IT HAS BEEN AGREED by many investigators that alterations in the

Transcription

1 Hypothyroidism in Relation to Reproductive Disorders Irving I. Kurland, M.D., and William Levine, M.D... IT HAS BEEN AGREED by many investigators that alterations in the supply of thyroid hormone influence the function of the gonads. However, others state that the mechanism involved is obscure. The success of thyroid therapy in menstrual abnormalities and infertility problems in actual hypothyroidism led to its empirical use even in cas'es without hypothyroidism. 7 The view that thyroid medication has great value in reproductive disorders has become so prevalent that one would assume that a reasonable basis for this attitude exists. With this thought in mind, Buxton and Hermann ( 1954), surveyed 339 euthyroid patients with complaints of sterility and menstrual disorders. They considered 131 cases for final analysis. These were divided into Group A (75 patients), who received thyroid extract empirically, and Group B (56 patients), who received only placebo tablets. All cases were initially tested by basal metabolic rate, serum cholesterol levels, protein-bound iodine, and radioactive uptake. Follow-up studies were performed in both groups over a period of 6 months. From this survey they concluded that the clinical signs of hyperthyroidism or hypothyroidism was of greater diagnostic value than any of the laboratory tests used, since the range of values were so wide. As to therapy, they failed to find any significant difference in the cure and improvement rate between the two groups. It was their impression that thyroid administration in euthyroid patients has questionable value since exogenous thyroid administered merely replaces and even From the Department of Gynecology and Obstetrics, and the Sterility Clinic, Beth-El Hospital, Brooklyn, N. Y. 132 ~I

2 . Vol. 10, No. 2, 1959 HYPOTHYROIDISM AND REPRODUCTIVE DISORDERS 133 interferes with endogenous thyroid production. They concluded that the term subclinical hypothyroidism is not a permissible expression. Comninos ( 1956) surveyed the thyroid function and treated 208 patients with reproductive disorders, namely, infertility, habitual abortion, and ovarian dysfunction. This projoot was undertaken in order to evaluate the empirical use of thyroid hormone in these three categories. Protein-bound iodine ( 4.0 to 8.0 p.g.) was the only laboratory test used to evaluate thyroid function. For possible increased clinical information all protein-bound iodine levels between 4.0 and 4.5 were considered "low normal" and those from 7.5 to 8.0 as "upper normal." His conclusions were strikingly similat to that of Buxton and Hermann, namely that thyroid-hormone therapy is beneficial and thmefore indicated only when thme is evidence of thyroid hypofunction. In euthyroid patiellits, he agreed that the use of exogenous thyroid was of no apparent advantage. Greenhill reviewing the role of thyroid therapy in sterility states, "We should not prescribe thyroid in the unproved belief that this substance is helpful in sterility even if women do not have hypothyroidism. A decision to use thyroid therapy on infmtile women should be based on the clinical findings of the patient as a whole as well as repeated basal metabolic rate, blood cholesterol and radio active uptake. From all indications thyroid substance should not be used empirically in all cases of infertility." The following report consists of 2 cases of postthyroideotomy hypothyroidism and 1 case of acquired adolescent hypothyroidism of the mild type. A follow-up study of the patients for 12, 10, and 2 years, respectively, afforded us an opportunity to better appreciate the vagaries of the symptoms IUld the difficulties in hormone therapy. The limitations in a short series of cases is balanced, we hope, by the lengthy follow-up studies available. Hypothyroidism presents remissions which depend upon the degree of stabilization reached and sustained by substitution therapy. A more comprehensive picture of the diagnostic pitfalls and the approach to therapy can thus be obtained by a lengthy study of a few cases rather than a short study of many cases. Of equal importance is thyroid therapy in the mild (subclinical) type associated with infertility and menstrual disorders. The purpose of this report is twofold. First to indicate that the use of thyroid hormone in reproductive disorders is not warranted unless they are associated with hypothyroid states, and that thyroid-hormone therapy especially in mild or moderate hypothyroidism should be neither excessive nor

3 134 KURLAND & LEVINE Fertility & Sterility prolonged. Second, to postulate the mode of action of thyroid hormone upon the complicated pituitary gonadal axis. CASE REPORTS Case 1 S. S., aged 31 years, presented herself on September 14, 1944, complaining of amenorrhea of 7 months' duration. The history revealed a thyroidectomy in " 1931, a spontaneous abortion in 1939, and a normal delivery in Menstrual history: 14 X 28 X S-4 day flow. Following the thyroidectomy, the intervals were prolonged to 5 to 6 weeks. She had one period shortly after the delivery (March 5, 1944) and was amenorrheic up to the time of examination. Her weight was 124 pounds and height 63 inches, pulse 58, blood pressure 100/60, basal metabolic rate was minus 26 per cent and blood cholesterol was 435 mg./ 100 mi. Thyroid % to 1 grain daily was instituted along with vitamins and improved diet. Her first period in 15 months occurred on June 19, For the next 16 months, periods occurred with some regularity starting with 8-week intervals and diminishing to 6-week intervals. During these 16 months, repeated endometrial biopsys revealed a follicular pattern. During 1947, the periods occurred at 5- to 6-week intervals, the patient attempted to conceive without success. Basal temperature readings were started in September, They revealed anovulatory type of cycles with prolonged intervals ranging from 40 to 50 days. In an attempt to produce ovulation pregnant mare serum therapy in the form of Gonadogen was instituted along with thyroid <luring the January, 1948 period. An apparent biphasic curve of 39 days resulted. The full potentialities of thyroid alone to accomplish this phenomenon was not realized at this time. A second course of Gonadogen was given during the February, 1948 period. No subsequent menstrual periods occurred and the temperature remained at a uniform high level. The Friedman test was positive on May 3, 1948, and she delivered at term a healthy baby on November 19, The patient returned to the sterility clinic on January 25, She had taken no medication during this 10-week postpartum period. Her weight was 131 pounds, pulse 60, blood pressure ll0/70, basal metabolic rate was minus 17 per cent and blood cholesterol was 425 mg./100 ml. In an attempt to prevent a recurrence of the prolonged postpartum amenorrhea which occurred with her previous delivery, thyroid therapy 1 to 1~ grains daily along with vitamin B complex and a high protein diet was reinstituted. No periods occurred. In April, :2 treatment consisting of estrogen and progesterone was added to the above routine. Repeated courses were given for the next 3 months, however, it failed to produce withdrawal bleeding and was discontinued. After 8 months of thyroid therapy, toxic symptoms occurred associated with a loss of 11 pounds. The patient had not taken a proper diet or vitamin supplements. She was placed on a high caloric diet and vitamins without thyroid. Three months later (January,

4 Vol. 10, No. 2, 1959 HYPOTHYROIDISM AND REPRODUCTIVE DISORDERS ), her nutritional status was improved and thyroid therapy ~ to ~ grain daily was resumed. An electrocardiogram revealed a sinus bradycardia and myocardial changes compatible with a myxedema heart. Thyroid therapy was varied between ~ and 1 grain daily in order to keep her symptom-free without producing any toxic effect. Her first period in 29 months occurred in April, Four more periods occurred in 1951 with intervals ranging from 7 to 11 weeks and all were of the anovulatory type. In 1952, eight periods occurred with intervals ranging from 35 to 60 days. All were of the anovulatory type as revealed by basal temperature readings and endometrial biopsy. On March 10, 1953, a period occurred after a 66-day interval with the preovulatory dip occurring on the thirty-sixth day. An endometrial biopsy taken on the forty-third day of this cycle revealed the endometrium in the secretory phase. The result was a surprise, for we did not expect thyroid hormone alone to accomplish this phenomenon. For the next 15 months, the patient continued to menstruate regularly with intervals ranging from 35 to 50 days. Basal temperature readings revealed a biphasic curve in most cycles with an occasional monophasic curve interspersed. During this period of time, the patient was maintained on ~ to ~ grain of thyroid daily along with vitamin supplements. Her weight was stationary and her electrocardiogram continued to improve. Her last regular period occurred on June 30, The temperature curve remained at a uniform high level. The Friedman test was positive on September 14, 1954, and she delivered at term a healthy baby on April 25, 1955 ( E.D.C. being April 6, 1955). The patient had continued on thyroid medication during her pregnancy. After a short interval postpartum, she again resumed taking * grain of thyroid daily. She returned to the sterility clinic on August 9, 1955, complaining of amenorrhea of ~ months' duration. The patient was now 42 years old, her weight was 12~ pounds, pulse 56, blood pressure 100/60. Resurvey revealed basal metabolic rate plus 11 per cent, blood cholesterol 338 mg./100 ml., protein-bound iodine 4.0 gamma, radioactive iodine 1.51 per cent (this value being consistent with hypothyroidism). To avoid the long interval of amenorrhea which occurred in her previous postpartum periods, thyroid hormone was increased gradually from ~ grain to 1~ grains daily. This was the patient's point of tolerance without producing excessive weight loss or toxic symptoms. Vitamin supplements and phenobarbital ~ grain twice daily was added to the routine, and a well-balanced diet was stressed. Her first period occurred on December 24, 1955, 8 months postpartum. An endometrial biopsy taken on the twenty-fourth day of the January, 1956 period revealed a late prolifera,tive stage with some glands manifesting early secretory activity. Up to the present time, the cycles have ranged from 30 to 41 days, all showing a biphasic curve but with a shortened luteal phase. The patient is being maintained on * grain thyroid daily along with vitamin B complex.

5 136 KURLAND & LEVINE fertility & Sterility Case2 E. P., aged 28, para , presented herself in March, 1946, complaining of increasing dysmenonhea of several months' duration. Menstrual history: 12 X 28 X S--4 day flow. The history revealed a thyroidectomy in Her weight was 107 pounds and height 6mf inches, pulse 66, blood pressure 130/90, basal metabolic rate was minus 15 per cent and blood cholesterol was 310 mg./100 mi. Thyroid ~f grain daily was instituted along with vitamins and improved diet. Her last regular period occuned on May 21, On August 6, 1946, vaginal staining began and continued for 3 weeks; thyroid hormone was increased to 1 grain daily along with bed rest and progesterone therapy. Repeated Aschheim-Zondek tests were positive. The remainder of the pregnancy was uneventful and she delivered at term a healthy baby on February 24, Medical history from 1947 to the present revealed at,tacks of gastrointestinal upsets and two attacks of renal colic. A gastrointestinal series revealed visceroptosis and a spastic colon (September, 1948). Two intravenous pyelograms were reported as negative. It is interesting to note in retrospect that these attacks occuned when the patient had been lax in maintaining thyroid medication. Obstetric history from 1947 revealed a dilatation and curettage for an incomplete abortion (November, 1949), a normal delivery (April, 1952), and a second dilatation and curettage for an incomplete abortion (January, 1955). Both incomplete abortions proven by pathologic reports. On September 29, 1955, the patient returned after a lapse of 7 months, during which no thyroid was taken. The last menstrual period was August Vaginal staining began on September 28 and continued for 10 days, in spite of thyroid medication along with bed rest and progesterone therapy. The patient was hospitalized on October 8 and discharged on October 12, since the Aschheim-Zondek test was positive and staining had ceased. She was readmitted on October 20, 1955, for a dilatation and curettage because of recurrent vaginal bleeding. Pathologic report was proliferative endometrium with hyperplasia. On October 24, thyroid therapy!14 to 1 grain daily was instituted and gradually increased to Hf grains daily. Basal metabolic rate was minus 18 per cent. Proteinbound iodine was 4.8 gamma, blood cholesterol 290 mg./100 mi. A period occurred on November 9-14 and was the first normal flow in months. Basal temperature readings were begun and revealed a biphasic curve which continued for several months. An endometrial biopsy taken on the twenty-fourth day of the November, 1955 cycle revealed a secretory endometrium. The patient is being maintained on 1 grain thyroid daily along with vitamin supplements and a wellbalanced diet. Case3 A. L., aged 21, para , presented herself in July, 1954, complaining of prolonged cycles of 1 year's duration and sterility of 2 years' duration. Menstrual

6 Vol. 10, No. 2, 1959 HYPOTHYROIDISM AND REPRODUCTIVE DISORDERS 137 history: 13 X 3~6 X 5 days. In the past year the patient had an increased weight gain of over 10 pounds and most of her cycles were prolonged to 50 days. Her weight was 128 pounds and height 63~ inches, pulse 60, blood pressure 115/70, basal metabolic rate was minus 10 per cent, blood cholesterol 297 mg./ 100 mi. Protein-bound iodine 4.8 gamma. Basal temperature readings revealed prolonged cycles with short luteal phases ( 8-11 days) with interspersed anovulatory cycles. Repeated endometrial biopsies revealed either proliferative endometrium or luteal phases with poor secretory activity. In August, 1954, thyroid hormone ~ to 1 grain daily was instituted, along with vitamins and a high protein diet. The patient lost 8 pounds over a period of 4 months. The basal temperature readings showed a progressive improvement in the cycles ranging at first from 38 to 42 days, and then from 32 to 35 days with nonnal luteal phases in all. Her last regular period occurred on July 30, The temperature curve remained at a uniform high level. The Friedman test was positive on September 16, 1955, and she delivered at term a healthy baby on May 8, The patient continued on thyroid medication during her pregnancy. After a short interval postpartum she was again maintained on thyroid~ grain daily. Her first period occurred 8 weeks postpartum, and up to the present time the cycles have ranged from 30 to 33 days, all showing normal biphasic curves. Case 1 DISCUSSION It has been demonstrated by Buxton and others that a dose of mg. of thyroid ( ~ to H grain) per day will stabilize a case of complete operative myxedema, and that 120 to 200 mg. ( 2 to 3.3 grain) per day will entirely suppress endogenous thyroid production. Heinbecker has shown that very small doses of thyroid extract given in strength below the physiologic limits has a stimulating effect, while large doses act as a depressant on the pituitary. Thus lru:-ge doses of thyroid extract may suppress the gonadotrophic activity of the pituitary, inhibit estrogen formation, and diminish the extent and quantity of the menstrual flow. This is seen in Case 1, where small doses of thyroid improved the patient's condition, whereas H~ grains per day produced toxic symptoms in a short period of time. If this is so with a case of proved myxedema, are we not overdosing milder cases of hypothyroidism in an empirical attempt to correct reproductive disorders? Repeated re-evaluation of the patient's nutritional status and reaction to thyroid hormone should be emphasized. Improvement in reproductive disorders may thereby be accomplished in a shorter period of time before depressive reactions occur.

7 138 KURLAND & LEVINE Fertility & Sterility Case2 In the management of sterility and menstrual irregularities the gynecologist should widen his horizons in order to better understand the vagaries of symptomatology of hypothyroidism. Abdominal pains in hypothyroidism may mimic peptic ulcer, gallbladder disease, appendicitis, or renal lithiasis, respectively. These hypothyroid patients complained of indefinite abdominal distress for which no organic basis could be found This is illustrated in this case where no organic cause was found to explain her attacks of abdominal pain and which required hospitalization on two occasions. The report of a positive Aschheim-Zondek test in a hypothyroid patient who complained of amenorrhea followed by vaginal staining masked the true picture of hyperplasia of the endometrium. The clinical impression of inevitable abortion, renal colic, and peptic ulcer made in the same patient over a 10-year period of time, demonstrates the role of hypothyroidism as a great masquerader. Case3 This case illustrates oligomenorrhea and sterility in adolescent hypothyroidism. This acquired hypothyroidism may follow relative insufficiency of iodine intake during the stress period of puberty and early adolescence. Relief of the stmin of physiologic adaptation as they grow older results in a return to an efficient endocrine balance and spontaneous resolution. However, continued strain of physiologic adaptation results in an inefficient endocrine balance, and acquired adolescent hypothyroidism occurs. The degree of hypothyroidism depends upon the degree of imbalance. The prognosis with treatment in this type is good and the efficiency of adequate hormone substitution therapy remarkable (Levitt). This is fully demonstrated in this case where a short course of thyroid hormone therapy was sufficient to correct the oligomenorrhea, and produce a normal secretory endometrium. The latter was reflected in an improved basal temperature curve which guided the patient as to optimum time for conception. COMMENT As previously stated, many authorities agree that alterations in the supply of thyroid hormone influences the function of the gonads. Yet many state that the mechanism involved is obscure. However, from the evidence available of the action of the various target glands upon each other as well as

8 Vol. 10, No. 2, 1959 HYPOTHYROIDISM AND REPRODUCTIVE DISORDERS 139 upon the trophic hormone of the pituitary, we may postulate the mode of action of thyroid on the pituitary gonadal axis. The generally accepted view of the balanced unit concept between each trophic hormone and its target organ is as follows: Each of the trophic hormones of the pituitary stimulates a dependent gland to secrete its hormone. The latter, in turn, has an inhibitory influence on the secretion of the respective trophic hormone, it "puts the brake" on the pituitary. Consequently, each pair, i.e., gonadotrophic hormone,and gonadal hormones, thyrotrophic hormone and thyroid hormone, adrenocorticotrophic hormone and adrenocortical hormones, represents, under physiologic conditions, a balanced unit. Release of gonadal hormone depends upon the level of circulating estrogen, release of thyrotrophic hormone depends upon the level of circulating thyroxin, and release of ACTH depends upon the level of corticoid hormone. An increased level depresses and a decreased level stimulates trophic production by the pituitary. Removal of the secondary hormone-producing gland (gonadectomy, thyroidectomy, adrenalectomy) releases the respective pituitary trophic hormone secretion, and by "removing the brake" leads to excessive secretion of gonadotrophic, thyrotrophic, and adrenocorticotrophic hormone, respectively 4 (Fig. 1 ). The following evidence demonstrates that a more complex endocrine mechanism exists between the trophins of the pituitary and the target glands: If excessive amounts of one of the secondary hormones from the particular gland is administered experimentally over a long period of time it will suppress not only the specific trophic hormone but the other pituitary hormones as well. For example, administration of large amounts of estrogen to young animals (rat, fowl) leads not only to atrophy of the gonads, but also to thyroid atrophy by suppressing the thyrotrophic hormone, and to dwarfing by suppressing the growth hormone. 4 Elevated ACTH levels and diminished urinary 17-ketosteroids (0.5 to 3.0 mg. ) have been observed in myxedema where it is known that the thyrotrophic tide is elevated and the thyroxin level is diminished. Thus a decrease level of thyroxin in myxedema seems to be accompanied by a decreased level of andosterone steroid, thus stimulating not only thyrotrophin production but also ACTH production by the pituitary. 4 In experiments on young mature guinea pigs, Kippen and Loeb, found, in addition to the specific reciprocal relations between the amount of circulating hormone and the intensity of production of its specific trophic hor-

9 140 KURLAND & LEVINE Fertility & Sterility T. TH. Thyroid I I I I ~ Ovary Adrenal Fig. I. The balanced unit concept between each trophic hormone of the pituitary and its target organ. The solid lines illustrate the stimulation from the pituitary trophins. The dotted lines illustrate the inhibitory action of the target organ on its individual trophin. T. TH. Thyrotrophic; F.S.H. Gonadotrophic; ACTH Adrenocorticotrophic Hormones. mone, a nonspecific relationship also exists. The lack of follicular hormone evidently induces in the pituitary gkmd an increased production of the thyrotrophic hormone, although it can be shown that the thyrotrophic and the follicular maturation-producing hormones of the anterior pituitary are distinct and usually not present under the same conditions. Animal experimentation points to the interrelationship between the gonadal and adrenal cortical hormones. A number of investigators2 15 have shown that injections of estrogen to rats, whether castrated or not, causes enlargement of the a<kenals. This effect on the adrenals depended upon the presence of the pituitary. Other investigators 2 18 believe that enlargement of the adrenals in female rats treated with estrogens is an indirect action mediated by the pituitary. Further work has shown that adrenalectomy is followed by a reduction of the gonadotrophic potency of the rat's pituitary,. and that pituitary implants will induce premature sexual maturity even in the absence of the adrenals.

10 Vol. 10, No. 2, 1959 HYPOTHYROIDISM AND REPRODUCTIVE DISORDERS 141 Thyroid Ovary Adrenal Fig. 2. Demonstrates the interrelationship of the target glands and the inhibitory action not only on its own trophin but also on the other trophins of the pituitary gland. This interplay illustrates the manner in which the hormone of a second gland may act as a substitute inhibitor where the action of the first gland is impaired. With the approach of the menopause, increasing amounts of gonadotrophins are produced in an effort to maintain the function of the failing ov'aries. There is reason to believe from the above animal experimentation that there is an associated overproduction of other pituitary factors, particularly the thyrotrophic and ACTH tides4 (Fig. 2). The evidence presented indicates the complex interrelationship of the gonads, thyroid, and adrenals mediated through the pituitary. It is also commonly observed that irregular gonadotrophin (follicle-stimulating hormone) excretion is as:sociated with infertility and various menstrual disorders.4 As a result of this irregular secretion of FSH normal active estrogen is not produced. Its effective inhibitory action on further FSH production is thereby impaired. Thyroid therapy when indicated may act as a substitute brake action on this excessive FSH production, thereby restoring the normal FSH, LH balance.

11 142 KURLAND & LEVINE Fertility & Sterility Schematically this becomes: Excessive FSH + LH (in small amounts) = abnormal estrogen production, which gives rise to irregular menstrual disorders. Thyroid hormone acts as a substitute inhibitor on excessive FSH production to restore the normal sequence which is as follows: Normal FSH + LH (in small amounts) = active estrogen. Active estrogen acts as a brake on further FSH production resulting in FSH + LH (the ratio changes in favor of the latter) = ovulation and corpus luteum formation. Corpus luteum stimulated by the luteotropic hormone = progesterone. Progesterone acts as a brake on further LH production. 9 Menstruation is the final and visible result of a chain of occult events involving several organs in a definite sequence of stimulation and response in which ovulation is considered to be the acme of perfection. A defective link in this chain will break the sequence. Thyroid therapy in hypothyroidism corrects the defective link. SUMMARY 1. Two cases of surgical and 1 case of adolescent hypothyroidism in association with reproductive disorders have been presented. 2. It has been demonstrated that small doses of thyroid had a stimulating effect while large doses had a depressing effect upon the pituitary gonadal axis. 3. The clinician should be aware of the vagaries of symptomatology of hypothyroidism, since mild cases cannot be detected solely by any single or multiple laboratory tests. 4. The mode of action of thyroid hormone upon the complicated pituitary gonadal axis is suggested. REFERENCES 1265 President Street.,.- Brooklyn 18, N. Y. 1. ALLEN, E., DANFORTH, C. H., and DmsY, E. Sex and Internal Secretion (ed. 2). Baltimore, Md., Williams & Wilkins, BuRRows, H. Biological Action of Sex Hormones (ed. 2). Cambridge, England, Cambridge Univ. Press, BuxTON, C. L., and HERMANN, W. L. Effect of thyroid therapy on menstrual disorder and sterility. ].A.M.A.155:1035, CAN'I'ARow, A., and TRUMPER, M. Clinical Biochemistry (ed. 5). Philadelphia, Saunders, 1955.

12 Vol. 10, No. 2, 1959 HYPOTHYROIDISM AND REPRODUCTIVE DISORDERS Cau, J.P., and You, S. S. The role of thyroid gland and oestrogen in the regulation of gonadotrophic activity of the anterior pituitary. ]. Endocrinol. 4:115, CoMNINos, A. C. Thyroid function and therapy in reproductive disturbances. ]. Obst. & Gynec. 7:260, GREENE, R., and RuNDLE, F. F. Practice of Endocrinology. London, England, Lippincott, GREENHILL, J.P. Yr. Bk. Obst. & Gynec CREEP, P. 0., VAN DYKE, H. B., and Caow, B. F. Gonadotrophin of the swine pituitary. Endocrinology 30:635, GROLLMAN, A. Essentials of Endocrinology (ed. 2). Philadelphia, Lippincott, HEINBECKER, P. Pathogenesis of hypothyroidism. Ann. Surg. 130:804, HoFFMAN, J. Female Endocrinology. Philadelphia, Saunders, KIPPEN, A. A., and LoEB, L. Effect of gonadectomy on the thyroid gland of the guinea pig. Endocrinology 20:201, KURZROK, R. The Endocrines in Obstetrics and Gynecology. Baltimore, Md., Williams & Wilkins, KoRENCHEVSKY, J., DENNISON, M., and SIMPSON, S. Prolonged treatment of female and male rats with androsterone and its derivatives alone, or together with osterone. Biochem. ]. 29:2534, LEVITT, T. The Thyroid. Edinburgh, Scotland, Livingstone, MEIGS, J. V., and STURGIS, S. H. Progress in Gynecology. New York, Grone, 1950, vol PARKES, A. S. The adrenal-gonad relationships. Physiol. Rev. 25:203, Society for the Study of Fertility Annual Conference, 1959 The Society for the Study of Fertility will hold its Annual Conference on Thursday, Friday, and Saturday, May 28, 29, and 30, 1959, in Dublin, Ireland, at The Department of Anatomy, Dublin University, Trinity College, at The Rotunda Hospital, and at The Veterinary College of Ireland, Ballsbridge. ' The Honorary Secretary is A. S. Parkes, C.B.E., F.R.S., National Institute for Medical Research, Mill Hill, London, N.W. 7, The Local Secretary is Raymond G. Gross, M.D., F.R.C.P., M.A.O., M.R.C.O.G., Rotunda Hospital, Dublin.