Cortisone in the Treatment of Infertility

Cortisone in the Treatment of Infertility Robert B. Greenblatt, M.D., William E. Barfield, M.D., and C. P. Lampros, M.D.

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INDUCTION of ovulation in infertile women with menstrual disorders has been one of the difficult problems encountered by the gynecologist. Women with primary, secondary, or functional amenorrhea, menorrhagia, polymenorrhea, and menstrual disorders associated with inadequately prepared endometriums (imperfect progestinal endometriums) have been treated in many and diverse ways in the hope of initiating, restoring, or improving cyclic ovulatory menses. The promise offered by the use of cyclic doses of gonadotropins such as pregnant mare's serum and chorionic gonadotropin has never been fulfilled. Cyclic estrogen and/or progesterone therapy has yielded good results in some instances. Wedge resection for polycystic ovaries has proved of considerable value and radiation therapy to the pituitary, ovaries, or both has its share of proponents. In 1953, another tool was offered for the solution of certain aspects of the problem. Jones et aU reported on the treatment of follicular-phase defects with cortisone, and Greenblatf2 reported on the use of this steroid in the management of hirsute amenorrheic women. The purpose of this paper is to extend our previous observations and to report the incidence of conceptions that occurred in our series of patients.

From the Department of Endocrinology, Medical College of Georgia, Augusta, Ga. Read before the Alabama Association of Obstetricians and Gynecologists, Montgomery, Alabama, April 20, 1955. This study was aided by grants from Merck and Company, Rahway, N. J., and The Upjohn Company, Kalamazoo, Mich. Grateful acknowledgment is made to Dr. Elmer Alpert of Merck and to Drs. H. F. Hailman and C. J. O'Donovan of Upjohn for generous supplies of cortisone acetate and hydrocortisone. Our thanks are due Dr. Edward Henderson of Schering Corporation, Bloomfield, N. J., who supplied the cortisone pellets. 203

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CONCEPT OF CORTISONE THERAPY IN GYNECIC DISORDERS In 1951 we began a study of the effect of cortisone therapy on hirsutism in amenorrheic women. While hirsutism was only slightly modified, it was noted that this mode of treatment had an unmistakably favorable influence on cyclic ovarian function. Meanwhile, Wilkins and his associates,3, 4, 5 in reporting their results in the treatment of congenital adrenal hyperplaSia with cortisone, noted that several of their female pseudohermaphrodites developed breasts, had ovulatory menses, and showed a decrease in urinary 17-ketosteroid excretion. Jones et aU extended this work to include the effect of cortisone in women with follicular-phase defects and observed that ovulatory menses and conception resulted in several of the patients so treated. In our own original series we included patients who belonged in the category of either mild adrenogenitalism or Stein-Leventhal syndrome, or possibly in both categories. The effectiveness of cortisone in certain types of amenorrhea has been confirrned. 6 ,7 SELECTION OF PATIENTS Thirty-seven patients with amenorrhea or other menstrual disorders comprise this study. Many of these patients were considered as mild cases of adrenogenitalism because of moderately raised urinary 17-ketosteroid excretion and mild-to-severe hirsutism. Others were thought to be typical of the Stein-Leventhal syndrome, having demonstrably enlarged ovaries by x-ray visualization or palpation. Thirty-two of the patients were married, and 28 of these complained of sterility or relative infertility. The ages of the patients in this general group ranged from 17 to 39 years. Two patients in this particular series had no hirsutism. METHOD OF THERAPY The cortisone dosage was adjusted to the level considered best for the individual case and ranged from 25 mg. to 100 mg. of cortisone acetate daily taken orally, with the majority of patients being placed on a dosage .,9f 50 mg. da~ (Figs. 1 and 2). Later in the study 20 mg. of hydrocortisone two or three times daily was employed in some cases. 11) a few patients the c.?urse of therapy was begun by an intramuscular injection of 100 m~ corti: J011e.l!£.etate or hydrocortisone acetate, and in several patients 6 to 10 pellets of 100 mg. each of cortisone were implanted (Fig. 3). Thyroid extract,

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~~

grain per day, was routinely administered to counterbalance any hypothyroidism that might be produced by cortisone. Potassium chloride, 5 W.f 17 (M.B.)

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Fig. 1. Record of a young unmarried female, aged 17 years, with increased urinary 17-keto steroids and low ll-oxycorticoid values. She had never menstruated and was quite hirsute. Urinary gonadotrophins were within normal limits. Five months after starting cortisone an ovulatory menstrual period occurred and cyclic menses have continued even after cessation of therapy. The hirsutism has been considerably modified and the 17-ketosteroids remain within normal limits. W f, 24(E.K.J

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DEC.

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Fig. 2. Record of a married white female, aged 24 years, who complained of irregular menses, infertility, hirsutism, and obesity. Her 17-ketosteroids were only slightly raised above the limits of normal and her 17-hydroxycorticoids were normal. Her basal temperature chart revealed that her menses were anovulatory. On cortisone therapy the patient began to ovulate and conception occurred. She carried uneventfully to term.

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grains 3 times daily, was added to compensate for excessive urinary excretion of this electrolyte. Patients were advised to remain on a high-protein, low-carbohydrate, low-fat, low-salt diet. The patients were checked periodically. Frequent urinary assays for W. F., 21 IE.B.l

65 10 Pellets Implanted (IOOmoms. cortisone)

10 Pellets Implanted (IOOmoms. cortisone)

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B

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Apr. May JuneJuly Aug. Sept. Oct. Nov. Oec. Jan .. Feb. Mar. Apr. May JuneJuly Aug. Sept.Oci. NOY. Oec. Jan.

1953

1954

A' 100mg. cortisone acetate I.M. doily x 14 days. B. Inadequate therapy, poor cooperation.

1955

C = Pellets implanted, erratic orol medication. 0 = 40 - 60mo. hydrocortisone per day.

Fig. 3. Record of an unmarried white female, 21 years of age, with full-blown adrenogenital syndrome. The symptomatology included hirsutism, an enlarged clitoris, amenorrhea, and voice changes. The very high urinary 17-ketosteroids were rapidly reduced by cortisone given intramuscularly. When medication was taken at very irregular intervals the 17-ketosteroid values returned to the pretreatment levels. Pellets of 100 mg. each of cortisone were implanted because of lack of cooperation on the part of the patient in taking oral medication regularly, and the 17-ketosteroid levels again fell. On a dosage of 40-60 mg. of hydrocortisone the 17-ketosteroid levels remain within normal limits. Ovulatory menses have set in and some breast development has taken place.

17-ketosteroids and 17-hydroxycorticoids* were performed and in many urinary gonadotropins were also done before and after therapy. Each patient was instructed to keep basal temperature records. A trial course of !!J.erapy varied from 3 to 6 months. If clinical improvement did not occur * Earlier in this study ll-oxycorticoid determinations were used.

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in that period of time, wedge resection of the ovaries or other forms of management were advised (Fig. 4). W. F. 34 tM. B.>

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Fig. 4. Record of an unmarried white female, aged 34, with secondary amenorrhea of 3 years' duration. Marked hirsutism necessitated daily shaving of the heavy beard. The urinary FSH assays were within normal limits. The 17-ketosteroids were elevated to 34.6 mg. per 24 hours, and the ll-oxycorticoids were low, 0.38 mg. per 24 hours. A 6-month course of cortisone therapy failed to induce menses. Following ovarian resection, however, ovulatory menses set in.

RESULTS Table 1 records the number of patients studied and the results obtained. Ten women became pregnant during cortisone therapy or afterward, while 3 more conceived after cortisone was discontinued and wedge resection p~rmed (Table 2). Of the women who became pregnant during c~ TABLE 1.

Effect of Cortisone Therapy on Menstrual Function and Incidence of Conceptions

No. patients

Unsatisfactory results

Increased ovulatory menses

No. patients who became pregnant during or after cortisone

37

12

25

10

No. patients who became pregnant after wedge resection following cortisone failure

Total no. pregnancies

3

15a

a Includes 4 abortions; 2 of the women who aborted had another successful pregnancy (see Table 2, Cases 2 and 10).

TABLE 2.

Summary of Thirteen Patients Who Became Pregnant

17-Keto- 17-Hydroxy- ll-Oxysteroids corticoids steroids before before before cortisone cortisone cortisone

Age

Prior menstrual history

Hirsutism

1 (TE) 2 (GG) 3 (BRW)

26 26 23

q 6-24 mo. 2 0 amenorrhea q 5-12 wk.

Mild Mild Marked

14.5a 9.6 22.6

4 (CA) 5 (EK) 6 (ML)

25 24 21

q6mo. q 1-5 mo. q 8-10 mo.

Moderate Moderate None

17.5 15.2 22.7

26 23 27 33

q3mo. q6mo. q 4-6 wk. 1 yr. previous menorrhagia

Moderate Moderate Marked Moderate

11 (BA)

22

q6mo.

12 (DS)

27

13 (YC)

21

Patient

7 8 9 10

a b

c

(MJW) (CP) (DD) (MP)

0.035

Living baby Aborted 3 mos. Not married at this stage Living baby Living baby [Not married]

15.9 12.7 26 19.1

0.08 0.37 0.21 0.71

Aborted 6 mos.

Moderate

9.5

0.26

q 6-12 mo.

Moderate

14.2

2.3

1-3 mo.

Mild

8.2

1.7

Normal 17-ketosteroids, 7-13. Normal 17-hydroxycorticoids, 2-9. Normal ll-oxysteroids, 0.2-0.8.

0.70"

Conception during cortisone

3.0 b

0.08 3.7 6.5

Conception after cortisone

Wedge resection after cortisone

Living baby Living baby

[Married] Living baby Living baby Living baby Living baby Living baby

Hesection prior to cortisone, inadequate results. Aborted at 3mo. Aborted at 4mo. Living baby

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therapy or after its discontinuation, 1 had wedge resection before the start of cortisone therapy. Her response to wedge resection was poor, but her response to cortisone was excellent and she conceived during the fifth month of cortisone therapy. She carried the pregnancy for 6 months, when spontaneous abortion occurred. Thirteen months later, after discontinuation of cortisone, she conceived again and carried to term. At the time of this writing she is 7 months postpartum, and menses are regular and ovulatory. It will be noted that 5 conceptions occurred during cortisone therapy; 2 of these ended in abortion. Nine conceptions occurred after cortisone therapy had been discontinued for 3-13 months; there were no abortions in this group. Of the 3 conceptions that occurred after cortisone was discontinued and wedge resection performed, 2 aborted and 1 carried to term. One nonhirsute amenorrheic woman in whom cyclic ovulatory menses were induced by cortisone conceived and carried to term. At 8 months postpartum she has a regular 35-day cycle.

DISCUSSION Cortisone is capable of improving cyclic ovarian function in many instances in females with menstrual abnormalities. In some of these patients the improvement in ovulatory menstruation continues after cessation of therapy.

Mechanism of Cortisone Activity Cortisone may produce its effect by depressing adrenocorticotropin (ACTH) production, allowing increased pituitary-gonadotropin production, or it may, in some unknown manner, modify pituitary activity as to permit a more orderly release of pituitary gonadotropins. The concept that this is brought about by a release of pituitary gonadotropins finds support in the work of Sohval and Soffer8 who found elevated urinary-gonadotropin titers following the administration of ACTH or cortisone. Wilkins 9 noted that in female pseudohermaphrodites the proper dosage of cortisone allowed somatic growth and development to proceed normally, indicating that some type of imbalance between the adrenal steroids and growth hormones had been corrected.

Source of Increased Androgen Production Many of the patients with gynecic disorders have an elevated urinary 17-

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ketosteroid level. In the patients with adrenal hyperplasia this is probably due to the increased androgenic steroid output which in many instances is associated with a hyperplastic zona reticularis. In patients with sclerocystic disease of the ovaries the increased androgen levels may be due to thecal hyperplasia of the ovaries. 10 • 11 However, there are some women who, on exploratory laparotomy, have neither adrenal hyperplasia nor sclerocystic ovariesY What is the likely source of the increased androgen values in these patients? It may possibly be explained on the basis of relative hyperplasia of the zona reticularis of the adrenal. What is the reason for this relative hyperplasia? Pregnanetriol is regularly found in the urine of patients with congenital adrenal hyperplasia. 13 This is suppressed by cortisone, but rapidly rellPpears when ACTH or 17-hydroxyprogesterone is administered. The pregnanetriol probably represents a metabolite of 17-hydroxyprogesterone, reflecting a defect in the synthesis of Compound F in t~is disease. To compensate for the relative deficiency of Compound F, ACTH is increased. This causes adrenal hyperplasia. The relative impairment in the synthesis of gluconeogenic hormones is not wholly corrected and their precursors are diverted toward the excessive production of androgenic and estrogenic substances.14 This is given support by the work of Jones and Jones, 15 who examined the adrenals of 15 patients with adrenal hyperplasia. The glomerulosa and fasciculata were either absent or devoid of lipoid, and the reticularis was hyperplastic and contained large amounts of lipoid. The ovaries of these patients showed a gradual failure of normal follicular growth without evidence of ovulation being present. The administered cortisone apparently substitutes for the defective or absent fasciculata and aids in suppressing ACTH production. This, in all probability, allows escape of pituitary gonadotropin, resulting in ovarian stimulation, estrogen production, and ultimate ovulation. Relation of 17-Ketosteroid level to Successful Therapy

I.!L!he p.atients under study a frequent finding was increased urinary 17:.ketQSteroids and d~d ~=~~J:.~_ or 1.2:hx~r~ycorticoRk It would appear that some disturbance in the pituitary-adrenal axis was present which cortisone helps to moderate. However, some patients had normal urinary 17-ketosteroids with normal or somewhat depressed urinary corticoids. In these instances cortisone frequently proved effective without having too much of a depressing effect on 17-ketosteroid production. It

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would seem that cortisone and the related glucogenic steroids are of value in both types of patient under discussion by, somehow, modifying the pituitary-adrenal-ovarian axis. 16 • 17. 18

SUMMARY 1. The use of cortisone in treatment of infertile women with poor or absent ovulatory function is discussed. 2. !.nfertile women with amenorrhea, anovulatory menses, or other menstrual disorders, especially when these are complicated by varying degre~ ~ hirsutism, should have the benefit of a S-6-month trial course of cortisone therapy before being subjected to wedge resection of the ovaries or radiation therapy. S. In a series of@cases, 25 women showed varying degrees of improvement in their ovulatory cycles. Ten women conceived while on cortis_one therapy or after therapy was dis~ntinued:. ive women had ovarian resection because of failure to respond satisfactorily to cortisone therapy, a 3 of these conceived. There was a total of 15 pregnancies, 4 of which ended in abortion. ~ 'J..:f Sb 4. An increased level of urinary 17-ketosteroids is a good but not necessary indication for cortisone therapy. Of the IS women who became pr,§gnant, § had increased 17-ketosteroid levels, 4 had a borderline increase, and 4 had values within our normal limits of 7-1S mg. per 24 hours. The ll-oxyor 17-hydroxycorticoid values were, as a rule, low normals. Hirsutism is not a necessary prerequisite for cortisone therapy in patients with ovulatory disorders. REFERENCES 1. 2. 3.

JONES, G.

5. 6. 7. 8. 9. 10. 11.

S., HOWARD, J.

E., and

LANGFORD, H.

Fertil. & Steril. 4:49, 1953.

F., JR., ROSENE., and MIGEON, C. J. /. Glin. Endocrinol. 11 :1,1951. WILKINS, L., GARDNER, L. I., CRIGLER, J. F., JR., SILVERMAN, S. H., and MIGEON, C. J. J. Glin. Endocrinol. 12:257, 1952. WILKINS, L., CRIGLER, J. F., JR., SILVERMAN, S. H., GARDNER, L. I., and MIGEON, C. J. J. Glin. Endocrinol. 12:277, 1952. JONES, G. E. S., and HOWARD, J. E. N. Y. State /. Med. 53:2463, 1953. BARNES, A. C. Obst. & Gynec. 3:322,1953. SOHVAL, A. R., and SOFFER, L. V. J. Glin. Endocrinol. 11 :677, 1951. WILKINS, L. /. Pediat. 41 :860, 1952. GREENBLATT, R. B. Postgrad. Med. 9:492, 1951. CULINER, A. J., and SHIPPEL, S. J. Obst. & Gynaec. Brit. Emp. 56:439, 1949.

BERG,

4.

E.

GREENBLATT, R. B. Am. /. Obst. & Gynec. 66:700, 1953. WILKINS, L., LEWIS, R. A., KLEIN, R., GARDNER, L. I., CRIGLER, J.

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12. BESSELL, H. W., and WILLIAMS, R. H. Ann. Int. Med. 22:773,1945. 13. BONGIOVANNI, A. M., CHERLEIN, W. R., and CARA, J. f. CZin. Endocrinol. & Metab. 14:409, 1954. 14. WILKINS, L., BONGIOVANNI, A. M., CLAYTON, C. W., CRUMBACH, M. M., and VAN WYK, J. The Human Adrenal Cortex. Ciba Foundation Colloquia on Endocrinology, Vol. 8, Boston, Mass., Little, 1955. 15. JONES, H. W., JR., and JONES, C. E. S. Am. f. Obst. & Gynec. 68: 1330, 1954. 16. STEIN, 1. F. Fertil. & Steril. 6:189, 1955. 17. FORSHAM, P. H., THORN, C. W., PRUNTY, F. T., and HILLS, A. C. f. Clin. En¢ocrinol. 8:15, 1948. 18. DAVIS, M. E., TEST, C. E., NAVORI, C. A., HRYSE, B., POTTINGER, R. E., and DUNKLE, F. f. CUn. Endocrinol. 12:697, 1952.