, followed by its regression. In all cases where the ovarian hormones are thus cyclically elaborated, although their absolute amounts, as well as their relative proportions may vary, the flow from the endometrium responding to them is considered "functional. U If, on the other hand; the growth of follicles does not result in the rupture of at least one, and the formation of a corpus luteum, the flow resulting from such disturbed activity is considered "dysfunctional." • Visiting Surgeon and Director of Fertility, Endocrine and Rhythm Clinics, Free Hospital for \Vomen, Brookline, Massachusetts; Research Associate in Obstetrics and in Gynecology, Harvard University Medical School. 1217
1218
JOHN ROCK
Functional Disorders of Menstruation.-From the end of adolescence to the beginning of the climacteric, the healthy mature ovary completes the cycle of follicular growth, ovulation and luteal activity in about 28 days, arbitrarily expressed as (28 + 2) ± 2 days, and the endometrium responds with flow on the 25th to the Brd day.* vVithin these limits, the normal individual usually, not always, completes the ovarian cycle in x + 2 days, x representing a single number within the range (28 + 2). Often the sequence of maturation, ovulation and luteinization takes up more or less than x + 2 days in the normal woman. If so, it usually does this repeatedly, for many months or years at a time. For no woman, however, is x a constant. Many ;women have "short" cycles or "long" cycles. The resultant flow is in short or long cycles, but so long as ovulation occurs, bleeding is ,fairly cyclic. If this cyclic flow following ovulation takes place regularly within the limits: (28 ± 2) ± 2, it is still to be considered typical and thus in order. TEMPORAL DEVIATIONs.-An habitual deviation from such limits of cycle length, provided ovulation occurs, is a functional disorder of menstruation, since it is caused by change in the length, and not the completeness, of the ovarian cycle. In other words, fairly regular postovulatory flow occurring habitually at intervals shorter than 24 days, or longer than 32 days, is occasioned by the breakdown of a predecidua built up by the normal sequence of ovarian hormones, estrogen and progesterone. The shorter type is called polymenorrhea, because there are more periods in the year than the usual thirteen; the longer type, oligomenorrhea, since there are fewer than thirteen of them. QUALITATIVE AND QUANTITATIVE DEVIATIONS AND THE FACTORS CONDITIONING THESE.-I shall discuss the nature of these temporal deviations and their treatment later. First we must consider differences in the kind of flow. The duration, amount and quality of all periods of functional flow are essentially similar in the individual female throughout many years. The over-all characteristics of flow may vary in one woman during different phases of her mature life, such as before or after marriage, or after parturition, or in succeeding decades, or when domiciled in different geographic areas; but from month to month they are closely alike. The determinants of these characteristics of flow -duration, amount and quality-are but ill-understood; indeed, many are doubtless unknown as such. They are, however, fairly constant for long periods of time. The absolute amount of the estrogen which stimulates proliferation of the endometrium and establishes therein the bleeding potential is one of these factors; the amount of progesterone which conditions the metabolism of estrogen and its degradation, causes the proliferative endometrium to change into the predecidua, and enhances, .. rThe cycle begins on the first day of menstruation and extends up to, but does not include, the first day of the succeeding flow.
DISORDERS OF MENSTRUATION
1219
but also inhibits, the activation of the bleeding potential, is another one; the endometrial response in thickness and vascularity to the ovarian hormones is a third factor; the reaction of the myometrium, as manifested by contraction and relaxation, may be a fourth agent; the intrinsic individual quality of time-rep air-growth must also be involved; and finally, the peculiar chemical and physical characteristics of the blood itself must be a sixth and very important factor. These six factors, and doubtless others, which condition the kind and duration of flow, are fairly constant, not only in the individual healthy mature female, but also in most of her kind. And so there occurs in these women what we consider the standard or typical menstrual flow. This typical flow lasts for about 3 to 7 days, usually 4 or 5; it requires an average of about four napkins per day; and it consists of a fluid mixture of blood, tissue elements, and mucus, occasionally accompanied by a very few small clots. Any appreciable deviation from this type is properly diagnosed a disorder of menstruation. Whatever the type of flow, it is still functional if it is preceded by maturation and rupture of the follicle (ovulation) and corpus luteum formation, for in such a case it is brought about by the normal sequence of estrogen and progesterone secretion and the final decrease of both. When such functional flow persists for less than three days, or requires less than an average of three napkins a day, we call it hypomenorrhea-"less menstrual flow." If it lasts more than seven days, or requires more than an average of four napkins per day, it is called hypermenorrbea-"more menstrual flow." Something will be said later of the causes of such disturbances and their treatment. COMBINATIONS OF TEMPORAL AND QUALITATIVE-QUANTITATIVE ABNORMALITIES.-Of functional disorders, we have then four main types: oligo-, poly-, hypo-, and hypennenorrhea. Besides these simple forms, there mav occur combinations of either of the first two with either of the s~cond two types. The commonest is oligo-hypomenorrhea; the other three forms, poly-hypermenorrhea, oligo-hypermenorrhea and poly-hypomenorrhea do occur, however. It should be emphasized that these types of flow, whether simple or compound, are fairly constant in any individual over long periods; some one of them constitutes the habitual character of her flow. Ovulation and Menstruatiol1.-In ordinary menstruation, occurring in cycles of x ± 2 days, x being any single figure within the limits (28 -+- 2), ovulation takes place within the range of (x - 14) -+- 2, or on about the 14th day before the first day of menstruation. 1 In women who, as we say, menstruate about every 28 days, ovulation, then, occurs not only about 14 days before each period, but also about 14 days after the onset of flow. The first 2 weeks are consumed in the growth of follicles with the maturation and rupture of usually only one of them. The consequent corpus luteum of the ruptured follicle
1220
JOHN ROCK
then functions for 14 days. During the preovulatory phase, estrogen, which stimulates proliferation of the endometrium, is produced in increasing amounts. From a short time preceding and during the 2 weeks after ovulation, the corpus luteum secretes estrogen and progesterone, the latter evoking in the endometrium those cytologic qualities denoting "secretion" or "function." In oligomel1orrbea, when periods of flow closely resembling each other in quality and duration occur at longer intervals than every 32 days, as for instance every six weeks or only every few months, the prolongation of the intermenstrual phase, as far as I have been able to discern, is invariably due to delay in the rupture of the follicle (ovulation)-never to protracted functioning of the corpus luteum. For some unknown reason, either the pituitary hormones, which cause the follicles to grow, fail to appear, or, for equally obscure reasons, the ovaries remain insensitive to these hormones for variable periods. My observations indicate, however, that once ovulation is accomplished, the corpus luteum goes into action and completes its function in 2 weeks. Treatment of this delay in ovulation is discussed later. In po/ymeno1'fbea, postovulatory or functional catamenia habitually occurs in cycles of from 22 to 23 days; i.e., menstruation starts on the 23rd or 24th day of the cycle.* As in oligomenorrhea, the flow is uniform in duration and quality. The underlying disturbance is often to be found in a shortening of the time taken to achieve ovulation. A sufficient number of carefully studied cases has not been analyzed to permit statement of what proportion of the instances of polymenorrhea are due to the speeding-up of follicle-maturation. My guess is that this is so in not less than 50 per cent of the cases. In these, it is important to note that ovulation occurs-as in typical menstruation and in oligomenorrhea-about 14 days before the first day of flow. In these cases, however, it does not occur 2 weeks· after menstruation begins, but in less time than this; i.e., the follicular phase of the cycle is shortened, contrary to the situation in oligomenorrhea where, as mentioned above, this stage is lengthened. The disturbance in this form of polymenorrhea is one of follicular activation to which curative treatment, if any, should be directed. There are two other forms of polymenorrhea in which, although ovulation occurs at the more common interval of 14 days after flow, the succeeding period starts sooner than the 25th day. One form, in which there is flowing about every 2 weeks, is due, not to displacement of the time of ovulation, but apparently to a delay in the immediately postovulatory secretion of sufficient progesterone by the corpus luteum to suppress the bleeding potential, which, as has been stated previously, is established in the endometrium by the estrogen • Flow recurring at intervals of less than 22 days is almost never cyclic for more than 3 or 4 months and is practically always a form of aperiodomenorrhea (discussed later).
DISORDERS OF MENSTRUATION
1221
from the young follicles and released by a change in estrogen metabolism at ovulation time. In such cases, there occurs "ovulatory flow," as is normally seen in many subprimates; for example, the bitch and the cow. Slight bleeding into the uterus of this character doubtless takes place in many women, as Hartman 2 has shown to be the case frequently in the macaque monkey where the bleeding was usually found to be in microscopic amounts. In women, Papanicolaou3 noted that almost 24 per cent of vaginal smears taken on the 14th day contained microscopic traces of bood. This flow at ovulation time is sufficiently gross to attract the attention of probably less than 5 per cent of women. In some cases, it may require protection for several days. The affected patient usually complains of periods occurring about every 2 weeks; or, more commonly, she says that she has troublesome flow which starts about 1 week after her regular period is over. Diagnosis is usually easy: only alternate periods resemble each other in quality, quantity and duration of flow. The intermenstrual discharge is occasionally constant in these characteristics, but more often it is variable, and in most cases it does not occur to a troublesome degree in all cycles. I have not attempted to stop this kind of functional flow. One or two well-timed intramuscular injections of about 5 mg. of progesterone theoretically would do so. The last group of cases of polymenorrhea (where catamenia habitually recurs on the 23rd or 24th day) are those in which ovulation takes place in the standard time of about 14 days after the flow, but the corpus luteum does not function for the full 2 weeks following. In these cases, progesterone is thus prematurely withdrawn and menstruation is found to take place from an incompletely developed predecidua. This functional deviation undoubtedly contributes to many cases in which the so-called "rhythm" practice of contraception fails, depending, as it does, on the theory that ovulation invariably occurs about 14 days before t~ first day of flow. Except in the interest of relieving infertility, I do not attempt to influence this minor disturbance of menstrual frequency. Daily ingestion of 0.1 mg. of diethylstilbestrol or of ethinyl estradiol, beginning on the tenth day of the cycle, together with intramuscular injections on the 16th and 19th days, of 3 to 5 mg. of progesterone, will prolong the cycle in about half the cases. Dysfunctional Disorders of Menstruation.-Amenorrhea, the absence of menstruation, is a dysfunctional disorder. It is called primary, if flow has never occurred, and secondary, if previously recurrent catamenia has ceased. For how long must this freedom from flow prevail before the patient is considered amenorrheic? Convention has said 3 months. Many such cases were better termed "oligomenorrhea," for in them ovulation takes place normally, about 14 days before the flow. Insight acquired during the last decade into the hormonal basis of amenorrhea makes it advisable to limit such a diagnosis to an interval
1222
JOHN ROCK
without catamenia of, shall we say, at least 6 months. Accepting such a limitation of the diagnosis, we may consider that amenorrhea is always due to hypoestrinism, an amount of estrogen insufficient to cause proliferation of the endometrium and the establishment of the bleeding potential. I shall mention later the frequent cases where flow is absent, usually for less than 6 months, in which highly proliferated endometrium denotes prolonged secretion of appreciable amounts of estrogen. On the other hand, cases of amenorrhea for 6 months or more are probably always due to abnormally low secretion of estrogen, which is caused either by a failure of the ovarian follicles to respond to a normal or an increased amount of hormones from the anterior pituitary gland, or to lack of these substances because of pituitary dystrophy. Treatment, as described below, must be varied with due regard to different causes. Aperiodomenorrhea.-Other nonpathologic disorders of menstruation, which are not included in the categories mentioned-amenorrhea, oligo-, poly-, hypo- and hypermenorrhea-I have grouped under the diagnosis aperiodo-, or "immeasurable," menorrhea. Even this is somewhat of a misnomer, as all patients thus affiicted do not flow with any degree of "monthly" regularity; but this is also the case with the terms "oligo-" and "polymenorrhea," wherein the syllable "men," meaning "monthly," is also not invariably applicable. They are old and honored terms, however, so can safely engross this newcomer. Aperiodomenorrhea corresponds to the well known category of dysfunctional flow, menometrorrbagia, metropatbia haemorrhagica, or uterine insufficiency of the older clinicians. In this condition, the bloody uterine discharge is immeasurable in incidence, duration, quantity and quality; it may occur every few days or weeks or be absent for months and last for days or weeks, even months. From time to time it may vary in amount from staining to excessive flow. Clots of various sizes may often be passed along with the fluid discharge. Aperiodomenorrhea is due to failure of tny one of many growing follicles to ovulate. Thus, no corpus luteum is formed; no progesterone is secreted. The bleeding potential is established in the endometrium by the estrogen of many active follicles, but is inhibited, not by progesterone, but only by this estrogen and then only so long as that critical change in the quantity or quality of the estrogen that will activate the bleeding mechanism fails to occur. Experimentally, in castrates, the sudden withdrawal of prolonged doses of estrogen is followed by bleeding from a proliferated endometrium. Likewise, if administration is continued indefinitely for many months, bleeding also occurs, even during the treatment. Without digressing into a discussion of the metabolism of estrogen and the control exerted on its degradation by progesterone,4 we may infer from observation of ovaries in these cases, as well as from experimental work on monkeys,5 that the absence of progesterone is the primary cause of the aperiod-
DISORDERS OF MENSTRUATION
1223
lClty of flow. Therapeusis, discussed later, is therefore directed to inducing ovulation and subsequent formation of the corpus luteum, and, failing this, to substitution of a synthetic progesterone for that which the ovary fails to produce. DIAGNOSIS OF MENSTRUAL DISORDERS
Recognition of the form of menstruation, normal or abnormal, functional or dysfunctional, is easily made by biopsy of the endometrium. This has been discussed in detail elsewhere6 - s and criteria are given for differentiation between early and late proliferation (stages which indicate follicular growth) and for successive phases of secretory activity denoting the presence and the age of the corpus luteum. Frequently one may dispense with biopsy, although without it one can never be absolutely sure of the true nature of bleeding tissue or of the quality of ovarian activity. We clinici:llls will profitably keep in mind the following: (1) When periods of flow occur at widely varying intervals or differ markedly in quality, quantity or duration of flow, ovulation is almost surely absent. (2) The anovulatory female may spontaneously ovulate any time. TREATMENT OF MENSTRUAL DISORDERS
From the above discussion it is evident that the treatment of menstrual disorders must be directed to three objectives: (1) To diminish the amount of flow: in hypermenorrhea and aperiodomenorrhea. (2) To cause ovulation: in amenorrhea; oligomenorrhea; aperiodomenorrhea. (2a) Failing ovulation, at least to produce regular flow. (3) To prolong the life of the corpus luteum, as in some cases of pol ymenorrhea. Since we do not admit that the blood lost in menstruation relieves the body of noxious elements, we see no need of increasing the flow in most cases of hypomenorrhea. In a few instances, when hypomenorrhea appears first in the thirties after previous habitually more profuse catamenia, this scanty flow may be considered as the forerunner of amenorrhea, or of a phase of aperiodomenorrhea, which will usher in an early menopause. In these cases the therapeutic aim is to preserve or reestablish normal ovulation and function of the corpus luteum; i.e., objectives (2) and (3) mentioned above. I. Means of Limiting the Flow of Blood.-Six factors have been mentioned which probably condition the actual bleeding from the uterus. The first is the amount of estrogen and the duration and degree of its proliferative effect upon the endometrium and its vascular system. Progesterone and testosterone have been used clinically to restrain this factor, but I know of no biochemical or cytologic studies in humans that show the actual effect of these hormones. In hypermenorrhea, treatment theoretically should be given during the preovulatory
1224
JOHN ROCK
or proliferative phase of the cycle when either hormone may unfortunately inhibit ovulation. Except by the use of pellets, treatment must be repeated during each cycle, and the cost of solutions for injection or, in the case of testosterone, of tablets, is prohibitive. Until more extensive studies of the use of pellets are made, this method of decreasing the effect of estrogen in the endometrium without inhibiting ovulation is denied to clinicians. Greenblatt9 reported the helpful effect of pellets of testosterone propionate in cases of "functional menometrorrhagia" (what I call "dysfunctional aperiodomenorrhea," since ovulation is absent), as well as in some cases of functional hypermenorrhea. In discussing this paper, Salmon stated that he and Geist did not get such good results. There is hope that in the future we may decrease excessive estrogen stimulation of the endometrium by the male sex hormone. At present, other methods must be used to diminish excessive flow. Years ago, the beneficial effect of injections of chorio1lic hormone (Antuitrin-S; Follutein; A.P.L.; Korotrin, etc.) of the order of 1500 rat units, divided into about three doses, given daily, was recognized. Continued use has shown a beneficial effect in only about 30 per cent of the cases, and then only if the hormone is given during the flow. At present, I occasionally use it in functional hypermenorrhea, beginning on the second or third day of the profuse period. Theoretically, its influence is exerted on the bleeding potential. Its use is unsatisfactory, since the effect is limited to the single treated catamenia. The second factor in bleeding is the amount of progesterone which conditions the metabolism of estrogen. Progesterone should not be used in functional hypermenorrhea. Although progesterone may inhibit expression of the bleeding potential, the latter may be enhanced by this hormone, so that withdrawal of it increases the flow. On the other hand, in hyper-aperiodomenorrhea, progesterone is the hormone of choice, as will be discussed later. The other four factors in bleeding are the tissue response of the mucosa to estrogen stimulation, the reaction of the myometrium, the repair potential of the remaining mucosa, and the clotting power of the blood. In respect to these, we must depend on a normal basal metabolic rate, a normal blood picture, a normal position of the fundus, a normal diet of high vitamin content, and good hygiene. I have found styptics and oxytocics of no avail. Curettage will relieve the condition sometimes for several months, more often for only one. Radium in doses of 1000 mg.-hrs. will stop the bleeding for many months, but should be used only in those cases of aperiodomenorrhea occurring so late in the thirties or in the forties that a prolonged or perhaps permanent suppression of ovulation, a not uncommon effect of such treatment, is no great hardship. I believe the same can be said of the only slightly less drastic but more popular use of x-ray in three divided doses, each of 50 roentgens. Even though he is unwarrantably not fearful of preventing ovulation, the careful clinician will
DISORDERS OF MENSTRUATION
1225
take heed of the geneticist's warning that x-rays may permanently affect genes to the detriment of distant descendants. 1o Treatment by irradiation is supposed to destroy the secretory activity of those follicles which are upsetting the endocrine balance. The same end is sought by those who recommend resection of the ovaries with careful removal of all existing follicles. I have had no convincing experience with this method, so, while recommending caution and conservatism, will refer the reader to the report by Robinson.ll When reproductivity is of no concern, debilitating hypermenorrhea in women in their late thirties or older is often best treated by hysterectomy without castration. 2. Induction or Acceleration of Ovulation.-Two substances are needed to produce ovulation: the follicle-stimulating hormone and a critical proportion of luteinizing hormone.12 The former we have in various preparations. Some are derived from anterior pituitary glands of sheep or horses; some are obtained from the serum of pregnant mares; and some are extracted from the urine of pregnant women. They will all stimulate growth of follicles to a greater or less extent, but only very rarely, ·if at all, and then by inexplicable accident, is their use followed by ovulation. The necessary luteinizing hormone is present in some of these, notably Gonadophysin (Searle) from sheep's anterior pituitary gland, and in the chorionic hormone from the urine of pregnant women, and in Synapoidin (Parke, Davis), a combined pituitary and chorionic hormone, but unfortunately, the proportions are not physiologic, nor do we know how to adjust them. And so we are forced to utilize ill-defined empirical means to encourage ovulation in amenorrhea, severe oligomenorrhea, and in aperiodomenorrhea. In all these conditions, our first concern is for the patient's basic mental and physical health. Especially anemia, disorders of the thyroid gland, obesity, leanness, or dietary deficiency, and any emotional strain should receive thorough study and treatment. I believe our present therapeutic limitations make it undesirable to do much more than this in true oligomenorrhea, in which ovulation, however infrequent, is demonstrated by endometrial biopsy done on the first day of the delayed flow. Such patients often complain of lassitude and irritability during the long intervals between infrequent catamenia. Small daily doses of a combined estr6gen, such as 1000 international estrone units of Estrogenic Hormone (Reed and Carnrick), obtained from pregnant mares' urine, or of such synthetic products' as ethinyl estradiol (Schering), or of diethylstilbestrol, in doses of only 0.1 mg., will usually relieve those symptoms and may possibly stimulate the gonadotropic activity of the anterior pituitary gland. The dosage must be kept below the critical level, variable among individual patients, at which the gland is inhibited, instead of stimulated. Another and purely haphazard treatment, indulged in by many clini-
1226
JOHN ROCK
cians and occasionally followed by improvement, consists of intramuscular injections of any of several preparations of estradiol, such as Progynon-B or OP (Schering), or of the ketohydroxyestrin, such as Theelin (Parke, Oavis), in doses of about 5000 I.U., given at weekly or biweekly intervals. In cases without vasomotor or emotional disturbances, others try weekly injections of progesterone, such as Proluton, (Schering) in doses of 5 mg. given intramuscularly. Use in this manner of either estrogens or progesterone is unscientific; but, with the reservation made above regarding hypophyseal-inhibiting doses of the former, it is apparently quite harmless; and no one can say these hormones surely do not enhance the effectiveness of general health measures in those cases· improved after the combined treatment. Because the extracts from human pregnancy urine, from the anterior pituitary gland, and from pregnant mares' serum are all folliclestimulating in varying degrees, injections of one or the other are still prescribed by some clinicians in the hope of evoking ovulation. I have seen no good results from such treatment, although I have experimented with many of these gonadotropes extensively during the last ten years. Whereas to produce ovulation in amenorrhea and in aperiodomenorrhea is our main objective, to produce flow in the former and to regulate it in the latter is often quite satisfactory to the patient, especially if fertility is not an object. In aperiodomenorrhea, estrogen is present in variable amounts, and usually there is an established bleeding potential. When aperiodic flow is scanty, regularity and increase in amount may frequently be obtained by oral use of an estrogen for 21 days; e.g., 0.1 to 0.2 mg. of diethylstilbestrol, or 0.1 mg. of ethinyl estradiol (Schering). Withdrawal flow usually occurs within 10 days of cessation of dosage. This sequence may be kept up for many months, each 21-day period beginning with the onset of flow. When the irregular flow is profuse, biopsy will show the endometrium to be in full proliferation. Secreted estrogen is already excessive so its therapeutic use is contraindicated. Likewise, the folliclestimulating chorion or pituitary hormone should not be used, except, as has been mentioned above, when, during the flow, divided doses totaling about 1500 R.U. of chorionic hormone may be given for its theoretical hemostatic effect in tbe endometrium. To regulate the flow in aperiodomenorrhea, progesterone is necessary. This is best given by 5 daily intramuscular injections, each of 5 mg. If these are started during the flow, it will almost invariably cease before the series is completed and recur in moderate amount within 10 days after the last injection. With this flow, subsequent to injection. the surface of the endometrium is shed, as in menstruation. This is what Albright13 calls "medical o. and c." After usually not more than 7 days, flow ceases, not to recur for several weeks. It is my
DISORDERS OF MENSTRUATION
1227
custom to repeat the series of five injections three or more times at intervals of 28 days. Each series is followed by a semblance of normal catamenia. Successive periods of flow may become more scanty, indicating that estrogen is not present in sufficient quantity. This is easily remedied by adding 1 or 2 mg. to the first two or three injections of progesterone. I usually use Progynon-B or OP (Schering) for this purpose. A very small percentage of patients treated thus will ovulate. Many more will flow fairly regularly for several months following the last of three or more series of injections. To establish flow in amenorrhea, the same methods are used. Some patients, in whom there is already an appreciable secretion of estrogen, will respond to the 21-day treatment with only oral estrogen, mentioned above as of value in cases of hypo-aperiodomenorrhea. More troublesome and expensive, but also more certain, is the use of 5 daily intramuscular injections of 5 mg. (10 mg. in severe cases) of progesterone, together with 1 to 2 mg. of estradiol, in repeated series every 28 days. 3. Prolongation of Corpus Luteum Ac:tivity.-The third main objective in the treatment of menstrual disorders is to prolong the functional activity of the corpus luteum, as in some cases of polymenorrhea. I know of no way to do this. It might be thought, from the biologic experiments of several years ago,14 that moderate doses of estrogen would stimulate the anterior pituitary gland to pour fonh the luteinizing hormone, which would invigorate the failing corpus luteum. Endo cri no logic relations are not so simple as once they seemed to be. Limitations of space and my knowledge forbid detailed discussion of the probability that not one, but two hormones function in establishing and maintaining the integrity of the corpus luteum for the usual 14 days, and that not only the anterior pituitary gland is involved as the source of the ovarian stimulant, but that the adjacent hypothalamus, reacting to stimuli from both the central and the autonomic nervous systems, also plays a major roleP Attention to the general physical and mental well-being of patients with polymenorrhea, as with other disorders of the reproductive system, already empirically indicated, will be further justified by extended psychosomatic study. At the moment, we may try small doses of ingested estrogen, such as daily doses of 1000 international estrone units of Estrogenic Hormone (Reed and Carnrick), or of 0.1 mg. of either ethinyl estradiol (Schering), or diethylstilbestrol, during the last 18 days of the cycle. If treatment with estrogen is started, even in this dosage, much before 4 days prior to ovulation time, maturation and release of the ovum may be inhjbited, as was found to be so in all cases when larger doses were given. Hi One is tempted to prolong the luteal phase by substitution with synthetic progesterone for the secretion of the failing corpus luteum. In my experience, this does not help in polymenorrhea.
1228
JOHN ROCK
I have found that in cases of inexplicable infertility, associated with short cycles, an injection of 5 mg. of Proluton (Schering) on the second and again on the fifth day after the estimated ovulation date, is often effective for the relief of barrenness. I believe it is useless to attempt to prolong the luteal phase except in such cases where fertility is the object. In others, our ignorance of means to regulate the complexities involved, especially as the misery, when its cause is explained to the patient, is minimal, renders unjustifiable the expense and the uncertainties of treatment. SUMMARY
1. Nonpathologic disorders of uterine flow may be divided into
two categories: functio1lal, in which ovulation occurs; and dysfll11ctional, in which follicles, however closely they approach rupture, fail to complete this process. Dialectics demands somewhat arbitrary limits to what we should call normal menstruation. The author's criteria are stated below. 2. The ovarian cycle of follicular growth, maturation of the ovum in at least one follicle, rupture of this follicle, corpus luteum formation and regression takes place ordinarily and normally in (28 -+- 2) ±2 days. For months or years at a time, the cycle in most women remains as of x -+- 2 days, x being any number within the limits (28 ± 2). Almost all women will have several cycles in the course of a year which extend beyond their pattern-range. When the cycles are habitually in the lower range of from 22 to 23 days in length, the condition is termed polymenorrhea. \-Vhen menstruation frequently occurs at intervals of 21 days, ovulation is almost certain to have failed, and the condition is dysfunctional. When cycles are habitually of the longer variety and menstruation takes place at intervals longer than 32 days, even up to several weeks or months, the condition is called oligonzenorrhea. Ovulation, in such cases, may occur as infrequently as only two or three times a year . . Flow occurring at fairly regular intervals but persisting for longer than 7 days, or requiring more than an average of four napkins per day, is called hypernzenorrbea. If fairly cyclic flow lasts less than 4 days and requires less than an average of four napkins per day, it is called hypomenorrbea. Functional disorders may also appear as combinations of these four main t~Tpes; i.e., oligo-bypomenorrbea, poly-bype1711e1l0rrbea, and so forth. The significant characteristic of functional flow (always preceded by ovulation) is that it occurs in fairly constant cycles and that the bleeding is fairly similar in duration, quality and quantity in all . the periods of flow. 3. The regularity and similarity of periods in normal menstruation, as also in functional disorders thereof, are due to the fact that the
DISORDERS OF MENSTRUATION
1229
corpus luteum normally develops only after ovulation and is a gland of finite activity. It functions for about 14 days, secreting the progesterone which enhances and controls the bleeding potential already established by estrogen from preovulatory follicles. This potential, the ability and tendency to bleed, is expressed by flow when the gland finally regresses. (a) In oligomenorrhea, the delay in flow is due to prolongation of the preovulatory phase; the luteal or postovulatory phase remains at about 14 days. (b) In polymenorrhea, the shortening of the cycle is due usually to acceleration of ovular maturation and early rupture of the follicle, occasionally to premature regression of the corpus luteum. In the latter case, ovulation deceptively occurs in less than the expected 14 ± 2 days before the first day of the succeeding flow. (c) False polymenorrhea appears in those who flow appreciably, not only on regression of the corpus luteum, but also, as do many sub primate mammals, with ovulation. Such a condition is easily recognized: only alternate periods of flow resemble each other, and the intervals between flowing are of the order of 14 days. (d) In hypomenorrhea, there is no failure of ovulation, and the corpus luteum functions normally. The endometrium is thinner than is usual, and the bleeding potential is less. (e) In hypermenorrhea, the ovarian cycle is normal, but proliferation of the endometrium is excessive and the bleeding potential is enhanced. 4. There are two dysfunctional nonpathologic disorders of menstruation: namely, amenorrhea and aperiodo- (or immeasurable) menorrhea. In both conditions, ovulation fails to occur for many months or years. (a) The habitually anovulatory woman may ovulate any time. (b) The term amenorrhea is best used to characterize the absence of flow for 6 months or longer. (If the flow occurs more frequently than this, and if the condition is not oligomenorrhea, it were more accurately classified as aperiodomenorrhea.) Amenorrhea, as defined, is caused by a failure of follicular devel,opment, and thus an insufficiency of estrogen necessary to establish a bleeding potential. (c) In aperiod01nenor-rhea, follicles approach maturity in ever varying numbers and degree, but none achieves ovulation, and so no normal corpus luteum, which would -regulate follicular development and estrogen metabolism, is fornled. The intensity of the bleeding pote'ntial is now great, now small. For variable periods it is built up and inhibited by increasing supplies of estrogen only to be released aperiodically, as some follicles regress, causing so-called "estrogen withdrawal bleeding." This' will vary in amount, quality and duration, according to the extent of endometrial proliferation, the inten-
1230
JOHN ROCK
sity of the bleeding potential, and the promptness of the growth of new follicles, which will raise the concentration of estrogen up to a recurring inhibitory point. 5. The treatment of menstrual disorders requires, first of all, meticulous attention to mental and physical hygiene. In addition, there are three more specific objectives: (a) to diminish the amount of flow, as in hypermenorrhea and in aperiodomenorrhea; (b) to cause ovulation, as in amenorrhea, marked oligomenorrhea, and aperiodomenorrhea; or, failing in this, at least to produce flow at acceptable intervals; (c) to prolong the life of the corpus luteum, as in some cases of polymenorrhea. To accomplish these ends, we have, besides measures of general health, various hormones and stilbestrol derivatives. (a) Extracts of the anterior pituitary gland of sheep, which are clinically follicle stimulating in varying degrees. They do not, except rarely and apparently accidentally, cause ovulation, although they do sometimes evoke slight flow. (b) Serum gonadotropes, derived from the serum of pregnant mares, which are similar in origin and effect to the anterior pituitary extracts. (c) Chorionic hormones, derived from the urine of pregnant women, which are mildly luteinizing and in addition have a slight inhibitory effect on the bleeding potential. (d) The estrogens, including stilbestrol derivatives, which stimulate the endometrium to proliferate and establish therein the bleeding potential. These hold in restraint this tendency to bleed, only to precipitate "withdrawal flow" when they themselves are withdrawn or catabolized. In small amounts, they may sometimes stimulate anterior pituitary gonadotropic activity. (e) Progesterone, which enhances but, more strongly than estrogen, inhihits the hleeding potential during its use, and promptly precipitates flow from the estrogen-conditioned endometrium when it is withdrawn. BIBLIOGRAPHY
I. Rock, .l. and Hcrtig, A. T.: Information Regarding thc Time of HUlllan
Ovulation Derived from a Study of 3 Unfertilized and 11 Fertilized Ova. Am . .l. Ohst. & Gyncc., 47:343-356 (March) 1944. 2. Hartman, C. G.: The Homology of Menstruation. New Observations on Intermenstrual Bleeding in the Monkey. .l.A.M.A., 92:1992-1995 (June 15) 1929.
3. Papanicolaou, G. N.: The Sexual Cycle in the Human Female as Revealed by Vaginal Smears. Am. J. Anat., 52:519-637 (May) 1933. 4. Smith, O. W., Smith, G. V. and Schiller, S.: Clinical Experiments in Relation to the Excretion of the Estrogens. Ill. Urinary Estrogens in a Normal Menstrual Cycle and in a Case of Essential Dysmenorrhea. Am. J. Obst. & Gynec., 45:15-22 (Jan.) 1943.
DISORDERS OF MENSTRUATION
1231
5. Hisaw, F. L.: The Interaction of the Ovarian Hormones in Experimental Menstruation. Endocrinology, 30:301-308 (Feb.) 1942. 6. Rock, J. and Bardett, M. K.: Biopsy Studies of Human Endometrium: Criteria of Dating and Information About Amenorrhea, Menorrhagia and Time of Ovulation. J.A.M.A., 108:2022-2028 (June 12) 1937. 7. Rock, J., Barlett, M. K. and Matson, D. D.: The Incidence of Anovulatory Menstruation Among Patients of Low Fertility. Am. J. Obst. & Gynee., 37:3-13 (Jan.) 1939. 8. Rock, J.: The Role of Endometrial Biopsy in Diagnosis. Am. J. Surg., 48:228237 (April) 1940. 9. Greenblatt, R. B.: Implantation of Testosterone Propionate Pellets in Gynecic Disorders. ].A.M.A., 121:17-24 (Jan. 2) 1943. 10. Little, C. C. and Bagg, H. J.: The Occurrence of Two Heritable Types of Abnormality Among the Descendants of X-rayed Mice. Am. J. Roentgenol., 10:975-989 (Dec.) 1923. 11. Robinson, M. R.: The Surgical Treatment of Ovarian Dysfunctions. A Clinical and Pathological Study. Am. J. Obstet. & Gynec., 30:18-36 (July) 1935. 12. Fevold, H. L.: The Follicle Stimulating and Luteinizing Hormones of the Anterior Pituitary. In Sex and Internal Secretions, 2nd ed., edited by AlIen, E., Danforth, C. H. and Doisy, E. A. Baltimore, Williams & Wilkins Co., 1939, pp. 966-1002. 13. Klinefelter, H. F., ]r., Albright, F. and Griswold, G. C.: Experience with a Quantitative Test for Normal or Decreased Amounts of Follicle Stimulating Hormone in the Urine in Endocrinological Diagnosis. J. Clin. Endocrinol., 3:529-544 (Oct.) 1943. 14. Fevold, H. L., Hisaw, F. L. and Greep, R.: Effect of Oestrin on the Activity of the Anterior Lobe of the Pituitary. Am. ]. Physiol., 114:508-513 (Jan.) 1936. 15. Sturgis, S. H.: The Use of Stilbestrol in the Relief of Essential Dysmenorrhea. New England J. Med., 226:371-376 (March 5) 1942.