The effect of oral contraceptive treatment on the serum concentration of dehydroisoandrosterone sulfate

The effect of oral contraceptive treatment on the serum concentration of dehydroisoandrosterone sulfate JAMES LEON

D.

MADDEN,

M.D.

MJLEWICH

C. RICHARD BRUCE

PARKER,

R.

ROBERT

CARR M.

PAUL

C.

Rallas,

Te.ms

JR.

BOYAR

MACDONALD,

M.D.

Dehydroisoandrosterone sulfate (IX), the major C,,-steroid in the human circulation, was measured in serum obtained from blood samples collected daity (8 to 10 A.M.) throughout the menSbval CyCkeS of eight normal, presumably ovulatory women and daily thfoughouf the treatment cycles in four women taking an oral contraceptive (norethindrone, I mg., plus mestranol, 60 mcg.). The serum concentrations of DS in the ovulatory women ranged from 1,025 to 4,200 ng. per milliliter; mean, 2,062 f 137 ng. per milliliter (mean and standard error; n = 213). Serum DS concentrations during the follicular and luteal phases of the menstrual cycles of these women were similar. In women taking the oral contraceptive, the plasma DS concentrations ranged from 475 to 1,400 ng. per milliliter (mean, 895 c 83; n = 119). The 24 hour secretory pattern of DS was evalttated in one subject during a nontreatment cycle and again after 20 days of oral contraceptive treatment. In this subject, the mean serum DS level was 34 per cent lower during oral contraceptive treatm6nt than the level before treatment. The decrease in the sertim concentration of DS during oral contracerptive treatment likely results from a reduction in adrenal DS secretbn since DS secretion by the r&mat human ovary is negligible and ovarian dehydroisoandrostemne secretion is small. Therefore, it is likely that the reduced serum DS levels in women taking oral contraceptives are the conaa@ance of reduced adrenal secretion of DS resulting from reduced release of adrenocorticotropic hormone. (AM.

J. OBSTET.

GYNECOL.

132: 380,

1978.)

TREATMENT w~~~oralcontraceptives,consistingofa combined preparation of a synthetic estrogen plus a synthetic progestin, produces a blocking effect on gonadotropin release through feedback inhibition in the hypothalamus and/or anterior pituitary. Indeed, it is by suppression of pituitary gonadotropin release that ovarian steroidogenesis is reduced, ovulation inhibited, and contraception achieved. While plasma cortisol From the Cecil H. and Ida Green Centerfor Reprodwtive Biology Sciences and the Department of Obstetrics and Gynecology, University of Terns Southwestern Medical School. Supported in part by Unitzd States Public Grants AM06912 and 5-MOI-RR00633-05. Sponsored

by the Societyfor

Gynecologic

Health

Seruicu

Investigation.

Reprint repuests: Dr. Paul C. MacDonald, Cecil H. and Ida Green*Centerfor Reproductive Biology Sciences, University of Texas Southwestern Medical School, 5323 Harry Hines Blvd., Dallas, Texas 75235.

levels are increased during oral contraceptive treatment, it has been demonstrated that there. is a decrease in the secretory rate of cortisol in such treated women.’ These findings are attributable to the estrogen-mediated increase in hepatic production of traqscortin (tfit high-affinity, plasma cot-t&l-binding globulin) together with an increase in the level of free cortiso12 which may effect a reduction in adrenocofticotropiti hormone (ACTH) release.” Furthermore, treatment with progestational agents alone is associated with suppression of the secretion of cortisoi by the adrenal cortex, presumably by influencing, directly or indirectly, the release of the tropic hormone, ACTH.4 Little is known of the effect of oral contraceptive treatment on the secretion of adrenal C,,steroids. The most abundant adrenal &-steroid in the- man is dehydroisoandrosterone sulfate (DS) and it.. synthesisis presumed to occur principally in the ret&&r zone of the adrenal cortex in response to the action of ACTH. 0002-9378/78/200380+05$00.50/0

0 1978

Tlw C;.V. hlosbyCo.

Volume Number

132 4

From the results of studies on an adrenalectomized woman, it is known that little or no DS is secreted by the normal human ovary,” and only small amounts of dehydroisoandrosterone are secreted by the normal ovary.fi The present study was designed to assess the effect of oral contraceptive treatment (norethindrone, 1 mg., plus mestranol, 80 mcg.) on the rate of secretion of DS by the human adrenal cortex.

Materials and methods Blood samples. Antecubital venous blood was obtained daily between 8 and 10 A.M. from eight normal, presumably ovulatory women and from four women taking the oral contraceptive. The blood was allowed to clot and the serum was separated and stored at -20” C. until assayed. In one subject, on two occasions, blood was also obtained at 20 minute intervals over 24 hours following the technique of Weitzman and colleagues.7 In the first study, this woman had not been taking the oral contraceptive, but in the second study she had been taking the oral contraceptive for 20 days. She was acclimated to the environment of the General Clinical Research Center of Parkland Memorial Hospital, Dallas, Texas, for 16 hours prior to beginning blood collection. Steroid measurements. Serum DS and cortisol were quantified by direct radioimmunoassay employing procedures described by Milewich and associates8 and by Gomez-Sanchez and associates9 The data were analyzed statistically using the Mann-Whitney U test.”

Results Mean serum DS concentrations in eight presumably ovulatory women measured daily during the menstrual cycle [2,062 ? 137 ng. per milliliter (mean and standard error; n = 213; range, 1,025 to 4,200 ng. per milliliter)] were compared with those of four women taking oral contraceptives [895 & 83 ng. per milliliter (n = 1 19; range, 475 to 1,400 ng. per milliliter)] (Fig. 1). The difference in DS concentration between the two groups is significant, p < 0.001. Thus, in the women taking oral contraceptives, the mean serum DS concentration was 57 per cent lower than the mean serum DS concentration in untreated women. There were no notable variations in DS concentration during the menstrual cycle in the presumably ovulatory women. The 24 hour pattern of serum DS levels was evaluated during days 15 and 16 of a nontreatment, presumably ovulatory menstrual cycle of one subject. Serum cortisol concentrations were also measured in each of these blood specimens (Fig. 2). The highest levels of serum DS were found in blood samples col-

Effect of oral contraceptives on serum DS 381

W

2500

2w _ 2000

k;,E

11

i? ol

-12

-8

I

I

0

4

-4 DAYS FRO:

LH ‘p4EaK

(NORMAL

+12

CYCLE)

DAYS*OF b&F!:AL (ORAL

+8

%LE

1

I

24

28

CONTRACEPTIVE)

Fig. 1. Daily mean concentrations

of dehydroisoandrosterone sulfate measured throughout the ovarian cycles of eight presumably ovulatory young women (o-o) and in four young women taking oral contraceptives (o----o).LH, luteinizing hormone.

lected at the beginning of the study, i.e., at the time of insertion of the catheter, 5 cm. in length, into the antecubital vein. We attribute this finding to a “stressrelated’ phenomenon that brought about increased ACTH release (Figs. 2 and 3). No true episodic DS secretion could be identified in this subject, presumably because of the relatively long half life of plasma DS (six to eight hours) I’; however, a gradual downward trend in DS concentrations during the day was apparent. DS concentrations were highest in the afternoon and, after a decline, began to rise again approximately two hours prior to awakening. In this woman the nontreatment, 24 hour secretory pattern of DS was compared to a 24 hour DS secretory pattern obtained on the 20th day of oral contraceptive treatment (Fig. 3). The mean DS concentration during the 24 hours in the nontreatment study was 1,973 ng. per milliliter, and the mean DS concentration during 24 hours while taking the oral contraceptive was 1,303 ng. per milliliter, a 34 per cent reduction in the mean serum DS concentration. The difference in DS concentrations in the two studies was significant, p < 0.001. It is noteworthy that there were qualitative similarities in the DS secretory patterns in this subject before and during oral contraceptive treatment. Adrenal DS secretion appears to be regulated primarily

by the

same

trophic

agent

that

controls

the

synthesis of cortisol, namely ACTH. This view is supported by the qualitatively similar patterns of serum DS and

cortisol

2). Both elevated

concentrations

cortisol immediately

over

and DS serum after

a 24 hour

period

concentrations

the insertion

(Fig.

were

of the catheter

382

Madden et al.

t

SLEEP i

CLOCK TtME Fig. 2. Dehydroisoandrosterone sulfate and cortisol plasma concentrations lected at 20 minute intervals over 24 hours in a normal, presumably ovulatory and 16 of the menstrual cycle. The time of sleep is shown by inset.

measured in blood c-01woman during days I .5

CLOCK TIME Fig. 3. Twenty-four-hour secretory patterns of dehydroisoandrostemne cycle (e-0) and after 20 days of oral contraceptive therapy (o----o). tration of DS. The times of sleep are shown by insets.

into the episodes

antecubital of cortisol

vein, secretion

and

this

was

followed

by

that in general appear to coincide with the levels of serum DS (Fig. 2). Cortisol concentrations fell to nearly undetectable levels during the early hours of sleep but began to rise prior to awakening. This rise in cortisol secretion occurred simultaneously in time with the rise in DS concentrations.

Comment The treatment of women with oral contraceptives is associated with an almost complete suppression of luteinizing hormone and follicle-stimulating hormone

sulfate in a pretreatment X = mean 24 hour conce‘en-

release and a partial suppression of ACTH release,‘$ the latter occurring either by direct disturbance of synthesis and/or release of ACTH or indirectly through an effect on corticotropin releasing factor. As a ctmsequence of the decreased plasma level of AC’I’H, adrenal cortical function is diminished and there is a decrease in cortisol and DS secretion. While co&sol serum concentrations are elevated during oral contraceptive treatment as a consequence of decreased clearance of plasma cortisol,’ DS serum concentratins are reduced. Plasma DS is bound nonspecificia~lg to albumin and there is no known major, rapid, irrevers-

Volume Number

I32 1

ible pathway of clearance induced by estrogen-progestin therapy. Thus, the substantial reduction in serum DS concentration during oral contraceptive treatment is likely not accounted for by an increase in its metabolic clearance rate. The diminished DS secretion during oral contraceptive treatment appears to be the consequence of decreased ACTH release and perhaps other intra-adrenal factors. Bulbrook and colleagues I2 found plasma DS concentrations to be significantly reduced in women receiving combined oral contraceptive therapy when compared to age-matched normal controls. BuIbrook and Hayward’” have also shown that urinary excretion of lldeoxy- 17-ketosteroids in women receiving combined oral contraceptives is subnormal. The latter finding is supportive of the view that the decrease in plasma concentration of DS in women taking combined oral contraceptives is not due to an increase in the metabolic cl.earance rate but rather is due to a decrease in adrenal secretion of DS. Mahajan and co-workers”’ studied the plasma DS levels in castrate women before and three days and three weeks after treatment with 200 mcg. of ethinyl estradiol daily. These investigators found no significant change in serum DS levels during estrogen treatment. Anderson and Yen’” measured serum DS levels in five women during estradiol infusions and after treatment with ethinyl estradiol, 50 mcg. daily, for four to six weeks and found very little variation in serum DS levels during estrogen treatment. Abraham and Maroulis16 found significantly higher serum DS levels in a group

REFERENCES

1. Beck, R. P., Morcos, F., Fawcett, D., and Watanabe, M.: Adrenocortical function studies during the normal menstrual cycle and in women receiving norethindrone with and without mestranol, AM. J. OBSTET. GYNECOL. 112: 364, 1972. 2. Sandberg, A. A., Rosenthal, H. E., and Slaunwhite, W. R., Jr.: Certain metabolic effects of estrogens, in Salhanick, H. A., Kipnis, D. M., and Vande Wiele, R. L., editors: Metabolic Effeds of Gonadal Hormones and Contraceptive Steroids, New York, 1969, Plenum Press, pp. 367378. 3. Carr, B. D., Parker, C. R., Jr., Madden, J. D., MacDonald, P. C.. and Porter. 1. C.: Effect of contraceptive steroids on plasma levels of i*CTH and cortisol in women. Submitted for publication. 4. Helhnan, L., Yoshida, K., Zumoff, B., Levin, J., Kream, J., and Fukushima, D. K.: The effect of medroxyprogestemne acetate on the pituitary-adrenal axis, J. Clin. Endocrinol. Metab. 42: 912, 1976. 5. Abraham, G. E., and Chakmakjian, Z. H.: Serum steroid levels during the menstrual cycle in a bilaterally adrenalectomized woman, J. Clin. Endocrinol. Metab. 37: 581, 1973.

Effect of oral contraceptives on serum DS 383

of postmenopausal women taking stilbestrol or conjugated estrogens than in a group of postmenopausal women who took no estrogen. Thus, it appears that the significant reduction in serum DS levels in women taking the combined form of the oral contraceptive, i.e., a synthetic estrogen plus a synthetic progestin, cannot be attributed to estrogen action alone. It is possible that the suppression of DS secretion noted in our study and by Bulbrook and his co-authors’* is related in part to the effects of the progestin component of the combined oral contraceptive. We believe that the findings of this study may have a significant bearing on the diagnosis of androgen excess and treatment of women with this problem. From a diagnostic standpoint, it is apparent from the results of these studies that “differential suppression” of the adrenal and ovary for purposes of assessing the source of androgen excess is unrealistic. If the combination-type oral contraceptives are utilized to effect ovarian suppression, the secretion of adrenal C,,-steroids is also reduced. However, treatment with the combination oral contraceptive for patients with constitutional hirsutism or with hirsutism due to androgen excess arising from ovarian or adrenal functional disorders may effect a suppression of both ovarian and adrenal androgen secretion. The authors are grateful to Mrs. Ellen her editorial assistance ig the preparation script. The authors express gratitude to field, George Crowley, Loretta Dice, and for their dedicated technical assistance.

Landfear for of this manuDebra BradLyle Larson

6. MacDonald, P. C., Vande Wiele, R. L., and Lieberman, S.: Precursors of urinary 1 I-desoxy17-ketosteroids of ovarian origin, AM, J. OBSTET. GYNECOL. 86: 1, 1963. E. D., Fukushima, D., Nogeire, C., Roffwarg, 7. Weitzman, H., Gallagher, T. F., and.Hellman, L.: Twenty-four hour Dattem of the episodic secretion of cortisdl in normal subjects, J. Clin. Bndocrinol. 33: 14, 1971. 8. Milewich. L.. Gomez-Sanchez. C.. Madden. 1. D.. Bradfield, D. j., Parker, P. M., Smith, S. L., Car;, B. k., Ed-

man, C. D., and MacDonald, P. C.: Dehydroisoandroster-

9.

10.

11.

1.2

one sulfate in peripheral blood of premenopausal, pregnant and postmenopausal women and men. J. Steroid Biochem. In press. Gomez-Sanchez. C.. Milewich. L.. and Holland. 0. B.: Radioiodinated ‘dehvatives for steroid radioimmunoassay. Application to the radioimmunoassay of cortisol, J. Lab. Clin. Med. 89: 902, 1977. Siegal, S.: Nonparametric Ststistics for the Behavioral Sciences, New York, 1956, McGraw-Hill Book Company, Inc., pp. 116-127. Sandberg, E., Gurpide, E., and Lieberman, S.: Quantitative studies on the metabolism of dehydroisoandrosterone sulfate, Biochemistry 3: 1256, 1964. Bulbrook, R. D., Herian, M., Tong, D., Hayward, J. L.,

384

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Swain, M. C., and Wang, D. Y.: Effect of steroidal contraceptives on levels of plasma androgen sulfates and cortisol, Lancet 1: 628, 1973. 13. Bulbrook, R. D., and Hayward, J. L.: Excretion of urinary 17-hydroxy-corticosteroids and 11-deoxy-17-oxosteroids by women usinq steroidal contraceptives, Lancer 2: 1033, 1969. 14. Mahajan, D. K., Billiar, R. B., Jassani, M., and Little, A. B.: Ethinyl estradiol administration and plasma steroid concentrations in ovariectomized women, AM. J. OBSTET. GYNECOL. 130: 398, 1978.

15. Anderson, D. C., and Yen. S. S. C.: Effects of estrogens on adrenal 3&hydroxysteroid debydrogenase in ovariectomized women, J. Clin. Endocrinol. Metab. 43: 561. 1976. 16. Abraham, G. E., and Maroulis, G. B.: Ef&ect ofcxogenous estrogen on serum ptegnenolone, cortisol, and andro gens in postmenopausal women. Obstet. Gynecol. 45: 271. 1975.

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