- Email: [email protected]
Endocrinopathies and Infertility
Endocrinopathies and Infertility III. Virilizing Adrenal Tumor (Adrenogenital Syndrome) ROBERT B. GREENBLATT, M.D., and ROSLYN SELIGMAN, M.D.
TRUE
VIRILIZATION of the adult female is frequently caused by an adrenocortical tumor and, in most instances, infertility is a concomitant. The purpose of this paper (third in a series ) 5 • 6 is to present the case of a patient with regular cyclic menstruation who complained of hirsutism, voice changes, and infertilitv, and in whom the removal of an adrenocortical adenoma resulted in res~lution of the infertility problem but did not bring about regression of the hirsute state.
CASE REPORT Mrs. B.F., a 24-year-old female was first seen in October 1959 with the complaints of acne, hirsutism, and infertility. The acne had been present for 8 years, while the hirsutism had become progressively worse over the last 4 years. Hairiness first appeared on the chin and then spread gradually to involve the breasts, thighs, and abdomen. There was no familial history of hirsutism. Deepening of the voice was first noted at about 20 years of age, and on her admission the voice was hoarse and of very low pitch. Her menstrual periods had begun at age 13 and had occurred regularly about every 29 days, with a duration of 3-4 days. Dysmenorrhea had always been present, but about 2 years prior to her first visit she ceased to experience dysmenorrhea as well as premenstrual molimina. There had been a gradual diminution of her libido. She had been married a little more than 2 years, and though conception was very much desired, it had not been accomplished. The patient was of masculine body build, with a male escutcheon. The hypertrichosis involved the face, chest, breasts, abdomen, and extremities. Her complexion was oily and acneform lesions were present (Fig. 1). The breasts were moderately well developed and apparently had not decreased in size. Slight enlargement of the clitoris was noted. On pelvic examination, no ovarian masses were palpable. · The hemoglobin, hematocrit, white blood cell count, differential count, urinalysis, From the Department of Endocrinology, Medical College of Georgia, Augusta, Ga.
208
VoL. 14, No. 2, 1963
ENDOCRINOPATHIES AND INFERTILITY
209
BUN, and serum electrolytes were within normal range. Serology was negative. The protein-bound iodine was 5.1 ~tg.%. Endometrial biopsy obtained on the first day of menses revealed an endometrium consistent with cyclic ovulatory menstruation (Fig. 2). The control urinary hormone assays revealed markedly elevated
Fig. 1. Twenty-four-old female (case report) with hirsutism, voice changes, and slight enlargement of the clitoris, who experienced normal cyclic ovulatory menses. Her urinary 17ketosteroids were 60 mg. per 24 hours. Note male escutcheon.
17-ketosteroids ( 63.4 mg.) and normal17-ketogenic steroids ( 6.7 mg.). The qualitative Allen test for dehydroepiandrosterone was negative, and neither pregnanetrial nor pregnanediol were found on assay. Following suppression studies with dexamethasone (2 mg. q.i.d. for 2 days) there was no fall in the 17-ketosteroid output (Table 1). Roentgen studies of the chest were negative. Intravenous pyelogram revealed the presence of a suprarenal mass which caused downward displacement and distortion of the right kidney, with a resultant mild degree of dilatation of the right pelvocalyceal system (Fig. 3). Surgical exploration of the right adrenal was undertaken. A large tumor mass was found and removed. The patient was given cortisone therapy before, during, and after the surgical procedure. Nine days after surgery, the 17-ketosteroid value had fallen to 9.4 mg. per 24 hours (Table 1). The patient made an uneventful recovery and was discharged 10 days after surgery.
210
GREENBLATT
& SELIGMAN
FERTILITY
& STERILITY
TABLE 1. Results of Urinary Hormone Assays on Patient Before and After Surgery for Removal of Adrenal Tumor DATES
DATA
17-KETOSTER 0 I DS
17-KETOGENIC STEROIDS 6. 7 mg
AUEN TEST FOR DEHYDROEPIANDOSTERONE PREGNANETR I 01. CREATININE
10 I 61 59
Control
63.4 mg
Negative
0
1773 mg
10 I 7 I 59
Control
61.5
0
Negative
0
1554
10 112159
Dexamethasone Suppress iori Test
73.2
3.6
Negative
0
1626
10 1241 59
10 days postoperative
6.3
1.4
....................
118160
2 1! months postoperative
17.0
11.1
.......................
More than 2 1! ye.Jrs after surgery
14.2
11.0
--------
-------
6110162
972 1300 1262
Three pregnanediol assays done during the first week after onset of menstruation showed 0, 0.5, and 0 mg. per 24 hours.
Fig. 2. Endometrial biopsy material obtained by suction cUiettage on day of onset of menses. Note secretory endometrium consistent with ovulatory menstruation.
The tumor consisted of a rounded, circumscribed, soft mass of tissue which was meaty in consistency, measuring approximately 7.5 em. in its greatest diameter and weighing approximately 130 gm. The histopathologic pattern was consistent with a diagnosis of benign adenoma of the adrenal although a mild degree of pleomorphism was seen (Fig. 4). Follow-up Observations. The patient was seen for the first follow-up examination 12 weeks after surgery. At this time the degree of hirsutism was unchanged and the
VoL.14,No.2,1963
ENDOCRINOPATHIES AND INFERTILITY
Fig. 3. Intravenous pyelogram; note displacement of right kidney downward. Arrow points to rounded mass.
Fig. 4. Histologic section of adrenal tumor diagnosed as benign adenoma. Note slight degree of pleomorphism.
211
212
GREENBLATT
& SELIGMAN
FERTILITY
& STERILITY
pitch of the voice remained deep. However, she stated that her menstrual periods had occurred regularly after surgery and that once again she experienced dysmenorrhea and painful breasts prior to the onset of menses. Urinary hormone assays at this time showed a value of 17 mg. per 24 hours for 17-ketosteroids and 11.1 mg. for 17-ketogenic steroids (Table 1). Seven months postoperatively, the patient showed signs and symptoms of early pregnancy. Her last menstrual period had occured on Mar. 26, 1960. The expected date of confinement was calculated as Jan. 5, 1961. Because of signs of impending toxemia, medical induction of labor was started on Dec. 19, 1960, and she was delivered of a normal female infant on that date. The postpartum course was uneventful for both mother and baby. About 5 months later the patient conceived again, and this time experienced a normal prenatal course, delivery, and parturition. At this writing, almost 3 years after removal of the adrenal adenoma, the hirsutism has not been modified to any degree and the harshness of the voice has lessened only slightly. DISCUSSION
The adrenogenital syndrome is comprised of a rather wide range of disorders of the adrenal glands and is manifested principally by changes in certain secondary sexual characteristics. The disorder may be due to hyperplasia of the adrenal, which is congenital in origin, or it may be caused by an adrenal cortical tumor. The common denominator of the various syndromes which come under the heading of "adrenogenital syndrome" is the excessive production of androgens by the adrenal cortex. The clinical picture resulting from excessive androgen secretion will vary slightly from patient to patient, depending somewhat on the sex and age of the patient as well as on the types of steroids being produced.9 The bizarre syndrome of virilization of the female may result from ovarian as well as adrenal pathology, and differentiation is not always a simple matter.7 To be considered in the differential diagnosis of an adult female who presents herself with hirsutism, voice changes, acne, and enlargement of the clitoris, with or without menstrual disturbances, are ( 1) adrenogenital syndrome (virilizing tumor) ( 2) congenital adrenal hyperplasia (with late manifestations) ( 3) masculinizing tumors of the ovary, and ( 4) the polycystic ovary syndrome of Stein-Leventhal and the many variants of this syndrome. The hormonal laboratory studies which should be utilized as aids in diagnosis include those for urinary 17-ketosteroids, 17-ketogenic steroids, dehydroepiandrosterone, and pregnanediol and pregnanetriol estimations. The Allen test, which provides a qualitative test for dehydroepiandroster-
VoL.14, No.2, 1963
ENDOCRINOPATHIES AND INFERTILITY
213
one, is often positive in women with a virilizing adrenal tumor/ but it may be negative in cases where the liver is able to metabolize excess steroids. According to our present knowledge, the adrenal secretes dehydroepiandrosterone as the principal 17-ketosteroid.U The dehydroepiandrosterone appears in urine only in very small quantities, whereas the major part is metabolized to androsterone and etiocholanolone. The appearance of large quantities of dehydroepiandrosterone, sufficient to yield a positive Allen test, would depend on the level of adrenal secretions as well as interference with the ability of the liver to metabolize this ketosteroid to androsterone and etiocholanolone.8 Whether the etiological background is adrenal hyperplasia or adrenal tumor, the 17-ketosteroid values will be elevated. Pregnanetriol values are usually markedly elevated in congenital adrenal hyperplasia. 3 In the presence of an adrenal tumor, the pregnanediol complex, as well as the 17ketosteroids, may reach very high levels. In one of our cases previously reported, the urinary 17-ketosteroids assayed more than 1000 mg. per 24 hours, and the pregnanediol values were higher than 500 mg. 2 In adrenal hyperplasia, a marked fall in the excretion of pregnanetriol and 17-ketosteroids may be brought about by the administration of glucocorticoidsP When a tumor is present, this fall usually does not take place. Thus, the "glucocorticoid suppression test" may be used as a diagnostic tool, but it must be recognized that it is not infallible. Amenorrhea or anovulatory menses occur in most instances where women harbor virilizing adrenal tumors. In a recent study of Southren et al., a case is reported of untreated congenital adrenal hyperplasia in which there was no interference with cyclic ovulatory menses. It is of interest to note that, in the patient under discussion, though regular cyclic ovulatory menses persisted, premenstrual molimina and dysmenorrhea ceased 2 years prior to surgery. It may well be that the high androgen production had an ameliorating effect on these symptoms. Clinically, androgens are employed with a modicum of success in management of premenstrual molimina as well as dysmenorrhea. 4 SUMMARY
1. A case of virilization caused by an adrenocortical adenoma is presented. 2. Interesting aspects of this case are: (a) regular cyclic ovulatory menses occurred while the patient harbored the tumor; (b) a negative Allen test for dehydroepiandrosterone was obtained in spite of the large output of urinary 17-ketosteroids; (c) almost S years after removal of the
214
GREENBLATT & SELIGMAN
FERTILITY & STERILITY
tumor the hirsutism remains unchanged and the voice continues to be harsh, although the patient's body contours have become more feminine. 3. After surgical intervention, urinary 17-ketosteroid values fell to normal levels. Within a 2-year period following her surgery, the patient conceived twice and was delivered of a normal female child on each occasion.
Medical CoUege of Georgia Eugene Talmadge Memorial Hospital Augusta, Ga.
REFERENCES 1. ALLEN, W. M., HAYWARD, S. J., and PINTo, A. A color test for dehydroepiandrosterone .and closely related steroids of use in the diagnosis of adrenal tumors. /. Clin. Endocrinol. 10:54, 1950. 2. CHANEY, R. H., and GREENBLATT, R. B. The adrenogenital syndrome. ].M.A. Georgia 39:482, 1950. 3. GoLD, J. J. The diagnosis of the adrenogenital syndrome. M. Clin. North America 43: 523,1959. 4. GREENBLATT, R. B. Syndrome of major menstrual molimina with hypermenorrhea alleviated by testosterone propionate. ].A.M.A. 115:120 (July 13) 1940. 5. GREENBLATT, R. B., VAZQUEZ, E., and McLENDON, I. C. Endocrinopathies and infertility: I. Acromegaly and pregnancy. Fertil. & Steril. 7:498, 1956. 6. GREENBLATT, R. B., SCARPA-SMITH, C., and METTS, J. C. Endocrinopathies and infertility: II. Cushing's syndrome and pregnancy. Ferta. & Steril. 10:323, 1959. 7. IsRAEL, S. L. Diagnosis and Treatment of Menstrual Disorders and Stemity. (ed. 4) Hoeber, New York, 1960. 8. MAHEsH, V. B., and GREENBLATT, R. B. Isolation of dehydroepiandrosterone and 17alpha-hydroxyprogesterone from the polycystic ovaries of the Stein-Leventhal syndrome. J. Clin. Endocrinol. 22:441, 1962. 9. PAScHKIS, K. G., RAKOFF, A. E., and CANTAROW, A. Clinical Endocrinology. Hoeber, New York, 1954. 10. SoUTHREN, A. L., SAITO, A., LAUFER, A., and SoFFER, L. J. Urinary hormones studies in untreated congenital adrenal hyperplasia during and after pregnancy. J, Clin. Endocrinol. 21:615, 1961. 11. VANDEWIELE, R., and LIEBERMAN, S. "The Metabolism of Dehydroisoandrosterone." In Biological Activities of Steroids in Relation to Cancer, Ed. by G. Pincus and E. P. Vollmer, Acad. Press, New York, 1960. 12. WILKINs, L., LEWIS, R. A., KLEIN, R., GARDNER, L. I., CRIGLER, J. F., RosEMBERG, E., and MIGEON, C. J. Cortisone therapy in congenital adrenal hyperplasia. J. Clin. Endocrinol.11:1, 1951.
TRUE
VIRILIZATION of the adult female is frequently caused by an adrenocortical tumor and, in most instances, infertility is a concomitant. The purpose of this paper (third in a series ) 5 • 6 is to present the case of a patient with regular cyclic menstruation who complained of hirsutism, voice changes, and infertilitv, and in whom the removal of an adrenocortical adenoma resulted in res~lution of the infertility problem but did not bring about regression of the hirsute state.
CASE REPORT Mrs. B.F., a 24-year-old female was first seen in October 1959 with the complaints of acne, hirsutism, and infertility. The acne had been present for 8 years, while the hirsutism had become progressively worse over the last 4 years. Hairiness first appeared on the chin and then spread gradually to involve the breasts, thighs, and abdomen. There was no familial history of hirsutism. Deepening of the voice was first noted at about 20 years of age, and on her admission the voice was hoarse and of very low pitch. Her menstrual periods had begun at age 13 and had occurred regularly about every 29 days, with a duration of 3-4 days. Dysmenorrhea had always been present, but about 2 years prior to her first visit she ceased to experience dysmenorrhea as well as premenstrual molimina. There had been a gradual diminution of her libido. She had been married a little more than 2 years, and though conception was very much desired, it had not been accomplished. The patient was of masculine body build, with a male escutcheon. The hypertrichosis involved the face, chest, breasts, abdomen, and extremities. Her complexion was oily and acneform lesions were present (Fig. 1). The breasts were moderately well developed and apparently had not decreased in size. Slight enlargement of the clitoris was noted. On pelvic examination, no ovarian masses were palpable. · The hemoglobin, hematocrit, white blood cell count, differential count, urinalysis, From the Department of Endocrinology, Medical College of Georgia, Augusta, Ga.
208
VoL. 14, No. 2, 1963
ENDOCRINOPATHIES AND INFERTILITY
209
BUN, and serum electrolytes were within normal range. Serology was negative. The protein-bound iodine was 5.1 ~tg.%. Endometrial biopsy obtained on the first day of menses revealed an endometrium consistent with cyclic ovulatory menstruation (Fig. 2). The control urinary hormone assays revealed markedly elevated
Fig. 1. Twenty-four-old female (case report) with hirsutism, voice changes, and slight enlargement of the clitoris, who experienced normal cyclic ovulatory menses. Her urinary 17ketosteroids were 60 mg. per 24 hours. Note male escutcheon.
17-ketosteroids ( 63.4 mg.) and normal17-ketogenic steroids ( 6.7 mg.). The qualitative Allen test for dehydroepiandrosterone was negative, and neither pregnanetrial nor pregnanediol were found on assay. Following suppression studies with dexamethasone (2 mg. q.i.d. for 2 days) there was no fall in the 17-ketosteroid output (Table 1). Roentgen studies of the chest were negative. Intravenous pyelogram revealed the presence of a suprarenal mass which caused downward displacement and distortion of the right kidney, with a resultant mild degree of dilatation of the right pelvocalyceal system (Fig. 3). Surgical exploration of the right adrenal was undertaken. A large tumor mass was found and removed. The patient was given cortisone therapy before, during, and after the surgical procedure. Nine days after surgery, the 17-ketosteroid value had fallen to 9.4 mg. per 24 hours (Table 1). The patient made an uneventful recovery and was discharged 10 days after surgery.
210
GREENBLATT
& SELIGMAN
FERTILITY
& STERILITY
TABLE 1. Results of Urinary Hormone Assays on Patient Before and After Surgery for Removal of Adrenal Tumor DATES
DATA
17-KETOSTER 0 I DS
17-KETOGENIC STEROIDS 6. 7 mg
AUEN TEST FOR DEHYDROEPIANDOSTERONE PREGNANETR I 01. CREATININE
10 I 61 59
Control
63.4 mg
Negative
0
1773 mg
10 I 7 I 59
Control
61.5
0
Negative
0
1554
10 112159
Dexamethasone Suppress iori Test
73.2
3.6
Negative
0
1626
10 1241 59
10 days postoperative
6.3
1.4
....................
118160
2 1! months postoperative
17.0
11.1
.......................
More than 2 1! ye.Jrs after surgery
14.2
11.0
--------
-------
6110162
972 1300 1262
Three pregnanediol assays done during the first week after onset of menstruation showed 0, 0.5, and 0 mg. per 24 hours.
Fig. 2. Endometrial biopsy material obtained by suction cUiettage on day of onset of menses. Note secretory endometrium consistent with ovulatory menstruation.
The tumor consisted of a rounded, circumscribed, soft mass of tissue which was meaty in consistency, measuring approximately 7.5 em. in its greatest diameter and weighing approximately 130 gm. The histopathologic pattern was consistent with a diagnosis of benign adenoma of the adrenal although a mild degree of pleomorphism was seen (Fig. 4). Follow-up Observations. The patient was seen for the first follow-up examination 12 weeks after surgery. At this time the degree of hirsutism was unchanged and the
VoL.14,No.2,1963
ENDOCRINOPATHIES AND INFERTILITY
Fig. 3. Intravenous pyelogram; note displacement of right kidney downward. Arrow points to rounded mass.
Fig. 4. Histologic section of adrenal tumor diagnosed as benign adenoma. Note slight degree of pleomorphism.
211
212
GREENBLATT
& SELIGMAN
FERTILITY
& STERILITY
pitch of the voice remained deep. However, she stated that her menstrual periods had occurred regularly after surgery and that once again she experienced dysmenorrhea and painful breasts prior to the onset of menses. Urinary hormone assays at this time showed a value of 17 mg. per 24 hours for 17-ketosteroids and 11.1 mg. for 17-ketogenic steroids (Table 1). Seven months postoperatively, the patient showed signs and symptoms of early pregnancy. Her last menstrual period had occured on Mar. 26, 1960. The expected date of confinement was calculated as Jan. 5, 1961. Because of signs of impending toxemia, medical induction of labor was started on Dec. 19, 1960, and she was delivered of a normal female infant on that date. The postpartum course was uneventful for both mother and baby. About 5 months later the patient conceived again, and this time experienced a normal prenatal course, delivery, and parturition. At this writing, almost 3 years after removal of the adrenal adenoma, the hirsutism has not been modified to any degree and the harshness of the voice has lessened only slightly. DISCUSSION
The adrenogenital syndrome is comprised of a rather wide range of disorders of the adrenal glands and is manifested principally by changes in certain secondary sexual characteristics. The disorder may be due to hyperplasia of the adrenal, which is congenital in origin, or it may be caused by an adrenal cortical tumor. The common denominator of the various syndromes which come under the heading of "adrenogenital syndrome" is the excessive production of androgens by the adrenal cortex. The clinical picture resulting from excessive androgen secretion will vary slightly from patient to patient, depending somewhat on the sex and age of the patient as well as on the types of steroids being produced.9 The bizarre syndrome of virilization of the female may result from ovarian as well as adrenal pathology, and differentiation is not always a simple matter.7 To be considered in the differential diagnosis of an adult female who presents herself with hirsutism, voice changes, acne, and enlargement of the clitoris, with or without menstrual disturbances, are ( 1) adrenogenital syndrome (virilizing tumor) ( 2) congenital adrenal hyperplasia (with late manifestations) ( 3) masculinizing tumors of the ovary, and ( 4) the polycystic ovary syndrome of Stein-Leventhal and the many variants of this syndrome. The hormonal laboratory studies which should be utilized as aids in diagnosis include those for urinary 17-ketosteroids, 17-ketogenic steroids, dehydroepiandrosterone, and pregnanediol and pregnanetriol estimations. The Allen test, which provides a qualitative test for dehydroepiandroster-
VoL.14, No.2, 1963
ENDOCRINOPATHIES AND INFERTILITY
213
one, is often positive in women with a virilizing adrenal tumor/ but it may be negative in cases where the liver is able to metabolize excess steroids. According to our present knowledge, the adrenal secretes dehydroepiandrosterone as the principal 17-ketosteroid.U The dehydroepiandrosterone appears in urine only in very small quantities, whereas the major part is metabolized to androsterone and etiocholanolone. The appearance of large quantities of dehydroepiandrosterone, sufficient to yield a positive Allen test, would depend on the level of adrenal secretions as well as interference with the ability of the liver to metabolize this ketosteroid to androsterone and etiocholanolone.8 Whether the etiological background is adrenal hyperplasia or adrenal tumor, the 17-ketosteroid values will be elevated. Pregnanetriol values are usually markedly elevated in congenital adrenal hyperplasia. 3 In the presence of an adrenal tumor, the pregnanediol complex, as well as the 17ketosteroids, may reach very high levels. In one of our cases previously reported, the urinary 17-ketosteroids assayed more than 1000 mg. per 24 hours, and the pregnanediol values were higher than 500 mg. 2 In adrenal hyperplasia, a marked fall in the excretion of pregnanetriol and 17-ketosteroids may be brought about by the administration of glucocorticoidsP When a tumor is present, this fall usually does not take place. Thus, the "glucocorticoid suppression test" may be used as a diagnostic tool, but it must be recognized that it is not infallible. Amenorrhea or anovulatory menses occur in most instances where women harbor virilizing adrenal tumors. In a recent study of Southren et al., a case is reported of untreated congenital adrenal hyperplasia in which there was no interference with cyclic ovulatory menses. It is of interest to note that, in the patient under discussion, though regular cyclic ovulatory menses persisted, premenstrual molimina and dysmenorrhea ceased 2 years prior to surgery. It may well be that the high androgen production had an ameliorating effect on these symptoms. Clinically, androgens are employed with a modicum of success in management of premenstrual molimina as well as dysmenorrhea. 4 SUMMARY
1. A case of virilization caused by an adrenocortical adenoma is presented. 2. Interesting aspects of this case are: (a) regular cyclic ovulatory menses occurred while the patient harbored the tumor; (b) a negative Allen test for dehydroepiandrosterone was obtained in spite of the large output of urinary 17-ketosteroids; (c) almost S years after removal of the
214
GREENBLATT & SELIGMAN
FERTILITY & STERILITY
tumor the hirsutism remains unchanged and the voice continues to be harsh, although the patient's body contours have become more feminine. 3. After surgical intervention, urinary 17-ketosteroid values fell to normal levels. Within a 2-year period following her surgery, the patient conceived twice and was delivered of a normal female child on each occasion.
Medical CoUege of Georgia Eugene Talmadge Memorial Hospital Augusta, Ga.
REFERENCES 1. ALLEN, W. M., HAYWARD, S. J., and PINTo, A. A color test for dehydroepiandrosterone .and closely related steroids of use in the diagnosis of adrenal tumors. /. Clin. Endocrinol. 10:54, 1950. 2. CHANEY, R. H., and GREENBLATT, R. B. The adrenogenital syndrome. ].M.A. Georgia 39:482, 1950. 3. GoLD, J. J. The diagnosis of the adrenogenital syndrome. M. Clin. North America 43: 523,1959. 4. GREENBLATT, R. B. Syndrome of major menstrual molimina with hypermenorrhea alleviated by testosterone propionate. ].A.M.A. 115:120 (July 13) 1940. 5. GREENBLATT, R. B., VAZQUEZ, E., and McLENDON, I. C. Endocrinopathies and infertility: I. Acromegaly and pregnancy. Fertil. & Steril. 7:498, 1956. 6. GREENBLATT, R. B., SCARPA-SMITH, C., and METTS, J. C. Endocrinopathies and infertility: II. Cushing's syndrome and pregnancy. Ferta. & Steril. 10:323, 1959. 7. IsRAEL, S. L. Diagnosis and Treatment of Menstrual Disorders and Stemity. (ed. 4) Hoeber, New York, 1960. 8. MAHEsH, V. B., and GREENBLATT, R. B. Isolation of dehydroepiandrosterone and 17alpha-hydroxyprogesterone from the polycystic ovaries of the Stein-Leventhal syndrome. J. Clin. Endocrinol. 22:441, 1962. 9. PAScHKIS, K. G., RAKOFF, A. E., and CANTAROW, A. Clinical Endocrinology. Hoeber, New York, 1954. 10. SoUTHREN, A. L., SAITO, A., LAUFER, A., and SoFFER, L. J. Urinary hormones studies in untreated congenital adrenal hyperplasia during and after pregnancy. J, Clin. Endocrinol. 21:615, 1961. 11. VANDEWIELE, R., and LIEBERMAN, S. "The Metabolism of Dehydroisoandrosterone." In Biological Activities of Steroids in Relation to Cancer, Ed. by G. Pincus and E. P. Vollmer, Acad. Press, New York, 1960. 12. WILKINs, L., LEWIS, R. A., KLEIN, R., GARDNER, L. I., CRIGLER, J. F., RosEMBERG, E., and MIGEON, C. J. Cortisone therapy in congenital adrenal hyperplasia. J. Clin. Endocrinol.11:1, 1951.