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Endocrinologic studies were done on a patient with “gonadotropin-resistant ovaries” syndrome presenting with secondary amenorrhea, increased secretion of gonadotropins, and unstimulated ovarian follicles. The feedback effects of estrogen upon the hypothalamic pituitary axis seemed to be present. Plasma levels of estradiol and estrone were in the low normal range. The levels of androgens in the plasma were slightly elevated, and the elevated levels appeared to be ovarian in origin. Clomiphene did not alter the levels of follicle-stimulating hormone (FSH) and luteinizing hormone significantly but increased the levels of estrone and estradiol. Histologic confirmation of unstimulated follicles and elevated levels of the gonadotropins, particularly FSH, are essential for diagnosis.

We have studied a family with an X/X translocation which was found in a 16-year-old daughter and in her 34-year-old mother. The daughter had short stature, secondary amenorrhea, and many Turner’s stigmata. The mother, 5-ft tall, had a few Turner’s stigmata and had developed secondary amenorrhea at age 24. Both peripheral leukocyte and skin fibroblast cultures of the daughter revealed, by conventional karyotype analysis, 46 chromosomes with one C-group chromosome missing and with an extra No. 2-like chromosome in all metaphase cells examined. By both Q- and G-banding techniques, this abnormal karyotype was identified as 46,X, + t(X;X)(p22;ql3). An identical translocation chromosome was demonstrated in the mother’s cells, but 50 % of the cells had a 45,X chromosomal constitution. Autoradiographic studies showed that the X/X translocation chromosome was the late-replicating X in all cells examined from both the daughter and the mother. The difference in the phenotypic manifestations of the daughter and of her mother can be explained perhaps by the different contents of the other active X chromosomes. When the same X chromosome is inactivated in all cells, mutations present in the active X chromosome are not compensated and therefore are expressed.

Thirty-five patients with secondary amenorrhea and an associated gonadotropinestrogen deficiency were treated in 233 cycles with clomiphene, 100 mg. per day for 5 days each cycle. The pretreatment mean duration of amenorrhea was 2.4 years. Eighty per cent of the patients ovulated in one or more cycles of treatment and 35 per cent became pregnant. No correlation was found between the pretreatment Metopirone pituitary function test results and the success of clomiphene treatment. This form of therapy is discussed. (See addendum.)

THE practitioner of medicine is often confronted with relatively young women who complain of scanty or absent menstruation and infertility. Their desire is primarily to become pregnant and secondarily to have normal menstrual periods. Yet, in the past, physicians have placed much emphasis on merely inducing menstrual bleeding, and too little attention has been directed to the problem of ovulation in these patients. It is the purpose of this communication to evaluate 50 patients treated for secondary amenorrhea in an attempt to draw certain conclusions regarding the production of ovulation and subsequent pregnancy. A very important contribution to our understanding . . .

Synthetic LRH was injected i.v. innormal menstruating women and in patients with various endocrine disorders, such as retarded growth, precocious onset of puberty, anovulation, secondary amenorrhea, S

Twenty-six patients with secondary amenorrhea and inappropriate lactation have been studied. There was no apparent cause in 8, while in 18, precipitating factors were present. Urinary estrogens were low, and assay of human growth hormone (HGH) in 9 patients did not reveal a constant pattern. Seventeen patients submitted to diagnostic gonadotropin stimulation and each showed a response compatible with potentially normal ovarian function. Nine patients without detectable lesions have been, or are being, treated with clomiphene citrate and/or human gonadotropins. All 9 have or had apparent ovulation, and 5 so far have conceived. Lactation has stopped in each of these 9 patients, but in none of those untreated.

The object of this paper is to emphasize the clinical entities resulting from ovarian hypofunction. We have observed a group of cases presenting diversified clinical pictures, in which the underlying factor was considered to be one of failure of ovarian function. This contention was verified not only by bioassays, endometrial biopsies (1, 2, 3), and histological studies of ovaries, but also by the response to therapy (estrin administration, or small-dose x-ray therapy for stimulation purposes). The cases have been considered under the following sub-groups: uterine bleeding (excessive and diminished), compensatory pituitary hyperfunction, and adreno-genital syndrome. Distinct and clear-cut cases of primary and secondary amenorrhea are not included in this paper.

Eatrone, estradiol-17β and estriol were isolated and identified from the urine of normal menstruating women, and from a case of secondary amenorrhea with apparently no increased urinary PSH. Quantitative estimation by fluorometry, coupled with tracing of added labelled estrone and estradiol-17β, throughout the various stages of the isolation procedure, confirmed the reliability of the fluorometric method. Neither of the estrogens could be isolated from urine of a patient with secondary amenorrhea with increased PSH excretion, nor from a patient with bilateral ovarieotomy. In both cases the fluorometric values were close to zero.

After gonadal dysgenesis or developmental failure have been ruled out and therapy initiated for secondary amenorrhea in appropriate cases, there remains a group of women in whom measures to overcome infertility can be undertaken with reasonable expectation of success. The first need is to determine if ovulation is occurring; if it is not, a variety of means is now available to induce it.

The frequency rates of secondary amenorrhea when examined epidemiologically appear to be quantitatively related to separation from home and family and to the extent of the threat associated with such separation. In peacetime circumstances the rates are low but increase to 100 per cent in those about to be executed. Such amenorrhea definitely antedates the malnutrition which is associated with many of the situations where high rates occurred. In the large majority of instances, amenorrhea developed immediately after the separation. The prognosis is excellent if the stress can be adapted to or removed. However, when the amenorrhea is preceded by evidence of psychosexual immaturity, neurotic or psychotic, the prognosis is more dubious. There is some evidence that age of menarche and age at separation influence the rates.

RECENTLY several members of our group (1) reported that a male excreted sodium pregnandiol glucuronide in the urine during the course of therapy which involved intramuscularly administered desoxycorticosterone acetate in oil. In view of this observation and of reports that desoxycorticosterone acetate was capable of inducing progesterone-like responses in certain experimental animals (2), a study of the possible progestational action of desoxycorticosterone acetate in women was initiated. Two groups of women were studied. One group of 5 women (average age 25 years) was characterized by the common symptom of secondary amenorrhea, the duration of which had ranged from 3 to 9 months. The other group comprised 3 women (average age 29 years) who received desoxycorticosterone preoperatively. The procedure in the first group was as follows. Endometrial responses prior to therapy were sampled by biopsies.

A female, aged 31, who had amenorrhea for ten years, received 25,500 rat units of antophysin over a period of eleven months in manner stated above, had four menstrual or pseudomenstrual periods, finally conceived and gave birth to a living child. The points of interest in this case are: 1. Menstruation or pseudomenstruation was restored after a ten-year period of secondary amenorrhea. 2. Patient conceived and carried to full term, giving birth to living child. 3. Despite the absence of a cyclic curve of estrone, treatment was attempted. 4. Patient was treated over a period of eleven months. Had treatment ceased at six months or less, the hormonal product would probably have been blamed for failure. 5. Treatment was given at thirty-day intervals, establishing a so-called cycle for treatment. 6. This case is not reported in order to represent the sole type of treatment for all cases of secondary amenorrhea. However, it suggests that we might some day arrive at the proper dosage and proper time of cycle for hormonal treatment of amenorrhea.

SummarySecondary amenorrhea has been defined and its pathophysiology discussed.The literature on the psychogenesis of, and psychic correlations with, secondary amenorrhea was reviewed.Twenty-six subjects were studied to determine if any correlations between secondary amenorrhea and psychic imbalance

FAILURE of normal ovarian function with the resultant cessation of the menses in an otherwise healthy, normal young woman may be due to a variety of causes. Most often it is an expression of a disturbance of the hormonal support necessary for normal cyclical activity. The failure may involve the ovary primarily, as in the menopausal period. It may be the result of malfunction of the gonadotropic activity of the anterior lobe of the hypophysis. It may possibly involve other endocrine glands such as the thyroid or adrenal, which support the hormonal balance necessary for the normal sex cycle. The role of the adrenal gland in ovarian function is not known. There is some evidence that adrenocortical activity is important in both normal and abnormal ovarian function. The present investigation was undertaken in order to study mild and severe ovarian failure in women in whom ovarian function had been established, and to demonstrate the metabolic effects of ACTH and its influence on disturbed ovarian activity.

Twenty-five patients with secondary amenorrhea or oligomenorrhea were studied with buccal smear, nuclear sex analysis, and leukocyte karyotyping. XX/XO Chromosomal mosaicism was found in 3 patients (12 per cent). The data, although preliminary, suggest that a buccal smear should be performed on all patients with secondary amenorrhea of greater than 6 months' duration or on those with oligomenorrhea.

DURING the course of investigations on the divergent pharmacology of estradiol, stilbestrol and several ethers of stilbestrol (1, 2) it was noted that some of the ethers seemed to have a marked pituitary potentiating capacity. Several substances were tested specifically for this property. One of them, the monobenzyl ether of stilbestrol, was found exceptional in this respect. It has been assayed in animals, and tested clinically in humans. The primary interest in the compound stems from its potential clinical value in the treatment of chronic secondary amenorrhea and other hypogonadotropic states. The present report will present some of the data obtained in the animal studies as well as the results thus far obtained from the use of monobenzyl ether of stilbestrol in the treatment of 18 women with chronic secondary amenorrhea. METHODS AND MATERIAL OF STUDY The substance has been tested in rabbits, immature rats, and humans. The material has been administered in an olive oil solution by subcutaneous or intr...

An 18-year-old girl had short stature, secondary amenorrhea, and an elevated level of serum gonadotrophins. Sex chromatin studies revealed variable numbers of X-chromatin bodies of smaller than normal size. Trypsin-Giemsa banding of the chromosomes demonstrated the deletion of part of the long arm of an X chromosome.

Fifty-four consecutive cases of secondary amenorrhea seen in the Department of Obstetrics and Gynaecology of Umea University Hospital were systematically studied from the somatic, endocrinologic and psychiatric points of view. The study showed that 51 patients had lost weight at or about the time of onset of amenorrhea and that 41 of these had symptoms characteristic of anorexia nervosa; some were cachectic. In none of these cases was there any reason to suspect a primary endocrine disturbance. On the other hand, two of the patients who had not lost weight, had significantIy elevated urinary 17-ketosteroids in both total and fractional analysis.The connection between starvation, psychogenic amenorrhea and anorexia nervosa is discussed.

Synthetic LRF in a dose of 150 μg was injected intravenously on two successive days in eight women with secondary amenorrhea. Two of the women received LRF injections only, three were treated with estradiol benzoate (EB) and three were treated with aqueous progesterone (P), each steroid being administered four hours after the start of the first test. Pre-treatment with both steroids had a marked suppressive effect on the magnitude of the pituitary response to exogenous LRF in the second test. The results, suggest a direct effect of ovarian steroids on pituitary gonadotropin producing cells.

Three patients with different types of Turner mosaicism including a 45,X line arepresented. Two patients were preadolescent girls who had normal linear growth during the first decade of their lives and inadequate growth thereafter. One of these girls has mosaicism of 45,X/47,XXX, and one is mosaic for 45,X/46,XXqi. The third patient, who has normal secondary sex characteristics but secondary amenorrhea, has 45,X/46,XXr mosaicism. It is apparent that detection of deceleration in linear growth in otherwise healthy preadolescent girls may be an important diagnostic clue for Turner mosaicism, as may secondary amenorrhea.

THE purpose of this paper is, first, to report a case in which the coexistence of diabetes mellitus and hypoadrenalism was further complicated by the presence of hypothyroidism and secondary amenorrhea and second, to report the results of the administration of purified growth hormone to this patient. The incidence of the coexistence of diabetes mellitus and hypoadrenalism in itself is very rare as only 32 cases (1–6) have been reported up to July 1, 1951. It will be brought cut in our discussion that this patient did not have panhypopituitarism but rather multiple “end organ failure.” A similar case has been reported (7) in a male, but to our knowledge a similar case has not been reported in a female. CASE HISTORY W.S., a 19-year-old white female was admitted to the University of Virginia Hospital on October 13, 1949, in a semi-comatose state. The patient had been known to have diabetes for approximately six years. Her insulin requirement had ranged from 45 to 60 units of protamine-zinc insulin daily. One...

Methopyrapone was administered to 4 control subjects and 2 patients with secondary amenorrhea in 2 dose schedules. In the control patients there was no change in urinary estrogen excretion after methopyrapone administration. In the 2 patients with secondary amenorrhea there was a significant increase in the 3 estrogen fractions after the 250 mg/2 hr per 24 hr dose schedule.

IN 1935 Stein and Leventhal1 reported 7 cases of amenorrhea associated with polycystic ovaries. In addition 4 of their patients complained of hirsutism, and 3 were obese. After wedge resection of the ovaries, normal menses reappeared in all 7 patients, 5 of whom eventually conceived. The amenorrhea and the polycystic ovaries were thought to be due to an imbalance of the pituitary-ovarian axis. The combination has become known as the Stein–Leventhal syndrome. Secondary amenorrhea as the main clinical symptom of this syndrome was emphasized by Leventhal and Cohen2 in 1951, when they stated that wedge resection was not indicated unless . . .

Amenorrhea, whether primary or secondary, is still a major therapeutic problem. With rare exceptions organotherapy has failed to elicit permanently good results. At best, bleeding is induced upon withdrawal of the experimentally administered hormone without, however, sustained cyclic menstruation thereafter. The ideal treatment has not been attained, because the etiology of amenorrhea remains unknown. Recently Pencharz1 reported maximum stimulation of the immature rat ovary with chorionic gonadotropin combined with diethylstilbestrol. The stimulation exceeded that of any other experimental hormonal stimulus. This combination of hormones was, therefore, given to 12 amenorrheic women in the hope that such therapy might effect more permanent results than were attained with cyclically administered sterols or with equine gonadotropins. The latter hormones had previously yielded very indifferent results in this clinic. Of the 12 patients, 4 complained of primary and 8 of secondary amenorrhea; only 8 were treate...

THE RESULTS of treatment of secondary amenorrhea are often a source of dissatisfaction both to the patient and her physician. We are reporting a case of secondary amenorrhea in which a careful diagnostic survey was completed and an unusually long and tedious course of therapy was given before a completely successful result was achieved. CASE REPORT The patient was first seen in March, 1941, at the age of 17. She was a thin, pale, white schoolgirl who had not had a menstrual period since June, 1940. Menarche occurred at 13 years of age. She had her first 3 periods at 6-month intervals and then had regular 6-week menstrual cycles which terminated abruptly in June, 1940. Her periods had been normal in duration and were never painful. She had never been operated upon and had had only the usual childhood diseases. Physical examination. Physical examination revealed a thin, white girl with no endocrine stigmata.

Ethinyl estradiol was prepared by Inhoffen and Hohlweg1 by the replacement of the 17th carbon atom in estradiol by an ethinyl group. When given subcutaneously in oil, ethinyl estradiol and estradiol are equal in potency, but when given orally, ethinyl estradiol is 15 to 20 times as active as estradiol. Clauberg and Ustun2 reported the use of ethinyl estradiol in secondary amenorrhea and oligomenorrhea and demonstrated proliferative changes in the uterine mucosa following doses of 56 mg. of ethinyl estradiol, given over a period of 20 days. No symptoms of toxicity were reported in their series. Salmon et al.3 administered ethinyl estradiol in the form of enteric-coated tablets and in alcoholic solution to 27 patients with menopausal symptoms and morphologic evidence of estrogen deficiency (tablets, 22 patients; alcoholic solution, 5 patients). Ethinyl estradiol in the form of entericcoated tablets was found to possess high estrogenic potency when administered orally, as demonstrated by the relief of menopa...

This little book is essentially a research monograph. It is solid yet at the same time baffling and elusive. Conceptually worthwhile, it reports the ketosteroid and hydroxycorticosteroid changes over a considerable period of time in seven women undergoing psychoanalysis, attempting to correlate these changes with phases in the analyses. The researchers have a clear and valid methodological approach, and, unaware of the pitfalls and complexities, recognize that their research falls short of yielding the correlates they seek. Yet the title is misleading, for this work does not fulfill its promise of enlarging the reader's understanding of psychosomatic gynecological disorders, but focuses on seven case histories in which secondary amenorrhea, premenstrual tension, and frigidity were presenting symptoms of serious personality disorders. The rather general and incomplete case reports (in contrast to the excellent and detailed steroid studies) are presented strictly in the opaque language of classical psychoanalysis, often expressing only the

A study of 9 patients with secondary amenorrhea which began after stopping oral contraceptives is presented. None of the women had evidence of organic disease. Urinary 17-oxosteroids and 17-hydroxysteroids were normal. Withdrawal bleeding could be induced by the administration of exogenous gonadal steroids. 7 of the 9 patients underwent diagnostic gonadotrophin stimulation. The response to exogenous gonadotrophins indicated that the women had potentially responsive ovaries and that the cause of the amenorrhea lay in the hypothalamus or pituitary. 2 of the patients were treated with clomiphene and they readily ovulated and conceived. It is postulated that the prolonged inhibition of FSH and LH release that is associated with the use of oral contraceptives may very occasionally cause long-term disruption of hypothalamic cycling just as very rarely may normal pregnancy. In most cases the condition is resolved spontaeously.