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Premature ovarian failure, permanent and temporary
Premature ovarian failure, permanent and temporary WILLIAM C. KEETTEL, M.D. JAMES T. BRADBURY, Sc.D. Iowa City, Iowa
women with primary and secondary amenorrhea have been seen. From this group we arc presenting observations on 24 patients. Group I consisted of 12 women with complete permanent early ovarian failure. Group II consisted of 9 young women with ovarian insufficiency. Group III consisted of 3 premenopausal patients with marked menstrual irregularities. These patients have been followed from 1 to 7 years. The examination has consisted of a complete history and physical examination, urinalysis, complete blood counts, vaginal cytologic examination, smears for cornification, endometrial biopsy, determination of protein-bound iodine, and serial determinations of 17-ketosteroids and pituitary gonadotropins. Occasionally visual field examination, x-ray of the sella turcica, and blood cholesterol levels were obtained. The vaginal smears were exposed to iodine vapor (Mack's stain) and judged for the type of cells present and the relative proportion of glycogen-containing cells. The cellular composition was graded from atrophic 1 to fully cornified' and the prevalence of glycogen-containing cells from 1 plus to 4 plus. The urine specimens were processed for gonadotropin by absorption on kaolin. 2 The extracts were assayed in immature female rats and the resulting ovarian weights were used as an index to relative amounts of gonadotropins. In an attempt to quantitate the output of gonadotropin we have used urine creatinine values as an approximation of comparable amounts of glomerular filtrate rather than depend on alleged ''24 hour" collections. On
As A PART of the evaluation of patients with secondary amenorrhea and infertility problems we have studied the 24 hour urinary excretion of pituitary gonadotropin. Since 1952 we have encountered 24 young women with elevated urinary gonadotropin. Some of these had persistent amenorrhea with consistently elevated pituitary gonadotropin. The others had infrequent scant periods with fluctuating levels of gonadotropin ranging from the normal to that of the castrate. A review of the literature revealed few references concerning the premature menopause or primary ovarian insufficiency and ovarian refractoriness. Bji:iro 1 studied 125 cases of secondary oligomenorrhea and among these were 7 women (aged 23 to 32) with con~istently elevated gonadotropin excretion which he classified as premature menopause. Thus, it seems important to report to physicians that permanent ovarian failure may occur spontaneously as early as age 16 and is encountered almost as frequently in our experience as the Stein-Leventhal syndrome.
Material and method of study Between 1952 and 1963 approximately 800 patients with infertility problems and 425 From the Department of Obstetrics and Gynecology, State Universit)• of Iowa Hospitals. This study was supported by United States Public Health Service Grant No. AM-01686. Presented at the Thirty-first Annual MeetinJ; of the Central Association of Obstetricians and Gynecologists, Denr•er, Colorado, Sept. 12-14, 1963.
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Fig. 1. Dose response curve showing increasing ovarian weights with increasing doses of gonadotropin. The biologic variation represented in the shaded area shows that an average weight of 90 to 95 mg. represents a dose range of 6 to 10 units. above 16 units the weight curve is so flat it cannot be used for quantitative estimations.
this basis we use a test dose of extract which represents an aliquot of urine containing 0.5 Gm. of creatinine. On the average a woman excretes about 1 Gm. of creatinine daily, so the initial test dose may approximate a 12hour aliquot. If the rat ovarian weight response is maximal (i.e., over 150 mg.), the next test dose is reduced to an aliquot representing 0.25 or possibly 0.125 Gm. creatinine with the expectation of getting ovarian weights in a 30 to 80 mg. range. Conversely, if the initial test fails to reveal any ovarian response, the next test dose is increased to represent a 1.0 Gm. creatinine aliquot. By the use of graded doses of pooled extracts a dose response curve has been developed (Fig. 1). From this response curve relative potencies can be expressed in gonadotropic activity per gram of creatinine. These are arbitrary units which are only relative approximations since the variability in test animals is of the order of plus or minus 25 per cent. In this presentation values of 30 to 50 units will be considered as castration levels representative of complete ovarian failure. Consistent levels of 5 to 20 units will be considered indicative of ovarian insufficiency.
Group I. Twelve patients with premature menopause in Group I ranged in age from 16 to 35 years. These patients have been seen at intervals during a 1 to 7 year period; two-thirds have been folowed for over 5 years. The entering complaints were secondary amenorrhea in 5, amenorrhea plus infertility in ,t_ and amenorrhea with lower abdominal pain in 3. All the patients were in excellent health with IlP physical disability. It is of interest to note that only five complained of vasomotor symptoms and this was only on direct questioning. In none of the patients did this appear to be a serious problem. Three women stated thev had increased nervousness and 2 had mild headaches. Ten of the individuals had regular menstrual periods prior to the appearance of the secondary amenorrhea, in 3 the amenorrhea occurred after a normal uncomplicated delivery. The typical menstrual history indicated a normal age at onset with regular periods for a number of years: gradually the periods became irregular with long intervals of amenorrhea, interspersed with scant periods; finally, menstrual tlow ceased entirely except for hormonally mduced withdrawal bleeding. The previous obstetric history Is of interest. Seven of the group were parous, 5 had two or less children, while 2 had four or more. None had a history of previous abortions. Only one patient in the group had had previous pelvic surgery, which consisted of a right salpingo-oophorectomy. The other tube and ovary were reported as normal. This patient had regular periods for 12 months prior to the appearance of amenorrhea. None of the patients gave any historical information concerning any serious febrilt~ illness or episodes of serious lower abdominal pain. There was no family history of premature ovarian failure. 1~he physical findings were essentially normal, with well-developed secondary sexual characteristics and normal pelvic findings (Fig. 2). The average height was 5 feet, 3;;2 inches. with a range from 5 feet, 2 inches, to 5 feet, 7 inches. The average weight was 132
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Premature ovanan failure
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pounds. There were two physical findings of interest: ( 1) Two young patients, aged 23 and 24, had consistent blood pressure readings of 150/90. (2) Two other patients had abnormal facial pigmentation similar to the cholasma of pregnancy, one also had a small spider nevus. Neither of these patients had ever been pregnant. These skin changes occurred early in the permanent amenorrhea. The usual laboratory data were within normal range. The protein-bound iodine levels varied from 4.4 to 7.9 p,g per cent.
Fig. 2. Premature menopause (La. at age 24). Spider nevus left cheek.
Blood cholesterol levels were not determined in all cases but were found to be elevated in one instance. Of the patients tested none had withdrawal bleeding with progesterone. The vaginal smears were atrophic in 8 instances, 2 showed precornified cells, and 2 well cornified. An endometrial biopsy was attempted on 6 patients; in 5 no tissue was obtained and in one the endometrium was atrophic. The 17 -ketosteroids were within a normal range in 11, but, one patient had consistently unexplained low levels. Serial determinations of the pituitary gonadotropins were constantly elevated in the castration range with no significant fluctuations except during suppression with adequate amounts of exogenous estrogen (Figs. 3 and 4). In one of our patients, aged 25, with a history of significant amenorrhea, who was particularly anxious for a pregnancy, an exploratory laparotomy was performed to ascertain whether there was gross and histological evidence of permanent ovarian failure. Fig. 5 shows the gross appearance of the ovaries which measured 2 by 0.5 by 0.5 em. These small atrophic ovaries were highly rugated with a yellowish fibrotic appearance, with no visible follicles . A small wedge of tissue was removed from each ovary, there was little bleeding from the resected ovaries, and no suturing would have been required. The uterus and tubes were atrophic in appearance. The microscopic sections (Fig. 6) showed very dense stroma with a few primordial follicles and no corpora albicantia. The hilar vessels showed evidence of sclerosis. In one area a follicle containing an ovum was noted (Fig. 7) . These ovaries had the appearance of those seen in a 76-year-old menopausal patient (Fig. 8). This patient has had no further menstrual periods (Fig. 9, normal ovary, for contrast). These women have accepted the diagnosis of permanent ovarian failure rather well. Some of them are taking stilbestrol, 0.5 mg. the first 25 days of each month. With this medication, withdrawal bleeding seldom occurs, the patients feel well and have no vasomotor symptoms. This therapy will be con-
86
Keettel and Bradbury :\nL
tinued until the age when the usual menopause occurs. Group II. The 9 patients with ovarian insufficiency ran,ged in age from 20 to 33 with
the aYerage being 25 years, and ha\T het•n followed from 1 to 7 years. The majorit\' were SPen because of secondary amenorrhea and infertility; one patient had an additional complaint of dysmenorrhea. There wen· 2 patients with mild vasomotor symptoms. [ n contradistinction to Group L these women always had irregular menstrual periods and 7 of the married patients had rwver bt•t·n pregnant. None of the individuals had had any peh·ic operation. There was no history of febrile illness or evidences of previous pelvic cliseast'. The physical findings were normal with well-developed secondary sexual characteristics and normal pelvic findings. The awragc height was 5 feet, 3 inches, and the weight was 120 pounds. In these patients the laboratory findings were within normal range. The protein-bound iodine ranged f rolll 4.3 to 7.8 p,g per cent. Three individuals had withdrawal ble~'ding with progesteronr· and :) did not. The va.ginal smears were well cornified in 2 instances and in 5 showed evidence of estrogen deficiency. Endometrial biopsies were performed six times, four were atrophic and two showed a proliferative endometrium. Th<" 17-ketosteroicls were within normal lewis PX-
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Fig. 3. Elevated levels of gonadotropin in 6 tests over a 7 year span (La. at age 24). Suppression of gonadotropin by estrogen therapy in 1963. Hormonally induced periods shown as squares.
Sterility 2 years Me C.-24yrs.
Delivery 1953- Amenorrhea I year
60
1956
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60 RDRD I Fig. 4. Elevated levels of gonadotropin on five occasions in 1 7 months ( McC. at age 24). Amenorrhea 1958 to 1963. Last spontaneous period in 1956 black block. Hormonally induced periods shown as squares.
1958
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cept for one patient who had borderline elevations. One patient (Fig. 10) was poorly nourished and had rather poor breast de\elopment.
87
In this group a characteristic feature is the presence of moderate amounts of gonadotropin in a majority of specimens. The quantity varied, approaching castrate levels at time'
Fig. 5. Atrophic ovaries at time of laparotomy (McC. at age 24).
Fig. 6. Left ovarian biopsy (McC. at age 24). High power. One oocyte, dense stroma. Absence of corpora albicantia.
88
Keettel and Bradbury
only to drop below detectable levels with the recurrence of spontaneous periods (Figs. 11, 12, and 13).
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These patients have been treated with ~l variety of hormones. including cyclic stilbestrol, intravenous Premarin, progesterone,
Fig. 7. Right ovarian biopsy, low power (McC. at age 24). Single Graffian follicle. Dense stroma, absence of corpora albieantia. Vaginal smear atrophic and gonadotropins elevated. No evidence of estrogen production.
Fig. 8. Menopausal ovary at age 76. Dense fibrous stroma devoid of oocytes. Corpus albicans typical of many throughout the section.
V v hurH: fiE) N uwtwr t
Premature ovarian failure
89
Fig. 9. Normal ovary of term pregnancy (Ch. at age 24). Many oocytes. Decidual plaque on surface.
and the 19-nor progestins, with no obvious benefit. Certain of the patients had one or two spontaneous cycles after treatment and then reverted back to long periods of amenorrhea. Others had occasional spontaneous periods without any treatment. Only one of the women has become pregnant, this conception occurred approximately 14 days after a bleeding episode induced by progesterone withdrawal. One of these patients appears now to have permanent ovarian failure. A recent letter indicated there have been no spontaneous periods in two years and the vasomotor symptoms have become so severe as to require hormone treatment. We have been most anxious to examine the ovaries in patients in this group but have not had adequate clinical indication. Group III. The third group, three patients with impending menopause, were healthy patients in their 40's whose only complaints were hot flushes and irregular menstrual periods. Periodic assays for gonadotropin reFig. 10. Ovarian insufficiency (Te. at age 19). This was the only patient in the group with hypoplasia of secondary sex characteristics. The lack of subcutaneous fat accentuates the hypoplasia of the secondary sex characteristics. Weight, 96 pounds.
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vealed fluctuating levels with occasionaljwak' in the castrate range which st·em compa tihlt· with their impending menopaust'. T!Ji, ,gwup is of interest in that the t•rrat ic pa ltt·tn < d gonadotropin excretion is similar to I ftd 1 found in the young women in Grottp I I.
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Fig. II. Oligomenorrhea and erratic levels of gonadotropin during + years of observation (Du. at ag
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On the basis of monophasic basal tt·mpcrature graphs and endometrial biopsies, it Ita' heen established that fairly regular tnt·nst·s may occur in the presence of anondar cycles. It is presumed that anovulation represents tht· first phase of ovarian insufficiency and 111a) account for the infertility of some wnmt·n approaching the menopause. Other indi\iduals have irregular bleeding· episodes illtl'rspersed between periods of amenorrhea. \\'itlt a progn·ssive decline in ovarian functicn tfll' m·arics become less n·sponsi\ e to pit11itan gonadotropic control and amenorrhea of tiH· mcnopausc is established. The cause of this physiologic ovarian failure remains a mystery seemingly peculiar tn the human race. It appears that the human fcrnale is endowed at birth with a cl'rtain ovarian "capital'' of primordial ova. Then· Sterility 2years Provera
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Fig. 12. OligomPnorrhca and erratic levels of gonadotropins during 3 y<'ars of observation (Pi. at age 22). No withdrawal bleeding afte"r medroxyprogeste"rone acetate on one occasion. Zeros on th<' base line represent urine assays in which gonadotropin was too low for detection.
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Premature ovar1an failure
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are no new additions to such stock by way of oogenesis either from germinal epithelium nr any other structures of the ovary. Thus, the aging of the ovary in one sense really hegins at birth and continues throughout life. In general the aging takes place in an orderly progressive fashion , resulting in a Go -2 4yrs
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gradual loss of primordial ova and a progressive thinning of the ovarian cortex. Externally, the ovary becomes increasingly wrinkled and rugated, gradually decreasing in size. The m edullary area seemingly becomes more prominent with well-developed stromal cells. The vessels of the hilum show progressive
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Fig. 13. Oligomenorrhea and erratic gonadotropins during 2 years of observation ( Go. at age 24 ) . No withdrawal bleeding after rn edroxyprogesterone acetate.
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92
May 1, 1964
Keettel and Bradbury Am.
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Fig. 15. Ovaries and uteri from 4 rats in which the test dose was halved progressively from left to right.
sclerosis. It is difficult to be certain whether these changes are the result of changes in function of the anterior pituitary gland or failure of the ovaries. Many physicians feel these changes cause ovarian failure, and the elevated pituitary gonadotropin levels are an attempt toward ovarian stimulation. H eller and Heller 3 have shown that women with normal menstrual cycles have low urinary gonadotropin levels, those having irregular cycles ran the whole gamut of titers from low normal to the castrate levels. Those with consistently high levels were women who had ceased cycling and had ovarian failure . In another study Heller and associates• have shown that individuals near the menopause having irregular bleeding with castrate levels of gonadotropins, had at the time of surgery, atrophic ovaries typical of the postmenopausal patient. Histologic sections showed no follicles or evidence of corpora a lbicantia. The vaginal mucosa in such patients was often well cornified even though there was low estrogen production indicating that the vaginal epithelium is maintained by rather small amounts of estrogen.
The Group I patients with premature menopause seem identical to the true postmenopausal patient except in age. Before making the diagnosis of permanent ovarian failure it is important to follow these patients at least 6 months to see if the pituitary gonadotropin levels are consistently elevated in the castrate range (Fig. 14). We have found no clue as to why certain women should have premature ovarian failure. These changes may have resulted from ( l) congenitally small ovaries with deficient primordial follicles, ( 2) an unsuspected disease process with partial ovarian destruction, or ( 3) an increased utilization of follicles secondary to pituitary overactivity. This period of increased activity could have been at puberty, during pregnancy or anytime of adult life. No matter what the cause, it is important that young women with permanent ovarian failure be properly evaluated so that they know the true nature of their problem, and not spend valuable time and money hoping for future pregnancies. Our working hypothesis is tha t patients in Group II represent phases of ovarian ir• -
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Premature ovanan failure
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sufficiency expressed as a refractoriness in the ovarian response to gonadotropin. The fact that the gonadotropin excretion is readily suppressed by estrogen administration is compatible with this concept. On the contrary, Beclere and Simonnet5 postulate a congenital hypergonadotropic condition of the pituitary as the basis of moderately elevated gonadotropins in young women with menstrual disorders. They dismiss any consideration of ovarian insufficiency on the basis of physical findings (normal breasts and normal-sized 11 terus) even though the estrogen excretion values are low. Their explanation is that the mines were not collected at an appropriate time to show the elevated estrogen production which is necessary for the documentation of an entity "hyperhormonal pituitary-ovarian syndrome" which they propose. Unfortunately they have too few gonadotropin estimations and inadequate follow-up to be sure their 5 young women are comparable to those in Group II. The possibility of temporary ovarian failure or ovarian refractoriness had never been given serious consideration in the etiology of amenorrhea or infertility. This possibility first became manifest in our study of postpartum amenorrhea 6 with or without lactation. We found that gonadotropins were excreted in variable amounts by about 50 per cent of women during this interval of amenorrhea and before they resumed normal cycles. In the postpartum patient the gonadotropinuria represents a temporary refractory state of the ovary in a fertile patient who subsequently resumes normal cycles. In general the pattern was similar to that found in Group II of this report; the majority of specimens containing 4 to 8 units with occasional specimens containing 32 to 48 units per gram of urinary creatinine. What does the future hold for the nine young women in Group II? Is their infertility temporary? One conceived after progesterone withdrawal bleeding. Or is their fertility potential as poor as their past performance? Is the presence of gonadotropin a prediction of an early menopause? In 12 women in Bjoro's study with moder-
93
ately elevated gonadotropins (his high normals) "the clinical impression was that these cases were analagous to the patients with a premature menopause . . . . but as these patients were young and presented infertility problems we were forced to treat them." Does the presence of gonadotropin indicate a relative inability of the ovary to produce estrogen and/or progesterone? If so, can this deficiency be corrected by judicious administration of sex hormones? The opposite possibility, namely, a refractory pituitary that requires excessive estrogen to bring it under control, remains to be explored. It should be emphasized these patients differ from the Stein-Leventhal patients in the following respects; normal to small -sized ovaries, excretion of excess FSH rather than LH and the lack of any hirsute or obese tendencies. While it would be interesting to learn of the ovarian histology in these cases there has been no obvious justification for laparotomy and ovarian biopsy. Further studies and longer intervals of observation are necessary to establish the prognosis or for a regime of management to be developed for these young women. Summary
Investigation of young women with infertility and/or amenorrhea has revealed the presence of a significant number with elevated urinary gonadotropin (primarily FSH) excretion which suggest varied degrees of ovarian insufficiency. Twelve young women (average age, 25 years) excreted gonadotropins consistently as high as encountered in the castrate or postmenopausal. These patients have had a complete ovarian failure and an early menopause. Three women (ages 39, 44, and 47) having irregular cycles seem to be examples of approaching menopause with erratic ovarian responsiveness as demonstrated by fluctuating levels of gonadotropin excretion. Nine young women (average age, 25 years) with infertility, menstrual irregularities, and fluctuating levels of urinary gonadotropin present unsolved problems in etiology, prognosis, and management.
94
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REFERENCES
J. P .. Morgan, D. :'i .. and Myers, G. B.: ]. Clin. Endocrine!. 4: 'i9. 19+4. 5. Beclere, C., and Simonnet, H.: Press<' mf•d. 71: :1, 1963. 6. Kt•ettel, W. C., and Bradbury, ]. T.: o\~1. J. 0BST. & GY:'\EG. 82:99.5, 1961.
.f.
I. Bjoro, K.: Acta obst. et gynec. scandina\·. (Suppl. 6) 41: .5, 1962. 2. Bradbury, J. T., Brown, E. S., and Brown, '\V. E.: Proc. Soc. Exper. Bioi. & Med. 71: 228, 1949. '1. Heller, C. G., and Heller, E. J.: J. Clin. Invest. 18: 17!, 1939.
Hf'ller, C. G., Farney.
Discussion DR. S. J. BEHRMA:\1, Ann Arbor, Michigan. The paper is important in that it draws attention
curring in th<' young woman in the :20 to 311 y•·ap; age group. It is important lwcaust· to date thn<'
the actual existPnce of a clinical entity of
is no way of reversing the condition, and lw-
prcmatun' nwnopaust' or secondary amrnorrhca
cause its diagnosis should avoid tht· tmncct•ssan
with JWnnanent pn•mature ovarian failun• oc-
risks and wast;• of time
to
in
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Table I. Summary of sixteen patients with prematun' ovarian failure 17-Ketosteroids in
Age
Duration (yr.)
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Volume 89
Premature ovanan failure
95
::"J"umber 1
wedge resections or giving experimental hormone therapy. Dr. Keettel neatly describes the evolution of the condition, firstly with the frequent occurrence of anovulation as evidence of the commencing ovarian insufficiency, followed by irregular bleeding cycles interspersed with lengthy periods of amenorrhea terminating in complete amenorrhea and permanent ovarian failure characterized by low estrogens and high gonadotropins. This he clinically divides into three phases, the first of ovarian insufficiency, then the premenopausal stage with fluctuating levels of gonadotropin, and then the high castrate levels of gonadotropins with permanent ovarian failure. The onus of diagnosis and classification rests therefore upon the accuracy of the levels of these gonadotropin estimations. The method described by the authors uses a test dose of an aliquot of urine containing 0.5 Gm. creatinine relative to the 12 hour output. Potency is expressed in units of gonadotropic activity per gram of creatinine. On this basis the normal gonadotropin output is equated as zero. ElPvated levels of gonadotropic activity vary from 5 to 20 and 35 to 50 units as castrate icvPls. This method is relatively rapid, unique, and original with the authors. Dr. KeettPl and Dr. Bradbury give a frequency of this condition of secondary amPnorrhea with permanent ovarian failure at l('ast equal to that of polycystic ovarian disease. This is not our experience. In a recent series of 196 casPs, an endocrine status compatible with complete ovarian failure was noted in only 16 cases, 12 per cent, when·as almost 40 per cent of the series was represented by polycystic ovarian disease. In our series we consider as castrate or menopausal levels repeated readings of 48 human mPnopausal gonadotropic units or higher where the unit reflects the amount of gonadotropin that induces a 100 per cent increase in the average weight of the uterine horns in mice. Among the sixteen patients of premature ovarian failure (the average age being 26), six reported hot flushes. The average duration of the secondary amenorrhea was 3 Y2 years (Table I). The diagnosis of permanent ovarian failure is a serious one to the patient, and, therefore, should be made with due caution and only after repeated analyses over a reasonable period of timt>, ideally including a culdoscopic t>xamination to rule out other pathology. I n1ention this brcause one of our cases, after 4 years of apparent
premature menopause, quietly settled down and became pregnant and went to term without difficulty. Can this condition be mimicked by psychic causes through the hypothalamus or, perhaps, by temporary gonadal defects? I would like to raise another question I believe to be of some importance: Does this premature menopause predispose the patient to ischemic heart disease? In a very recent study by Sznajderman and Oliver 2 we find that in 25 of 35 women studied, who stopped menstruating before the age of 35, and who wPre followPd over a period of 10 years, ischemia developed in 4, 1 more died of myocardial infarction, and another 7 had significant cardiovascular complications. This gives an incidence of seven times the average expectation of cardiac complications. In another report 3 cardiovascular disease was found in 25 per cent of 112 womPn who had had bilateral oophorectomy under the age of 40 and who had not had any form of estrogen therapy, compared with 10 per cent of 45 women who also had oophorectomy but who had estrogen rt>placement therapy. I would like to ask Dr. Keettel whetht>r hP has any follow-up studies on the series with specific reference to serial values of cholesterol and triglycerides, as this seems to be elevated in the menopause. Should these tests not routinely be dont> where premature menopause is suspected? Finally, I too feel as Dr. Keettel suggests, that once the diagnosis of premature ovarian failure is established, treatment with cyclic estrogen to permit menses and inhibiting the pituitary is advised and well tolerated. A treatise emphasizing this clinical entity has long been ovPrdue, and I commend the authors for bringing it into sharp focus. REFERENCES
1. Behrman, S. J.: Secondary Amenorrhea [Searle Symposium], 1963, in press. 2. Sznajderman, M., and Oliver, M. F.: Lancet 1: 962, 1963. 3. Higano, N., Robinson, W., and Cohen, W.: New England J. Med. 268: 1123, 1963.
DR. jAMES T. BRADBURY, Iowa City, Iowa. Dr. Behrman has pointed out the fact that the determination of urinary gonadotropin is the critical factor or the basis of judgment in this study. Actually there is no specific biologic assay for gonadotropins. This is a terrible admission to make after 30 years but it is time for true confessions. The method used by any investigator is st>leckd on the basis of personal prdPrPnce
96
Keettel and Bradbury
rather than on one of scientific validity. We prefer the rat ovarian response because it offers several qualitative aspects as \vell as some quanti .. tative approximations. Fig. 15 (numbered in reference to those in the text) shows the ovaries and uteri from 4 rats in which the test dose was halved progessively from left to right. This shows specimens from a series of rats in which the dose was doubled in each step from right to left. The 20 mg. ovaries show little or no weight response. The 44 and 66 mg. ovaries contain many vesicular follicles of uniform size. Grossly they are pale honeycombed ovaries. The 130 mg. ovaries are hyperemic and luteinized. Further increase in dose leads to further luteinization without much further increase in weight. In this test the significant doses are those which stimulate ovaries to the 44 to 66 mg. weight range, with the pale vesicular follicles as evidence of FSH. The uteri from these animals show that the maximum uterine weight ( 182 mg.) was achieved with a lower dose. This is the reason that many investigators prefer the uterine weight response as a more sensitive test. Offsetting this advantage of sensitivity is the lack of specificity. The uterus responds to estrogen from the ovaries whether they are stimulated by pituitary extract, menopause urine, pregnant mare's serum, or human pregnancy urine. Quantitatively the uterine weight response in the test rat or mouse is useful for small quantities if it is known what type of gonadotropin is being tested. However when a random urine extract is being tested the uterine response gives no clue as to the type of gonadotropin in the extract. In a report to this Association a few years ago on the Stein-Leventhal syndrome we judged the type of gonadotropin on the basis of the rat ovarian response. In that study if we found the ovaries were hyperemic and were in the 30 to 40 mg. weight range they were fixed and sectioned. The presence of thecal luteinization was judged as evidence of an LH effect. The uterine distention with fluid was merely noted as additional evidence of ovarian stimulation. We rely on the gross appearance of the ovaries, hyperemia in the lower weight range, as to whether the gonadotropin is primarily LH as in the Stein-Leventhal syndrome or ischemia with vesicular follicles as evidence for FSH in the ovarian insufficiency states as presented in the present study. The dose response cure (Fig. I) was devel-
May I, 196-1 Am, J, Obst. & Gynec.
oped from a series of tests like those just shown (Fig. 15). In any dose response curve the useful part is the steeper portion. In doses beyond 3~ units the curve flattens and is not usable. It is not feasible to designate menopausal or castrate levels on a curve of this type because, as was mentioned, the final unitage is based on creatinine aliquots. Ordinarily, the average woman puts out about 1 Gm. of creatinine in a 24 hour urine specimen. If the entire 24 hour collt'ction was concentrated into the dosage given to one rat and this resulted in an ovarian weight of about '15 mg. as shown by the horizontal line, the assar would read out as 8 units per gram of creatinine. The same ovarian response ( ')5 mg.) obtained with a 12 hour aliquot of urine ,0.5 Urn. creatinine) would be 8 divided by 0.5 or 16 units per gram of creatinine. Similarly the sam•· ovarian response obtained from a dos<' of t>xtract derived from a 0.25 Gm. aliquot would indicate 8 divided by 0.25 or 32 units per gram of creatinine. For comparison with reports in the literatur<' which report urinary gonadotropin ( prim;uily FSH) in terms of mouse uterine units, multiplying our units by 10 would result in the sanw numerical range of values. DR. KEETTEL (closing). Dr. Behrman has raised the question concerning thr effects of a premature menopause on the vascular system. In our material, two patients had consistent minor elevation of blood pressure and two patients had elevated serum cholesterol levels. To prevent vasomotor symptoms, decrease atrophic vaginal changes and perhaps to prevent atherosclerotic changes, cyclic estrogen therapy is t'mployed in our patients with proved permanent ovarian failure. In the future we are planning to study chromosome counts on these patients, perhaps this will give helpful information. The incidence of polycystic ovarian dis•·ase varies widely, dependent upon the criteria employed for the diagnosis. In order to substantiak the diagnosis the following criteria arc employed in our clinic: infertility, amenorrhea, bilateral enlargement of the ovaries, the presence of LH in most of the urines studied, and increas<'d ovanan enlargement produced by exogrnouo;
FSH. In conclusion, I would likP to point out this is not an uncommon problem since from two teaching institutions 28 cases of patients with permanent premature ovarian failure have bePn presented.
women with primary and secondary amenorrhea have been seen. From this group we arc presenting observations on 24 patients. Group I consisted of 12 women with complete permanent early ovarian failure. Group II consisted of 9 young women with ovarian insufficiency. Group III consisted of 3 premenopausal patients with marked menstrual irregularities. These patients have been followed from 1 to 7 years. The examination has consisted of a complete history and physical examination, urinalysis, complete blood counts, vaginal cytologic examination, smears for cornification, endometrial biopsy, determination of protein-bound iodine, and serial determinations of 17-ketosteroids and pituitary gonadotropins. Occasionally visual field examination, x-ray of the sella turcica, and blood cholesterol levels were obtained. The vaginal smears were exposed to iodine vapor (Mack's stain) and judged for the type of cells present and the relative proportion of glycogen-containing cells. The cellular composition was graded from atrophic 1 to fully cornified' and the prevalence of glycogen-containing cells from 1 plus to 4 plus. The urine specimens were processed for gonadotropin by absorption on kaolin. 2 The extracts were assayed in immature female rats and the resulting ovarian weights were used as an index to relative amounts of gonadotropins. In an attempt to quantitate the output of gonadotropin we have used urine creatinine values as an approximation of comparable amounts of glomerular filtrate rather than depend on alleged ''24 hour" collections. On
As A PART of the evaluation of patients with secondary amenorrhea and infertility problems we have studied the 24 hour urinary excretion of pituitary gonadotropin. Since 1952 we have encountered 24 young women with elevated urinary gonadotropin. Some of these had persistent amenorrhea with consistently elevated pituitary gonadotropin. The others had infrequent scant periods with fluctuating levels of gonadotropin ranging from the normal to that of the castrate. A review of the literature revealed few references concerning the premature menopause or primary ovarian insufficiency and ovarian refractoriness. Bji:iro 1 studied 125 cases of secondary oligomenorrhea and among these were 7 women (aged 23 to 32) with con~istently elevated gonadotropin excretion which he classified as premature menopause. Thus, it seems important to report to physicians that permanent ovarian failure may occur spontaneously as early as age 16 and is encountered almost as frequently in our experience as the Stein-Leventhal syndrome.
Material and method of study Between 1952 and 1963 approximately 800 patients with infertility problems and 425 From the Department of Obstetrics and Gynecology, State Universit)• of Iowa Hospitals. This study was supported by United States Public Health Service Grant No. AM-01686. Presented at the Thirty-first Annual MeetinJ; of the Central Association of Obstetricians and Gynecologists, Denr•er, Colorado, Sept. 12-14, 1963.
83
84
May 1, l%1
Keettel and Bradbury
Am .
160 140
,§
120
:<:
100
~
80
-~
~
·~
,.
Oht-t. & ( ~VJII'('
Observations
180
-._ <:;,
.f.
60
Cl
40
20 16 Gonadotrophin
32
Units
Fig. 1. Dose response curve showing increasing ovarian weights with increasing doses of gonadotropin. The biologic variation represented in the shaded area shows that an average weight of 90 to 95 mg. represents a dose range of 6 to 10 units. above 16 units the weight curve is so flat it cannot be used for quantitative estimations.
this basis we use a test dose of extract which represents an aliquot of urine containing 0.5 Gm. of creatinine. On the average a woman excretes about 1 Gm. of creatinine daily, so the initial test dose may approximate a 12hour aliquot. If the rat ovarian weight response is maximal (i.e., over 150 mg.), the next test dose is reduced to an aliquot representing 0.25 or possibly 0.125 Gm. creatinine with the expectation of getting ovarian weights in a 30 to 80 mg. range. Conversely, if the initial test fails to reveal any ovarian response, the next test dose is increased to represent a 1.0 Gm. creatinine aliquot. By the use of graded doses of pooled extracts a dose response curve has been developed (Fig. 1). From this response curve relative potencies can be expressed in gonadotropic activity per gram of creatinine. These are arbitrary units which are only relative approximations since the variability in test animals is of the order of plus or minus 25 per cent. In this presentation values of 30 to 50 units will be considered as castration levels representative of complete ovarian failure. Consistent levels of 5 to 20 units will be considered indicative of ovarian insufficiency.
Group I. Twelve patients with premature menopause in Group I ranged in age from 16 to 35 years. These patients have been seen at intervals during a 1 to 7 year period; two-thirds have been folowed for over 5 years. The entering complaints were secondary amenorrhea in 5, amenorrhea plus infertility in ,t_ and amenorrhea with lower abdominal pain in 3. All the patients were in excellent health with IlP physical disability. It is of interest to note that only five complained of vasomotor symptoms and this was only on direct questioning. In none of the patients did this appear to be a serious problem. Three women stated thev had increased nervousness and 2 had mild headaches. Ten of the individuals had regular menstrual periods prior to the appearance of the secondary amenorrhea, in 3 the amenorrhea occurred after a normal uncomplicated delivery. The typical menstrual history indicated a normal age at onset with regular periods for a number of years: gradually the periods became irregular with long intervals of amenorrhea, interspersed with scant periods; finally, menstrual tlow ceased entirely except for hormonally mduced withdrawal bleeding. The previous obstetric history Is of interest. Seven of the group were parous, 5 had two or less children, while 2 had four or more. None had a history of previous abortions. Only one patient in the group had had previous pelvic surgery, which consisted of a right salpingo-oophorectomy. The other tube and ovary were reported as normal. This patient had regular periods for 12 months prior to the appearance of amenorrhea. None of the patients gave any historical information concerning any serious febrilt~ illness or episodes of serious lower abdominal pain. There was no family history of premature ovarian failure. 1~he physical findings were essentially normal, with well-developed secondary sexual characteristics and normal pelvic findings (Fig. 2). The average height was 5 feet, 3;;2 inches. with a range from 5 feet, 2 inches, to 5 feet, 7 inches. The average weight was 132
Volume 89
Premature ovanan failure
85
Numbc:-r I
pounds. There were two physical findings of interest: ( 1) Two young patients, aged 23 and 24, had consistent blood pressure readings of 150/90. (2) Two other patients had abnormal facial pigmentation similar to the cholasma of pregnancy, one also had a small spider nevus. Neither of these patients had ever been pregnant. These skin changes occurred early in the permanent amenorrhea. The usual laboratory data were within normal range. The protein-bound iodine levels varied from 4.4 to 7.9 p,g per cent.
Fig. 2. Premature menopause (La. at age 24). Spider nevus left cheek.
Blood cholesterol levels were not determined in all cases but were found to be elevated in one instance. Of the patients tested none had withdrawal bleeding with progesterone. The vaginal smears were atrophic in 8 instances, 2 showed precornified cells, and 2 well cornified. An endometrial biopsy was attempted on 6 patients; in 5 no tissue was obtained and in one the endometrium was atrophic. The 17 -ketosteroids were within a normal range in 11, but, one patient had consistently unexplained low levels. Serial determinations of the pituitary gonadotropins were constantly elevated in the castration range with no significant fluctuations except during suppression with adequate amounts of exogenous estrogen (Figs. 3 and 4). In one of our patients, aged 25, with a history of significant amenorrhea, who was particularly anxious for a pregnancy, an exploratory laparotomy was performed to ascertain whether there was gross and histological evidence of permanent ovarian failure. Fig. 5 shows the gross appearance of the ovaries which measured 2 by 0.5 by 0.5 em. These small atrophic ovaries were highly rugated with a yellowish fibrotic appearance, with no visible follicles . A small wedge of tissue was removed from each ovary, there was little bleeding from the resected ovaries, and no suturing would have been required. The uterus and tubes were atrophic in appearance. The microscopic sections (Fig. 6) showed very dense stroma with a few primordial follicles and no corpora albicantia. The hilar vessels showed evidence of sclerosis. In one area a follicle containing an ovum was noted (Fig. 7) . These ovaries had the appearance of those seen in a 76-year-old menopausal patient (Fig. 8). This patient has had no further menstrual periods (Fig. 9, normal ovary, for contrast). These women have accepted the diagnosis of permanent ovarian failure rather well. Some of them are taking stilbestrol, 0.5 mg. the first 25 days of each month. With this medication, withdrawal bleeding seldom occurs, the patients feel well and have no vasomotor symptoms. This therapy will be con-
86
Keettel and Bradbury :\nL
tinued until the age when the usual menopause occurs. Group II. The 9 patients with ovarian insufficiency ran,ged in age from 20 to 33 with
the aYerage being 25 years, and ha\T het•n followed from 1 to 7 years. The majorit\' were SPen because of secondary amenorrhea and infertility; one patient had an additional complaint of dysmenorrhea. There wen· 2 patients with mild vasomotor symptoms. [ n contradistinction to Group L these women always had irregular menstrual periods and 7 of the married patients had rwver bt•t·n pregnant. None of the individuals had had any peh·ic operation. There was no history of febrile illness or evidences of previous pelvic cliseast'. The physical findings were normal with well-developed secondary sexual characteristics and normal pelvic findings. The awragc height was 5 feet, 3 inches, and the weight was 120 pounds. In these patients the laboratory findings were within normal range. The protein-bound iodine ranged f rolll 4.3 to 7.8 p,g per cent. Three individuals had withdrawal ble~'ding with progesteronr· and :) did not. The va.ginal smears were well cornified in 2 instances and in 5 showed evidence of estrogen deficiency. Endometrial biopsies were performed six times, four were atrophic and two showed a proliferative endometrium. Th<" 17-ketosteroicls were within normal lewis PX-
__l 30
1960
r
~~ t
1963 ::
~- . . ·- _____ j __
l~
-' tl:_~_ 4
6
3
10
II
MaY I. I 'lh4 Ohst. & Cynt·c
.J.
IL_
months
Fig. 3. Elevated levels of gonadotropin in 6 tests over a 7 year span (La. at age 24). Suppression of gonadotropin by estrogen therapy in 1963. Hormonally induced periods shown as squares.
Sterility 2 years Me C.-24yrs.
Delivery 1953- Amenorrhea I year
60
1956
•
40
20
60
1957
40
20
60 RDRD I Fig. 4. Elevated levels of gonadotropin on five occasions in 1 7 months ( McC. at age 24). Amenorrhea 1958 to 1963. Last spontaneous period in 1956 black block. Hormonally induced periods shown as squares.
1958
40
20
['
Hot Flashes
I
I
,I 2
3
4
5
6
7
months
,I 8
9
10
I
~~
'-'-'Y·
II
12
\'ululllt' H~J
Premature ovarian failure
\'umber I
cept for one patient who had borderline elevations. One patient (Fig. 10) was poorly nourished and had rather poor breast de\elopment.
87
In this group a characteristic feature is the presence of moderate amounts of gonadotropin in a majority of specimens. The quantity varied, approaching castrate levels at time'
Fig. 5. Atrophic ovaries at time of laparotomy (McC. at age 24).
Fig. 6. Left ovarian biopsy (McC. at age 24). High power. One oocyte, dense stroma. Absence of corpora albicantia.
88
Keettel and Bradbury
only to drop below detectable levels with the recurrence of spontaneous periods (Figs. 11, 12, and 13).
Am.
J.
Mav 1, 19h4 Ohst. & Gynec.
These patients have been treated with ~l variety of hormones. including cyclic stilbestrol, intravenous Premarin, progesterone,
Fig. 7. Right ovarian biopsy, low power (McC. at age 24). Single Graffian follicle. Dense stroma, absence of corpora albieantia. Vaginal smear atrophic and gonadotropins elevated. No evidence of estrogen production.
Fig. 8. Menopausal ovary at age 76. Dense fibrous stroma devoid of oocytes. Corpus albicans typical of many throughout the section.
V v hurH: fiE) N uwtwr t
Premature ovarian failure
89
Fig. 9. Normal ovary of term pregnancy (Ch. at age 24). Many oocytes. Decidual plaque on surface.
and the 19-nor progestins, with no obvious benefit. Certain of the patients had one or two spontaneous cycles after treatment and then reverted back to long periods of amenorrhea. Others had occasional spontaneous periods without any treatment. Only one of the women has become pregnant, this conception occurred approximately 14 days after a bleeding episode induced by progesterone withdrawal. One of these patients appears now to have permanent ovarian failure. A recent letter indicated there have been no spontaneous periods in two years and the vasomotor symptoms have become so severe as to require hormone treatment. We have been most anxious to examine the ovaries in patients in this group but have not had adequate clinical indication. Group III. The third group, three patients with impending menopause, were healthy patients in their 40's whose only complaints were hot flushes and irregular menstrual periods. Periodic assays for gonadotropin reFig. 10. Ovarian insufficiency (Te. at age 19). This was the only patient in the group with hypoplasia of secondary sex characteristics. The lack of subcutaneous fat accentuates the hypoplasia of the secondary sex characteristics. Weight, 96 pounds.
90
Ma' L l'lf,+
Keettel and Bradbury Am.
Sterility Gyeors-Amenorrhea 6months
Du.-24yrs.
20 10
30
1960
Prog."
20
fl.
D fl. 0
fl. 0
10~·-~-30
1961
20 10
c
Pro g. Enov 1 d
1962 20 10
•
IIOOI ftO fl-O
•
• I 30
1963 20 ~ ~ 10
~
Ft
•
ft
fl,
~LI L~ ,_LLll~-L.4
6
& C\nj·c_
Comment
•••••••••
30
Oh~t.
vealed fluctuating levels with occasionaljwak' in the castrate range which st·em compa tihlt· with their impending menopaust'. T!Ji, ,gwup is of interest in that the t•rrat ic pa ltt·tn < d gonadotropin excretion is similar to I ftd 1 found in the young women in Grottp I I.
30
1959
J.
9
10
II
12
months
Fig. II. Oligomenorrhea and erratic levels of gonadotropin during + years of observation (Du. at ag
Pi.-22yrs. 30
1960
20 10
30
1961 20 10
On the basis of monophasic basal tt·mpcrature graphs and endometrial biopsies, it Ita' heen established that fairly regular tnt·nst·s may occur in the presence of anondar cycles. It is presumed that anovulation represents tht· first phase of ovarian insufficiency and 111a) account for the infertility of some wnmt·n approaching the menopause. Other indi\iduals have irregular bleeding· episodes illtl'rspersed between periods of amenorrhea. \\'itlt a progn·ssive decline in ovarian functicn tfll' m·arics become less n·sponsi\ e to pit11itan gonadotropic control and amenorrhea of tiH· mcnopausc is established. The cause of this physiologic ovarian failure remains a mystery seemingly peculiar tn the human race. It appears that the human fcrnale is endowed at birth with a cl'rtain ovarian "capital'' of primordial ova. Then· Sterility 2years Provera
•• •
•••
•
0
•
•
I
1962 30
1963 20 10
Hot Flashes on Estrogen F} 2
3
4
5
6
7
8
9
10
II
12
Fig. 12. OligomPnorrhca and erratic levels of gonadotropins during 3 y<'ars of observation (Pi. at age 22). No withdrawal bleeding afte"r medroxyprogeste"rone acetate on one occasion. Zeros on th<' base line represent urine assays in which gonadotropin was too low for detection.
Volumt· Hq
Premature ovar1an failure
!\ uwltn 1
are no new additions to such stock by way of oogenesis either from germinal epithelium nr any other structures of the ovary. Thus, the aging of the ovary in one sense really hegins at birth and continues throughout life. In general the aging takes place in an orderly progressive fashion , resulting in a Go -2 4yrs
Prover a
•
•• •
20 10
Alrophoc
30
1961
20
gradual loss of primordial ova and a progressive thinning of the ovarian cortex. Externally, the ovary becomes increasingly wrinkled and rugated, gradually decreasing in size. The m edullary area seemingly becomes more prominent with well-developed stromal cells. The vessels of the hilum show progressive
Sterility 4yeors
30
1960
91
•
VOQ
10
30
1962
F} F}
F}
20
•
10
1963
10 2
3
4
5
6
7
8
9
10
II
12
Fig. 13. Oligomenorrhea and erratic gonadotropins during 2 years of observation ( Go. at age 24 ) . No withdrawal bleeding after rn edroxyprogesterone acetate.
Sequent1al Gon ad otrophin Assays
"t> ...... ...e"'
.
..'"' 0:::
!10
40
Group I
Group II
30
"
...... 0:::
.::
20
t> t>
10
~ ...
" 0:::
()
1.:>
McC Fig. 14. Comparison of first 4 or 5 urina ry gonadotropin titers in representative patients of Groups I and II. Group II had variable titers whereas Group I had consistently elevated titers.
92
May 1, 1964
Keettel and Bradbury Am.
J. Oust . & G yncc.
Total dose of urinary gonadotrophin extract 0.8cc O~cc 0.2cc 0.1 cc
OVAR
Fig. 15. Ovaries and uteri from 4 rats in which the test dose was halved progressively from left to right.
sclerosis. It is difficult to be certain whether these changes are the result of changes in function of the anterior pituitary gland or failure of the ovaries. Many physicians feel these changes cause ovarian failure, and the elevated pituitary gonadotropin levels are an attempt toward ovarian stimulation. H eller and Heller 3 have shown that women with normal menstrual cycles have low urinary gonadotropin levels, those having irregular cycles ran the whole gamut of titers from low normal to the castrate levels. Those with consistently high levels were women who had ceased cycling and had ovarian failure . In another study Heller and associates• have shown that individuals near the menopause having irregular bleeding with castrate levels of gonadotropins, had at the time of surgery, atrophic ovaries typical of the postmenopausal patient. Histologic sections showed no follicles or evidence of corpora a lbicantia. The vaginal mucosa in such patients was often well cornified even though there was low estrogen production indicating that the vaginal epithelium is maintained by rather small amounts of estrogen.
The Group I patients with premature menopause seem identical to the true postmenopausal patient except in age. Before making the diagnosis of permanent ovarian failure it is important to follow these patients at least 6 months to see if the pituitary gonadotropin levels are consistently elevated in the castrate range (Fig. 14). We have found no clue as to why certain women should have premature ovarian failure. These changes may have resulted from ( l) congenitally small ovaries with deficient primordial follicles, ( 2) an unsuspected disease process with partial ovarian destruction, or ( 3) an increased utilization of follicles secondary to pituitary overactivity. This period of increased activity could have been at puberty, during pregnancy or anytime of adult life. No matter what the cause, it is important that young women with permanent ovarian failure be properly evaluated so that they know the true nature of their problem, and not spend valuable time and money hoping for future pregnancies. Our working hypothesis is tha t patients in Group II represent phases of ovarian ir• -
Volume 89
Premature ovanan failure
:;\.'umber 1
sufficiency expressed as a refractoriness in the ovarian response to gonadotropin. The fact that the gonadotropin excretion is readily suppressed by estrogen administration is compatible with this concept. On the contrary, Beclere and Simonnet5 postulate a congenital hypergonadotropic condition of the pituitary as the basis of moderately elevated gonadotropins in young women with menstrual disorders. They dismiss any consideration of ovarian insufficiency on the basis of physical findings (normal breasts and normal-sized 11 terus) even though the estrogen excretion values are low. Their explanation is that the mines were not collected at an appropriate time to show the elevated estrogen production which is necessary for the documentation of an entity "hyperhormonal pituitary-ovarian syndrome" which they propose. Unfortunately they have too few gonadotropin estimations and inadequate follow-up to be sure their 5 young women are comparable to those in Group II. The possibility of temporary ovarian failure or ovarian refractoriness had never been given serious consideration in the etiology of amenorrhea or infertility. This possibility first became manifest in our study of postpartum amenorrhea 6 with or without lactation. We found that gonadotropins were excreted in variable amounts by about 50 per cent of women during this interval of amenorrhea and before they resumed normal cycles. In the postpartum patient the gonadotropinuria represents a temporary refractory state of the ovary in a fertile patient who subsequently resumes normal cycles. In general the pattern was similar to that found in Group II of this report; the majority of specimens containing 4 to 8 units with occasional specimens containing 32 to 48 units per gram of urinary creatinine. What does the future hold for the nine young women in Group II? Is their infertility temporary? One conceived after progesterone withdrawal bleeding. Or is their fertility potential as poor as their past performance? Is the presence of gonadotropin a prediction of an early menopause? In 12 women in Bjoro's study with moder-
93
ately elevated gonadotropins (his high normals) "the clinical impression was that these cases were analagous to the patients with a premature menopause . . . . but as these patients were young and presented infertility problems we were forced to treat them." Does the presence of gonadotropin indicate a relative inability of the ovary to produce estrogen and/or progesterone? If so, can this deficiency be corrected by judicious administration of sex hormones? The opposite possibility, namely, a refractory pituitary that requires excessive estrogen to bring it under control, remains to be explored. It should be emphasized these patients differ from the Stein-Leventhal patients in the following respects; normal to small -sized ovaries, excretion of excess FSH rather than LH and the lack of any hirsute or obese tendencies. While it would be interesting to learn of the ovarian histology in these cases there has been no obvious justification for laparotomy and ovarian biopsy. Further studies and longer intervals of observation are necessary to establish the prognosis or for a regime of management to be developed for these young women. Summary
Investigation of young women with infertility and/or amenorrhea has revealed the presence of a significant number with elevated urinary gonadotropin (primarily FSH) excretion which suggest varied degrees of ovarian insufficiency. Twelve young women (average age, 25 years) excreted gonadotropins consistently as high as encountered in the castrate or postmenopausal. These patients have had a complete ovarian failure and an early menopause. Three women (ages 39, 44, and 47) having irregular cycles seem to be examples of approaching menopause with erratic ovarian responsiveness as demonstrated by fluctuating levels of gonadotropin excretion. Nine young women (average age, 25 years) with infertility, menstrual irregularities, and fluctuating levels of urinary gonadotropin present unsolved problems in etiology, prognosis, and management.
94
\!"'I. l'lM
Keettel and Bradbury
,\ll\.
J.
()IJ..,L & (
;Vill"l',
REFERENCES
J. P .. Morgan, D. :'i .. and Myers, G. B.: ]. Clin. Endocrine!. 4: 'i9. 19+4. 5. Beclere, C., and Simonnet, H.: Press<' mf•d. 71: :1, 1963. 6. Kt•ettel, W. C., and Bradbury, ]. T.: o\~1. J. 0BST. & GY:'\EG. 82:99.5, 1961.
.f.
I. Bjoro, K.: Acta obst. et gynec. scandina\·. (Suppl. 6) 41: .5, 1962. 2. Bradbury, J. T., Brown, E. S., and Brown, '\V. E.: Proc. Soc. Exper. Bioi. & Med. 71: 228, 1949. '1. Heller, C. G., and Heller, E. J.: J. Clin. Invest. 18: 17!, 1939.
Hf'ller, C. G., Farney.
Discussion DR. S. J. BEHRMA:\1, Ann Arbor, Michigan. The paper is important in that it draws attention
curring in th<' young woman in the :20 to 311 y•·ap; age group. It is important lwcaust· to date thn<'
the actual existPnce of a clinical entity of
is no way of reversing the condition, and lw-
prcmatun' nwnopaust' or secondary amrnorrhca
cause its diagnosis should avoid tht· tmncct•ssan
with JWnnanent pn•mature ovarian failun• oc-
risks and wast;• of time
to
in
incnrrt'ctly doinl(
Table I. Summary of sixteen patients with prematun' ovarian failure 17-Ketosteroids in
Age
Duration (yr.)
D.M.
972791
~7
7
B. P.
919105
~6
+
E.M.
rt'L
'l!
·1
Parity
FSH*
Toted estrogens
+7.1 0 0
Remark.'
5.8
+.0
lR
mg. per J.f. hours
2.
j
2.1
192 382
J.K.
ref.
29
M.R.
64080-t
:H
A.R.
rt'f
2!
H
R.B.
822700
~1
3
C. S.
66+179
~.f
M.M.
879620
:n
3
0 () I)
II
()
3
910-+32
2+
3
J
941 :~98
22
2
(I I)
].K.
79+1193 76+347
Ill
1.7
48.il
i.O
-18 96
9 1.5
() ()
:21
:i 1
3
L. W.
015916
21
3
S.K.
8675+8
19
2
017 ·1-70
·*Rf'pOltt·d in HMC unit-.
29 set• text.
1
v"
9ti
+
96
3.2
192 192 96 96
+8 192
<1
+8
96
E. L.
ifi.i
Dialwtic
·l8
')
S.M.
L. F.
i.D
() I)
I) ()
S.
192
l.'i ..'i
Flushes
4.9
Flushes
1.5
1.1 1.7 FlushPs
1.0
<2
~
Fiusht's
7.8 !I ()
')
:~
78A
:u
.;:~.2
1.0
-18 --l-8
6.8 1.0
7.9 7.0
Flushes
7.:1
FlushPs
Volume 89
Premature ovanan failure
95
::"J"umber 1
wedge resections or giving experimental hormone therapy. Dr. Keettel neatly describes the evolution of the condition, firstly with the frequent occurrence of anovulation as evidence of the commencing ovarian insufficiency, followed by irregular bleeding cycles interspersed with lengthy periods of amenorrhea terminating in complete amenorrhea and permanent ovarian failure characterized by low estrogens and high gonadotropins. This he clinically divides into three phases, the first of ovarian insufficiency, then the premenopausal stage with fluctuating levels of gonadotropin, and then the high castrate levels of gonadotropins with permanent ovarian failure. The onus of diagnosis and classification rests therefore upon the accuracy of the levels of these gonadotropin estimations. The method described by the authors uses a test dose of an aliquot of urine containing 0.5 Gm. creatinine relative to the 12 hour output. Potency is expressed in units of gonadotropic activity per gram of creatinine. On this basis the normal gonadotropin output is equated as zero. ElPvated levels of gonadotropic activity vary from 5 to 20 and 35 to 50 units as castrate icvPls. This method is relatively rapid, unique, and original with the authors. Dr. KeettPl and Dr. Bradbury give a frequency of this condition of secondary amPnorrhea with permanent ovarian failure at l('ast equal to that of polycystic ovarian disease. This is not our experience. In a recent series of 196 casPs, an endocrine status compatible with complete ovarian failure was noted in only 16 cases, 12 per cent, when·as almost 40 per cent of the series was represented by polycystic ovarian disease. In our series we consider as castrate or menopausal levels repeated readings of 48 human mPnopausal gonadotropic units or higher where the unit reflects the amount of gonadotropin that induces a 100 per cent increase in the average weight of the uterine horns in mice. Among the sixteen patients of premature ovarian failure (the average age being 26), six reported hot flushes. The average duration of the secondary amenorrhea was 3 Y2 years (Table I). The diagnosis of permanent ovarian failure is a serious one to the patient, and, therefore, should be made with due caution and only after repeated analyses over a reasonable period of timt>, ideally including a culdoscopic t>xamination to rule out other pathology. I n1ention this brcause one of our cases, after 4 years of apparent
premature menopause, quietly settled down and became pregnant and went to term without difficulty. Can this condition be mimicked by psychic causes through the hypothalamus or, perhaps, by temporary gonadal defects? I would like to raise another question I believe to be of some importance: Does this premature menopause predispose the patient to ischemic heart disease? In a very recent study by Sznajderman and Oliver 2 we find that in 25 of 35 women studied, who stopped menstruating before the age of 35, and who wPre followPd over a period of 10 years, ischemia developed in 4, 1 more died of myocardial infarction, and another 7 had significant cardiovascular complications. This gives an incidence of seven times the average expectation of cardiac complications. In another report 3 cardiovascular disease was found in 25 per cent of 112 womPn who had had bilateral oophorectomy under the age of 40 and who had not had any form of estrogen therapy, compared with 10 per cent of 45 women who also had oophorectomy but who had estrogen rt>placement therapy. I would like to ask Dr. Keettel whetht>r hP has any follow-up studies on the series with specific reference to serial values of cholesterol and triglycerides, as this seems to be elevated in the menopause. Should these tests not routinely be dont> where premature menopause is suspected? Finally, I too feel as Dr. Keettel suggests, that once the diagnosis of premature ovarian failure is established, treatment with cyclic estrogen to permit menses and inhibiting the pituitary is advised and well tolerated. A treatise emphasizing this clinical entity has long been ovPrdue, and I commend the authors for bringing it into sharp focus. REFERENCES
1. Behrman, S. J.: Secondary Amenorrhea [Searle Symposium], 1963, in press. 2. Sznajderman, M., and Oliver, M. F.: Lancet 1: 962, 1963. 3. Higano, N., Robinson, W., and Cohen, W.: New England J. Med. 268: 1123, 1963.
DR. jAMES T. BRADBURY, Iowa City, Iowa. Dr. Behrman has pointed out the fact that the determination of urinary gonadotropin is the critical factor or the basis of judgment in this study. Actually there is no specific biologic assay for gonadotropins. This is a terrible admission to make after 30 years but it is time for true confessions. The method used by any investigator is st>leckd on the basis of personal prdPrPnce
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rather than on one of scientific validity. We prefer the rat ovarian response because it offers several qualitative aspects as \vell as some quanti .. tative approximations. Fig. 15 (numbered in reference to those in the text) shows the ovaries and uteri from 4 rats in which the test dose was halved progessively from left to right. This shows specimens from a series of rats in which the dose was doubled in each step from right to left. The 20 mg. ovaries show little or no weight response. The 44 and 66 mg. ovaries contain many vesicular follicles of uniform size. Grossly they are pale honeycombed ovaries. The 130 mg. ovaries are hyperemic and luteinized. Further increase in dose leads to further luteinization without much further increase in weight. In this test the significant doses are those which stimulate ovaries to the 44 to 66 mg. weight range, with the pale vesicular follicles as evidence of FSH. The uteri from these animals show that the maximum uterine weight ( 182 mg.) was achieved with a lower dose. This is the reason that many investigators prefer the uterine weight response as a more sensitive test. Offsetting this advantage of sensitivity is the lack of specificity. The uterus responds to estrogen from the ovaries whether they are stimulated by pituitary extract, menopause urine, pregnant mare's serum, or human pregnancy urine. Quantitatively the uterine weight response in the test rat or mouse is useful for small quantities if it is known what type of gonadotropin is being tested. However when a random urine extract is being tested the uterine response gives no clue as to the type of gonadotropin in the extract. In a report to this Association a few years ago on the Stein-Leventhal syndrome we judged the type of gonadotropin on the basis of the rat ovarian response. In that study if we found the ovaries were hyperemic and were in the 30 to 40 mg. weight range they were fixed and sectioned. The presence of thecal luteinization was judged as evidence of an LH effect. The uterine distention with fluid was merely noted as additional evidence of ovarian stimulation. We rely on the gross appearance of the ovaries, hyperemia in the lower weight range, as to whether the gonadotropin is primarily LH as in the Stein-Leventhal syndrome or ischemia with vesicular follicles as evidence for FSH in the ovarian insufficiency states as presented in the present study. The dose response cure (Fig. I) was devel-
May I, 196-1 Am, J, Obst. & Gynec.
oped from a series of tests like those just shown (Fig. 15). In any dose response curve the useful part is the steeper portion. In doses beyond 3~ units the curve flattens and is not usable. It is not feasible to designate menopausal or castrate levels on a curve of this type because, as was mentioned, the final unitage is based on creatinine aliquots. Ordinarily, the average woman puts out about 1 Gm. of creatinine in a 24 hour urine specimen. If the entire 24 hour collt'ction was concentrated into the dosage given to one rat and this resulted in an ovarian weight of about '15 mg. as shown by the horizontal line, the assar would read out as 8 units per gram of creatinine. The same ovarian response ( ')5 mg.) obtained with a 12 hour aliquot of urine ,0.5 Urn. creatinine) would be 8 divided by 0.5 or 16 units per gram of creatinine. Similarly the sam•· ovarian response obtained from a dos<' of t>xtract derived from a 0.25 Gm. aliquot would indicate 8 divided by 0.25 or 32 units per gram of creatinine. For comparison with reports in the literatur<' which report urinary gonadotropin ( prim;uily FSH) in terms of mouse uterine units, multiplying our units by 10 would result in the sanw numerical range of values. DR. KEETTEL (closing). Dr. Behrman has raised the question concerning thr effects of a premature menopause on the vascular system. In our material, two patients had consistent minor elevation of blood pressure and two patients had elevated serum cholesterol levels. To prevent vasomotor symptoms, decrease atrophic vaginal changes and perhaps to prevent atherosclerotic changes, cyclic estrogen therapy is t'mployed in our patients with proved permanent ovarian failure. In the future we are planning to study chromosome counts on these patients, perhaps this will give helpful information. The incidence of polycystic ovarian dis•·ase varies widely, dependent upon the criteria employed for the diagnosis. In order to substantiak the diagnosis the following criteria arc employed in our clinic: infertility, amenorrhea, bilateral enlargement of the ovaries, the presence of LH in most of the urines studied, and increas<'d ovanan enlargement produced by exogrnouo;
FSH. In conclusion, I would likP to point out this is not an uncommon problem since from two teaching institutions 28 cases of patients with permanent premature ovarian failure have bePn presented.