Some Contributions of Endocrinology to Obstetrics and Gynecology*

SOME CONTRIBUTIONS OF ENDOCRINOLOGY TO OBSTETRICS AND GYNECOLOGY* E.

c. RAMBLE~, M.D., DURHAM, N. c.

(From the Endocrine Division of the Depa-rtment of Obstetrics and Gyn~c.olofiy, llnh University School of Medicine and Dulce Hospital)

title of this addres.'> would be phmsed more appropriately, perhaps, T itHEread, ''Some Contributions hy Obstetricians and Gynecologists to

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Endocrinology." Some of the most outstanding of these contributions have come from the University of Chicago and, in particular, from its Department of Obstetrics and Gynecology. Endocrinology has been accepted as a faithful handmaiden of our specialty. We have learned that the varied genesiologic functions of woman are monitored by her endocrine system, and our expanding knowledge of the mechanisms of this system has given a foundation for the present ''physiologic phase'' of obstetrics and gynecology. Application of this new knowledge of gynecic physiology has clarified the etiology of many enigmatic disturbances of woman's reproductive processes, and has permitted correlation of them to functional aberrations of her endocrine system rather than to speculative diseases or to obstinate perversity. The conservative treatment of these functional vagaries with appropriate endocrine substances has rendered less frequent any recom·se to fnnctioudestroying surgery and roentgenotherapy and, thereby, has p1·eserved, aud has effected, physiologie salvage of the childbearing fun<:tion of eonntless women.

Historical Background It is fitting on this occasion that we should pause to examine br·ieiiy the status of endocrinology and the concepts of gynecic physiology fifty years ago. when the Chicago Lying-In Hospital was founded. Endocrinology about 1895.'-Clinical endocrinology was a newborn itself when the first baby was born at Chicago Lying-in Hospital. Brown-Sequard. the F'ather of Clinical Endocrinology, had died the year before, in 1894. Th JouNUtl Lancet of April 7, 1894, in an obituarial editorial, had observed that "it is to the recently deceased savant that the medical world owed the initiation of treatment of disease by injection of animal extracts.'' Brown-Sequard had described, in 1889, the rejuvenating effects which he had produced in himself-then 72 years old-by injections of an extrad composed of blood of the testicular veins, of semen, of liquid from crushed testes, and of distilled water. Successful treatments of myxedema by injections of thyroid extract and by the oral administration of thyroid gland were reported respectively in 1891 and 1892. One year later, in 1893, a patient with ''menopausal psychosis" was said to have been cured by the subcutaneous administration of ovarian juice. Organotherapy was well on its way! *Address delivered at the celebration of the Fiftieth Anniversary of the Chlcai"O Lying-In Hospital, University of Chicago, Chicago, Ill., October 29, 1945.

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Knowledge, however, of the physiology, and even of the detailed anatomy, of no gland wa.'l complete in 1895. An organic combination of iodine was reeogni,;ed in 1895 as a constituent of the normal thyroid gland: here was the beginning of the fruitful studies of iodochemistry which still continue. The adrenal medulla in 1894 was shown to contain a pressor substance and, two years later, this principle was isolated. Although Brown-Sequard, in 1856, had concluded from experimental adrenalectomy that the adrenals were essential for life, no cortical extracts with life-preserving properties were prepared until1927. In 1893, experimental studies gave proof that the pancreas had an endocrine function and, three yem·s later, the islet cells were shown to contain secretory granules. The first complete anatomic and embryologic description of both pairs of the parathyroids was given in 1895 and, the following year, tetany was related to parathyroid deprivation. In 1898, it was demonstrated that ovarian grafts, in previously oophorectomized women, reestablished menstruation, sexual desire, and a sense of wellbeing. Two years later, ovarian control of the female reproductive system was established; however, the same year of 1900 the members of the American Gynecologic Society heard the statement that ''there is not one iota of proof that the ovary has any other function than to manufacture eggs. " 2 Although Kundrat and Englemann, in 1873, described cyclic alterations of the endometrium, these observations went unnoticed or were forgotten until Hitschmann and Adler, in 1908, rediscovered and amplified them. Accordingly, in 1907, in Kelly's and Noble's Gynecology and Abdorninal Surgery, we find an illustration of a normal full-blown progestational endometrium labelled as glandular hypertrophy of the endometrium, and this condition (or as it was also called, glandular endometritis) was described as pathologic. In 1893, it was shown that injury of the anterior pituitary increased the output of urine. The next year, acromegaly was correlated with hypertrophy and overactivity of the pituitary and a pressor action of pituitary extracts was demonstrated. Vie1rs on .lfenstnu:ttion and Ovulation Ab&nt 1895. 1-Now let us examine briefly some of the views on menstruation and ovulation which were current about 1895. The ovum-producing function of the ovaries was generally accepted. Most physicians believed that, in some way, menstruation was related to ovarian function. There were some dissenting views. Robinson/ for instance, maintained in 1891 that menstruation was governed by so-called ''automatic menstrual ganglia'' which were situated in the walls of the Fallopian tubes and uterus, and that ovulation was quite unrelated to menstruation, menstruation occurring only when periodic and rhythmic peristalsis of the tubes was established. Playfair in his Science and Practice of Midwifet·y (Sixth 1\merican Edition, 1893) observed: ''That there i8 an intimate connection between ovulation

798 and menstmation is admitted by most physiologists, and it is !wid hy many thai the determining cause is the periodi<· mat ttmtion of the Uraafian follides. '· Skene in hi:,; Diseases of Womrn (Third Edition, 1~B7) ohsened: "'l'Jw function of the ovaries is primary in the pmeess ot' r·eproduction. ThPi 1· ph~·:;io­ logical activity preeedes tlw utPl'ine run(·tion.s, and <·ontinnes, a;; a !'llie, until the menopause, and possihly after it. Ht'!H•e the t'nnetions of the otlwr sexual organs appear to he n~spousiYe to the influew·e ol' 1ht> ovaries.'' Skene, however, in listing "ecrtain eonditions" whic-h he held to he necessary to the fulfillment "of the laws of menstrual fmH•tion"
Some Present Concepts and Clinical Applications Any sm·n·y of the role which endoerinology plays in present obstetric and gynecolog·ic thought and practice must he limited in its ::;eope. A ff'W of the outstanding <·oneepts and eliuical applir.ations will he discussed. Physiology of the Jlensttual C,1tcle.- -The isolation of estrogen from human ovarian follit•los in 1925, b.r Edgar Allen and his as;;odates, was the starting point of our present eoneepts of the menstrnal eyrie. (Progestin, subsequently in 1936, -was irkntified in human eorpora lutea). Utt•rine bleeding, in 1926, was shown to follow a deprivation of estrogen, either resulting· from castration after the middle of the eyele, oJ· !'rom the withdrawal of estrogrm therapy, or its reduction to snbtlueshold a mounts. It wn;-; ;;ho\VIl also i hat this withdrawal bleeding eonld he prevented hy estrop;e11 therapy. Pharmacologic studies of estrogen and progestin eorrdated the interval growth phase and the progestational differentiative pha.~e of the endometr·ium as 1·esnlts of the respective actions nf estrogen, and of e::;trogen and progestin, during the menstrual cycle. Accordingly, a hormonal fonndatio11 wns supplied for menstrual blt'eding and for the endometrial alteration"" of the menstrual cycle. Our present concepts of the mcehanism of uterine hleeding rest fundamentally upon the cytologi(• und vasC'ula t· studies.; initiated herr at the University of Chieago by Professor Bar1eln:ez alHl his gTonp. whieh ineluded 0 'Lem·~·

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and Markee. The detailed studies of Markee upon ocular endometrial implants in the monkey have afforded basic data upon the physiologic changes of the living endometrium. The theory of menstruation, which, in my opinion, provides the best clinical tool for working with the diverse functional irregularities of uterine bleeding, is the one currently held by Markee. 7 It is summarized. The cyclic waves of estrogen seeretion by the ovaries cause characteristic growth of the endometrium. Regressional changes, which end in menstruation, occur when the hlood estrogen levels fall to levels which are 50 per cent or less of those which characterizf' the peak of estrogen secretion. Progestin levels are not regarded as contributing significantly to endometrial growth or as being involved in the withdrawal phenomena which initiate uterine bleeding; however, the levels of progestin are adequate for endometrial differentiation and for other physiologic functiom; attributed to progestin. This "grnwth wave theory" of menstruation, accordingly, is applicable both to ovulatory and anovulatory cycles. When estrogen levels become insufficient to maintain endometrial growth, regression begins. Regression may or may not end in hleeding, dependent upon the degree of estrogen deficit and upon the scope and rapidity of the regression. When a critical fall in estrogen levels occurs, the following train of events ensues. Regression and decrease in the thickness of the endometrium produce characteristic changes in the spiral arterioles: increased coiling, knotting, and buckling. 'fhese result in stasis and anoxemia of the functional layer of the endometrium, which in turn cause necrobiosis, impairment of vascular integrity, and the liberation of a ''menstrual toxin.'' This toxin produces vasoconstriction of the undamaged lower portions of the spiral arterioles. Bleeding occurs as the vasoconstriction effect on isolated arterioles wears out, and continues until the arterioles again become constricted. Menstruation ceases when a new growth wave of estrogen secretion begins and permits reepithelialization by growth and reestablishment of an adequate circulation in the remains of the functional area. Endometrial Biopsy a.nd Anovulatory Bleeding.-The technique of endometi·ial biopsy has provided a simple, safe, and clinically practical method of gauging the quality of ovarian function. 8 In 1931, Bartelmez obsel'Ved that the total number of menstruating uteri studied histologically was so small that "no one can be justified in setting up a norm for the process. "H At present, however, many clinics perform routinely endometrial biopsy at the onset of bleeding when investigating functional disturbances of uterine bleeding and sterility. Accordingly, some clinirs now have studied many thousands of endometrial biopsies, taken during bleeding. Corner,t" in 1923 and 1927, submitted conclusive evidence that cyclic anovulatory bleeding occurred in the Macaque, and he listed several instances from the clinical literature which provided convincing evidence that a woman might bleed cyclically without antecedent ovulation. During the past decade, cyclic anovulatory bleeding has been diagnosed frequently by endometrial biopsies, and its causal relationship to some sterility and to many functional disturbances of uterine bleeding: has been genet·ally accepted.

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1'he 'J'i,me of Ov,ulation.-The preponderance of clinical data indieat1'" tlw1 ovulation occurs approximately fourteen days before the onset of the next menstruation. 11 Endometrial biopsies taken immediately after the supposed time of ovulation commonly show early progestational alterations.'" Pregnanediol is not present in the urine until after the time of ovulation. Studies of basal rectal temperatures, when these are kept carefully throughout tht~ menstrual cycle, permit a simple clinical method for timing ovulation,'" Th1' characteristic rise in basal rectal temperature, which signalizes the postovulaton, phase of the cycle, has been related to the action of progestin. The data from records of basal rectal temperatures emphasize the fact that variabilities in cycle length concern the estrogen phase and not the progestational phas\', whi(•h appears to be consistently fourteen days in length. Biology of the Vagina.-Studies of the biology of the vagina. prominen1 among which are those of Davis and Pearl, 14 have related cornification of the vaginal mucosa, its glycogen content, and its acidity to the action of estrogen. These studies paved the way for an effective estrogen therapy of gonorrheal vaginitis of children, and of atrophic vaginitis of the aged, and supplied the rationale for estrogen therapy prior to and following plastic vaginal operations in postmenopausal women. Cytologic studies of vaginal spreads have been used to gauge levels of ovarian function.' 5 Considerable histologic acumen is required for suitably stained preparations and their interpretation. A recent extension of this method has been its employment in searching for diverse, wandering cancer cells as an implement for the early diagnosis of genital cancer. 16 Biology of the Cervix.-Glandular and stromal ehanges in the endoeervix have been described during the menstrual cycle.H These alterations have been related to the ovarian steroids. The suggestion has been made that these cyclir changes may be mistaken for low grade cervicitis. Estrogen liquefaction of the cervical mucous plug for reception of the spermatozoa, about the time of ovulation, has been established. 18 Steroid Metabolism.--Urinary levels of pregnanediol, a metabolic product of progestin, have been studied. These appear to be more reliable as an index of chorioplacental activity than of corpus luteum activity.' 9 Kenyon's fruitful studies 20 of steroid metabolism have emphasized the metabolic or extragenital effects of androgens, estrogens, and progestin. The nitrogen, sodium, and water storage effects of these steroids play important roles in the physiology of pregnancy. Menstrual edema, doubtlessly, is related to sodium and water storage produced by estrogen and progestin. Studies of urinary 17-ketosteroids, which are end products of adrenocortical steroid metabolism in the female, have revealed significant reciprocities of ovarian and adrenal steroid metabolisms. The suggestion has been offered that the adrenal cortices serve as the ''gonads of the aged,'' in view of the fact that there is an upswing in 17-ketosteroid excr·etion when ovarian function fails. 2 ' IIorrnonal Pigmentntion .-The hyperpign1enta l.ion:-~ of pregnan1·y, induding that of the nipples and areolae, the linea nigra. (•hJoasma, and the ''mask of pregnaney,'' are due to the physiologic hyperestrogenism of gestation. Tht> nongestational pigmentation of the areolae, nipple.-,, and Jahia is also dne to

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estrogens. 'fhese facts are proved conclusively by the pigmentary changes which result from intensive estrogen therapy of young women with delayed sexual maturation. A recent study by Davis and his associates22 has emphasized that elements other than estrogen alone are involved in this pigmentary mechanism. These workers called attention to the fact that estrogens fail to produce pigmentation in women of menopausal age, and they made the suggestion that the functional status of the pituitary may condition the pigmentary response to estrogens. Arvdrogens and Vit·ilizational Syndromes.-A large measure of our knowledge of androgens is due to the fundamental studies by Professor Koch, Professor Moore, and their associates. The physiologic import of woman's androgenic moiety, however, has not been established. It is likely that androgeffti in woman may have important extragenital roles. The consensus is that androgens play no significant part in woman's reproductive physiology; in other words, woman is a woman, not by virtue of her androgens, but despite them. An unfortunate tide of empiric androgen therapy in gynecology-now in its ebbclearly established the relationship of androgens to the virilizational syndromes of woman. The irreversibility of clitoridal hypertrophy and the voice changes !Jrodured by androgen therapy, when the therapy was discontinued, parallel the course of these changes following successful surgical removal of an androgenproducing ovarian tumor. It is our opinion that, at present, none of the i>"''.tpposed indications for androgen therapy of woman warrants woman's exposure to possible virilization. Functional Uterine Hernorrhage.-Functional uterine hemorrhage usually is associated with a disturbed ovariopituitary system, in which growth waves of estrogen secretion are altered, often with estrogen values teetering for long intervals at bleeding levels. Other manifestations of this changed function indude a disturbance of the storage and release of luteinizing g·onadotropin of the pituitary, a failure of ovulation, an absence of progestin from the hormonal mechanism of the cycle and characteristic alterations in estrogen metabolism. 23 The control of depleting hemorrhages in the young woman, in whom the preservation of rhildbearing function demands conservative therapy, has heen, in the past, one of the most difficult and vexing problems of gynecology. The hemo. static action provided by oral e~trogen therapy affords a prompt, inexpensive and conservative method of stopping a functional hemorrhage. Several series of oral cyclic estrogen and progestin therapy, given in a fashion similar to normal ovarian secretion, usually regulate the bleeding cycle and restore norma] steroid metabolism and ovariopituitary re~iprocities. 1 In my opinion, this therapeutic endocrine application has been the most fruitful of all those made in gynecology. Incornplete Sexual Jfaturation With Absence of Bleeding.-~This condition is due usually to an intrinsic incapability of the ovaries to be aroused to full adolescent function by the individual's own pituitary gonadotropins. As a rule, incompletely developed fetal ovaries persist in the adult epoch. The gonadotropic function of the pituitary is normal or commonly elevated. Oral estrogen therapy usually provides dramatic sexual, somatic, and cosmetic responses. The ovaries of these individual..,, however, uniformly remain nn-

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responsive to gonadotr·opie thPnlp~·. l';l/tlvagp of l'Ppl'oChH'JiV(' JurwtioiJ IS impossible. Intercnt-re.nt Estrooenic }'(J;ilnre of the Ovrtries.-~.:Ylost intercurrent amenot·rhea, whieh is not related to eonsti1 utional di;;east\ or to metabolie disturbances. is due to nn intrinsie estrogenic failure of the ovaries, that is, a premature menopause. Hegardless of the flowing:-: whieh may Jollow oral cyclic estrogen therapy, or the mo1·e expPnsive estrogen and progestin injec·tions, the ovarim1 status remains the same. Uonadott•opi(• t ht•rapy usunll~' fails to rt>store normal ovulatory functions. O·mricrn 8terility.--'l'he routine use of the endometrial biopsy technique in the study of sterility has established that 5 to 15 per rent of wives of ehildless couples have ovarian sterility, i.e., bleed from estrogenic endometriums. 1 Approximately one-half of these women may be restored to a fertile ovarian status by gonadotropic therapy. 24 The ability of equiiH• gonadotropin to stimulate the human ovat·y was proved condusively by Davis and Koff.2° For the treatment of sterility due 1:1 anovulator~- ovarian failnre, we have found the cyclic and sequential use or both equine and ehorionie gonadotropins to he neeessar.\-: we have ealled this regime, one-two eydic gonadotropic therapy. 24 Unfortunatel,v, this therapy requires injeetions and, furthermore, it may not he given for prolonged periods since it may provoke sensitivity phenonwna and untihormone responses. Accordingly, its use is best reserved for trials at eoneeption. To:umia of Pn::gtwncy.~-George aiHl Olive Smith 2 '; lmve described chara(•teristic hormonal disturbam'PH in edamptogenie toxemia of pregnancy. These include all (•]evation of serum <·horionic g·onadotropin. a progr·essive progestiu deficiency, a similar emwomitant estroge11 d(>fieieney, and a changed steroid metabolism which is eharaeterized by an inereased destruction of estrogens. These workers have attrilmtcd etiologie siguifieanee to their findings. Employing large doses of estradiol benzoate, prog·esterone, and pregnanediol, the Smiths WN'e able to stahiliz(' the hormonal disturbance of eclamptogeuie toxemia and to improve the elinieal state of their patients. They did not eonsider, however, their therapeutic regime to he yet clinieally praetif'al. Application of the Smiths· :- snggPstion has !wen offt-,rt>tl that the luteinizing gonadotropin of the pituitary may he responsible, not only for the formation of progestin by the corpus luteum, but also for the c01·tical elaboration of androgens, progestin, and their related 17-ketosteroids.

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As grateful as estrogen therapy may prove to be to the dimacteric woman, its use often has been too frequent and too uncritical, and its dosage schedules often have been too large and too haphazardly given. A few comments, accordingly, appear justified. Few climacteric women require estrogens. Estrogen therapy fails to cure basic psychopathies which may simulate climacteric disturbances. Injeetional therapy is no longer necessary; its psychologic approach is unhealthy. Infrequent injections of large amounts of estrogens are an ideal formula for keeping the endocrine system in a state of flux and chaos. \Vhen estrogens are employed, the usual daily dosage, in my opinion, should be no greater than the equivalent of one-half milligram of diethylstilbestrol. Therapy should be given cyclically, with a week of no therapy intervening between series of treatment. These precautions will prevent upsetting of the bleeding cycle and the provocation of postmenopausal flowing. Therapy should be limited in its seope to a few months, and should not be prolonged for years.

Summary A few of the significant endocrine contributions to obstetric and gynecologic thought and practice have been • surveyed. It is not too much to hope that the next fifty years may bring many further endocrine solutions to physiologic, diagnostic, and therapeutic problems of our specialty. It may well be that the ultimate solution of eclamptogenic toxemia and genital carcinoma may be efferted through the medium of an expanding knowledge of the endocrine system.

References L. Hamblen, E. C.: Endocrinology of Woman, Springfield, Ill., 1945, Charles C Thomas. 2.•Johnstone, A. W., quoted by R. T. Frank: AM. J. 0BS1'. & GYNEC. 40: 574, 1940. a. Robinson, quoted by W. S. Playfair: A Treatise on the Science and Practice of Mid· wifery, ed. 6, Philadelphia, 1893, Lea Brothers & Co. 4. Bischoff, T. L. W., quoted by G. W. Bartelmez: AM. J. OBST. & GYNEC. 21: 623, 193]. ;), Novak, E.: Menstruation and Its Disorders, New York, 1924, D. Appleton-Centnry Co. 6. Bartelmez, G. W.: Physiol. Rev. 17: 28, 1937. 7. Markee, J. E., and Berg, B.: Stanford M. Bull. 2: 55, 1944. S. Burch, J. C., and Phelps, D.: J. Clin. Endocrinol. 3: 475, 1943. 9. Bartelmez, G. W.: AM • •T. 0BS'r, & GYNEC. 21: 623, 1931. 10. Corner, G. W.: Physiol. Rev. 3: 457, 1923; idem: J. A. M. A. 89: 1838, 1927. 11. Hartman, C. G.: • Time of Ovulation in Women, Baltimore, 1936, WilliamH and Wilkins Co. 12. Rock, J., and Hertig, A. T.: AM. J. OBST. & GYNEO. 47: 343, 1944. 13. Tompkins, P.: J. A. M. A. 124: 698, 1944. 14. Davis, M. E., and Pearl, S. A.: AM. J. 0BST. & GYNEC. 35: 77, 1938. 15. Papanicolaou, G. N.: Am.•L Anat. 52: 519, 1933. 16, Papanicolaou, G. N., and Traut, H. F.: Diagnosis of Uterine Cancer by Vaginal Smear, New York, 1943, Commonwealth Fund. 17. Wollner, A.: Am. J. Surg. 57: 331, 1942. 18. Guttmacher, A. F., and Shettles, L. B.: Human Fe!'til. 5: 4~ 1940. 19. Hamblen, E. C., Cuyler, W. and Baptist, M.: AM . •T. 0BST. & GYNEC. 44: 442, 1942. 20. Kenyon, A. T.: Bioi. Symposia 9: 11, 1942. 21. Hamblen, E. C., Cuyler, W. and Baptist, M.: J. Clin. Endocrinol. 1: 777, 1941. 22. Davis, M. E., Boynton, M. W ..• Ferguson, .T. H., and Rothman, S.: J. Clin. Endocrinol. 5: 138, 1945. 23. Smith, G. V. S., and Smith, 0. W.: .J. Clin. Endocrinol. 5: 319, 1945. Hamblen, E. C., and Davis, C. D.: A~L J. OBST. & GYN~:c. 50: 137, 1945. Davis, M. E., and Koff, A. K.: AM. J. 0BST. & GYNEC. 36: 183, 1938, 26. Smith, G. V. S., and Smith, 0. W.: J. Clin. Endo~rinol. 1: 470, 1941. 27. White, P.: J. A. M. A. 116: 645, 1941. 28. Reifenstein, E. C., :F'orhPR, A. P., Alhrig-ht, F., and DonRlrl~on, F:.: .T. Clin. Investigation 24: 4Hi, 1945. ·