EFFECT OF DEXAMETHASONE AND CLOMIPHENE CITRATE ON PERIPHERAL STEROID LEVELS AND OV ARIAN FUNCTION IN A HIRSUTE AMENORRHEIC PATIENT*

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1 FERTILITY AND STERILITY Copyright 1976 The American Fertility Society Vol. 27, No, 6, June 1976 Printed in UB.A. EFFECT OF DEXAMETHASONE AND CLOMIPHENE CITRATE ON PERIPHERAL STEROID LEVELS AND OV ARIAN FUNCTION IN A HIRSUTE AMENORRHEIC PATIENT* R. JEFFREY CHANG, M.D., AND GUY E. ABRAHAM, M.D.t Division of Reproductive Biology, Departl71 nt of Obstetrics and Gynecology, UCLA School of Medicine, Harbor General Hospital Campus, Torrance, California A 22-year-old infertile woman with amenorrhea and mild hirsutism failed to experience uterine bleeding following withdrawal of progestin therapy and failed to ovulate or menstruate following treatment with clomiphene citrate in doses up to 200 mglday for 5 days. Clomiphene citrate, 200 mglday, plus 10,000 IU of human chorionic gonadotropin given on day 13 also failed to induce either ovulation or menses. Serum androgen levels were: cortisol, 186 nglml; dehydroepiandrosterone sulfate, 6400 nglml; dehydroepiandrosterone, nglml; androstenedione, 4.68 nglml; testosterone, 1.28 nglml; and dihydrotestosterone, 0.75 nglml. Upper limits of normal values for these androgens in our laboratory are, respectively: 140, 2500, 8.0,2.3,0.5, and 0.35 nglml. The dexamethasone (Dex) suppression test indicated predominantly an adrenal source of the hyperandrogenism. Except for androstenedione, the levels of all androgens measured returned to normal following treatment with 0.5 mg of De xl day. Four months of this treatment had a beneficial effect on the hirsutism but failed to induce ovulation or menses. Clomiphene citrate, 100 mglday for 5 days, given concurrently with Dex therapy resulted in ovulation and conception. Adrenal androgen excess has been postulated to be a cause of ovarian dysfunction. Our data support this postulate. Clomiphene citrate (Clomid) is the most commonly used drug to induce ovulation in patients with anovulatory infertility.j However, if dynamic tests of adrenal and ovarian functions indicate that there is a hyperfunction of the adrenal gland, glucocorticoid therapy has been advocated. 2 We present a patient with anovulatory infertility and hirsutism, due predominantly to adrenal hyperandrogenism, who failed to ovulate when given Clomid or Accepted January 5, *Presented at the Twenty-Third Annual Meeting of The Pacific Coast Fertility Society, October 15 to 19, 1975, Palm Springs, Calif. treprint requests: Guy E. Abraham, M.D., Department of Obstetrics and Gynecology, Harbor General Hospital, 1000 West Carson Street, Torrance, Calif dexamethasone (Dex) alone but who responded to a combination of the two drugs. MATERIALS AND METHODS A 22-year-old white woman came to the endocrinelinfertility clinic with primary infertility, secondary amenorrhea, and mild hirsutism. She had been oligomenorrheic since menarche at age 12, with menses every 6 months. At age 17, she noted increased facial and body hair. A few months following the onset of hirsutism, she was given a combination oral contraceptive (Enovid) for 1 year, which produced monthly withdrawal bleeding but a worsening of hirsutism. The oral contraceptive was discontinued, followed by amenorrhea. At age 21 she was evaluated for infertility at another

2 Vol. 27, No.6 DEXAMETHASONE AND CLOMIPHENE IN AMENORRHEA AND HIRSUTISM 641 institution. A I-month course of estrogen and progestins resulted in withdrawal bleeding. An exploratory laparotomy revealed normal-appearing ovaries. Treatment with Clomid, 50 mg/day for 5 days, failed to induce ovulation or menses. Subsequent increases in the daily dose by 50-mg increments, up to 200 mg/day, also were without success. Addition of 10,000 IU of human chorionic gonadotropin on day 13 of Clomid treatment for 2 consecutive months also proved ineffective. At the time of the initial visit to our clinic, physical examination revealed a well-developed white female weighing 134 lbs and measuring 65 inches, with normal vital signs. Fine, pigmented hair was noted about the chin and upper lip, and she had sideburns. We classified this amount of hirsutism as mild. 3 The remainder of the physical examination, including pelvic examination, was normal. There was no evidence of galactorrhea. Routine laboratory tests, including x-rays of the sella turcica, were normal. Single determinations of serum follicle-stimulating hormone and luteinizing hormone concentrations were 4 and 13 miu/ml, respectively. After a 5-day course of Provera, 10 mg/day, the patient did not experience withdrawal bleeding. In order to evaluate the hirsutism, serum levels of various androgens were measured prior to and after administration of 0.5 mg of Dex four times daily for 7 days.3 Because the suppression test indicated predominantly an adrenal source of her hyperandrogenism, the patient was treated with Dex 0.5 mg/day at bedtime. Over the next 4 months she noted a significant improvement of her hirsutism. However, she remained amenorrheic. During the 5th month of Dex treatment, concomitant administration of Clomid, 100 mg/day for 5 days, resulted in a biphasic basal body temperature charlo On day 35 of that induced ovulatory cycle, the serum chorionic gonadotropin level was 4 IU/ml, confirming pregnancy. Following an uneventful pregnancy, she delivered two female infants weighing 5 lbs and 5 lbs, 7 ounces 40 weeks after Clomid therapy. Serial blood samples were obtained monthly by antecubital venipuncture between 8 and 10 A.M. for 6 months following initiation of Dex treatment. Mter collection and retraction ofthe blood clot, the serum was separated by centrifugation and stored at 4 C until assayed. Serum levels of cortisol (F), dehydroepiandrosterone sulfate (DHEA S), dehydroepiandrosterone (DHEA), androstenedione (A), testosterone (T), and dihydrotestosterone (DHT) were measured to evaluate the hirsutism. In addition, serum progesterone (P), 17-hydroxyprogesterone (17-P), and 17,B-estradiol (E 2) were measured prior to and during Dex treatment to evaluate ovarian function. The techniques used to measure these steroids have been reported previously.4 TABLE 1. Serum Cortisol and Androgen Levels before and after Dexamethasone Suppression Treatment period F DHEA S DHEA A T DHT Nonhirsute premenopausal women" Control Post-Dex Hirsute infertile patient Control Post-Dex 2 mg/day for 7 days mg/day for 13 daysb "Mean upper limits of normal: follicular phase. btaken at bedtime. ng/ml

3 642 CHANG AND ABRAHAM June Dex 0.5 mg H.S. Clomid 5Omg/doy N '"." C o a.!::: a: E "- '" c M2, , 'y / 2 ;" '< 1.0 Q " lj M AUGSEPTOCTNOVDECJANFEB FIG. 1. Peripheral levels of progesterone, 17 -hydroxyprogesterone, and 17{3-estradiol in a hirsute infertile patient during treatment with dexamethasone and clomiphene citrate (Clomid). RESULTS The upper limits of serum levels of F, DHEA-S, DHEA, A, T, and DHT in normal, nonhirsute, premenopausal women before and after Dex suppression are compared in Table 1 with control and post Dex serum levels of these steroids in the patient. Control values for all steroids measured were above normal. Dex, 2 mg/ day for 7 days, adequately suppressed serum F levels, but failed to suppress serum DHEA-S levels adequately. Dex was then administered for a longer period of time at a lower dose, 0.5 mglday.3 After 13 days of Dex treatment, 0.5 mw Dex 0.5 mg H.S. Clemid 50mg I dey u. 160 E '" r:: Upper Normal DHEA-S f:'" 4000 '" :I: IT! l> U, B AUG SEPT OCT -----i NOV----< DEC----< JAN-----i FEB I, FIG. 2. Peripheral levels of cortisol and dehydroepiandrosterone sulfate in a hirsute infertile patient during treatment with dexamethasone and clomiphene citrate (Clomid).

4 Vol. 27, No.6 DEXAMETHASONE AND CLOMIPHENE IN AMENORRHEA AND HffiSUTISM 643 De, 05mg H.S oclomid 50mg / day 2.0 I "C c: o I E "' '" c oil "' i g a. '" ===* o_ AUG-----i SEPT ----I OCT I NOV------I DEC------< JAN < FE FIG. 3. Peripheral levels of testosterone and dihydrotestosterone in a hirsute infertile patient during treatment with dexamethasone and clomiphene citrate (Clomid). day, the serum level of DHEA-S was suppressed to 460 ng/m!. At that time, serum levels of all androgens, except A, were adequately suppressed, indicating a mixed hyperandrogenism with predominantly an adrenal source. Serum levels of P, 17-P, and E2 during Dex and Clomid treatment are depicted in Figure 1. Serum P levels fluctuated between 0.2 and 0.6 ng/ml and remained within normal limits prior to and during Dex treatment. Sixteen days following Clomid treatment, P levels rose sharply to reach a plateau between 18 and 24 ng/ml, suggesting ovulation and normal corpus luteum function. 5.6 Serum 17-P levels fluctuated between 0.4 and 0.8 ng/ml during Dex treatment. Oil day 8 post-clomid, 17 -P levels increased to 1.3 ng/m!. On day 16 post-clomid, 17 -P and P levels increased sharply to reach peaks between 10 and 12 ng/ml on days 31 De, 0.5 mg H.S. Ii Clomid Omg / day 5 4 <l 3 E "' go 2 1 f't; A / I r I I I 9---& I I 9.. / I (> /,,/ 1/ o "'\ / " ",,/'-... Il I! \ p... / ',,,"... l/ -\.t- \ I... ' :h' " Upper Normal A Upper NormaiOHEA => 12 '" 8 "' '" I rr1 \/\ DHEA AUG---< SEPT ----< OCT I NOV----< DEC I JAN-----< FE FIG. 4. Peripheral levels of androstenedione and dehydroepiandrosterone in a hirsute infertile patient during treatment with dexamethasone and clomiphene citrate (Clomid).

644 CHANG AND ABRAHAM June 1976 to 50 post-clomid. Serum E2 levels were undetectable «0.02 ng/ml) prior to administration of Dex. Thirteen days after Dex treatment, E2 levels increased to 0.

5 644 CHANG AND ABRAHAM June 1976 to 50 post-clomid. Serum E2 levels were undetectable «0.02 ng/ml) prior to administration of Dex. Thirteen days after Dex treatment, E2 levels increased to 0.07 ngiml and fluctuated afterward between 0.04 and 0.07 ng/ml. Following initiation of Clomid therapy, E2 levels rose sharply to reach a peak of 0.3 ng/ml on day 10 post-clomid, followed by a drop to 0.16 ng/ml on day 16 post-clomid and a secondary rise to 1 ngiml on day 52 post Clomid. Serum DHEA-S levels decreased to normal within 7 days of Dex administration (Fig. 2) and were maximally suppressed on day 13 post-dex. Thereafter, serum DHEA-S levels remained within the normal range throughout the study, including the period following Clomid administration. Serum F levels were suppressed adequately during Dex treatment and fluctuated between 20 and 60 ng/ml. Following Clomid treatment, F levelstose to 80 to 120 ng/ml, indicating a decreased response of the pituitary-adrenal axis to Dex during the luteal phase of the induced cycle. Serum T levels decreased to normal after Dex administration (Fig. 3). Clomid administration was followed by markedly elevated T levels, in the range of 1.3 to 1. 7 ngiml. Serum DHT levels rapidly decreased to the normal range after Dex administration (Fig. 3) and remained suppressed until Clomid treatment was discontinued; the levels then rose slightly above the normal range. Serum HHEA levels decreased to normal by day 8 post-dex and remained low throughout the study period (Fig. 4). Serum A levels were not adequately suppressed during Dex administration and fluctuated above the normal range, indicating that the excess A was predominantly of ovarian origin (Fig. 4). Serum A levels rose to 5 ngiml following Clomid treatment. DISCUSSION In 1953, Jones et al. 7 reported the beneficial effects of cortisone in patients with follicular phase defects associated with mild adrenal hyperandrogenism and in patients with polycystic ovaries (PCO). Subsequently, other reports confirming these findings have appeared in the literature Smith et aj.12 in a study of 174 patients with the diagnosis of PCO found that induction of ovulation using prednisone gave rates comparable to those obtained with ovarian wedge resection. These findings led them to recommend initial glucocorticoid treatment for 6 to 12 months in patients with PCO. In Smith et al.'s study12 and other similar ones, no attempt was made to locate the source of androgen excess in patients classified as having PCO. It is likely that, in a large percentage of patients diagnosed as having PCO, adrenal hyperfunction is the underlying pathology. In many of the hirsute oligo-amenorrheic patients we have studied, the source of excess androgens was found to be of adrenal origin. 3 These patients probably would have been diagnosed as having PCO if a comprehensive evaluation of their hyperandrogenism had not been made. We have observed a worsening of acne and hirsutism during hormonal contraceptive therapy in some hirsute patients with adrenal hyperandrogenism. In this regard, the patient studied experienced a worsening of her hirsutism during treatment with a synthetic estrogen-progestin combination, suggesting that ovarian suppression was the wrong treatment for her hirsutism. Exogenous estrogen stimulates secretion of adrenal androgens in postmenopausal women. 13 It is likely that the same mechanism is involved in these patients. In some patients with adrenal hyperandrogenism, ovulation does not occur after adequate suppression of androgens by exogenous glucocorticoids, which may

Vol. 27, No.6 DEXAMETHASONE AND CLOMIPHENE IN AMENORRHEA AND HIRSUTISM 645 reflect the influence of chronic exposure to androgen excess on ovarian function.

6 Vol. 27, No.6 DEXAMETHASONE AND CLOMIPHENE IN AMENORRHEA AND HIRSUTISM 645 reflect the influence of chronic exposure to androgen excess on ovarian function. For example, Shearman14 noted that a patient with the diagnosis of virilizing adrenal hyperplasia failed to ovulate despite adrenal suppression with prednisone. Ovulation eventually was successfully induced by administration of Clomid while the patient remained on prednisone. In our patient, all androgens except A were suppressed to the normal range within 2 weeks of Dex administration. Failure to suppress serum A levels during the Dex suppression test and during Dex treatment indicated that the ovary was in part responsible for overproduction of A. The persistently elevated serum A levels and continued amenorrhea in our patient implied a causal relationship. However, when comparing eumenorrheic hirsute women with oligo-amenorrheic hirsute women, we found that the only androgen level significantly different between the two groups was DHEA-S, being significantly higher in oligoamenorrheic hirsute patients.15 At this time it is not known which androgen or androgens are responsible for the ovarian dysfunction. In the rat, polycystic ovaries can be produced with exogenous A or DHEA For obvious reasons no such studies have been performed in women. It is interesting that, prior to Dex treatment, E2 levels in our patient were low «0.02 ng/ml) and she did not experience withdrawal bleeding following exogenous progestin administration. The low estrogen level may account for the lack of response to Clomid. Following Dex treatment, E2 levels rose to those found during the normal follicular phase,5 suggesting an increased ovarian secretion of estrogen in response to Dex. The mechanisms by which Dex suppression of adrenal androgens induces an increased secretion of ovarian estrogen are unknown at present. It has been recently reported that various androgens are potent inhibitors of ovarian aromatization,19 and this may well be the mechanism involved in Dex-induced ovarian secretion of estrogens. It has been suggested by Dupon et al 20 that increased serum A and T levels may interfere with conception when ovulation is induced with Clomid. Of five patients who became ovulatory while taking Clomid, Dupon et al noted that the only conception occurred in a patient whose serum A and T levels were not elevated following Clomid administration. In spite of the elevated serum A and T levels in our patient following Clomid treatment, ovulation and conception occurred. This finding casts some doubt on Dupon et al's postulate. Although a case report, this study emphasizes the need for adequate evaluation and treatment of hyperandrogenism in infertile patients with concomitant hirsutism. REFERENCES 1. Kistner RW: Induction of ovulation with clomiphene citrate. In Progress in Infertility, Second Edition, Edited by SJ Behrman, RW Kistner. Boston, Little, Brown and Co, 1975, p Schneeberg NG: Adrenal cortical factors in infertility. In Progress in Infertility, Second Edition, Edited by SJ Behrman, RW Kistner. Boston, Little, Brown and Co, 1975, p Abraham GE, Maroulis GB, Buster JE, Chang RJ, Marshall JR: The effect of dexamethasone on serum cortisol and androgen levels in hirsute patients. Obstet Gynecol 47:395, Abraham GE: Radioimmunoassay of steroids in biological materials. Acta Endocrinol [Suppl 183] (Kbh) 75:1, Abraham GE, Odell WD, Swerdloff RS, Hopper K: Simultaneous radioimmunoassay of plasma FSH, LH, progesterone, 17-hydroxyprogesterone, and estradiol-17f3 during the menstrual cycle. J Clin Endocrinol Metab 34:312, Abraham GE, Maroulis GB, Marshall JR: Evaluation of ovulation and corpus luteum fimction using measurements of plasma progesterone. Obstet Gynecol 44:522, Jones GES, Howard JE, Langford H: The use of cortisone in follicular phase disturbances. Fertil Steril 4:49, 1953

7 646 CHANG AND ABRAHAM June Jefferies WMcK, Weir WC, Weir DR, Prouty RL: The use of cortisone and related steroids in infertility. Fertil Steril 9:145, Jefferies WMcK, Levy RP: Treatment of ovarian dysfunction with small doses of cortisone or hydrocortisone. J Clin Endocrinol Metab 19:1069, Greenblatt RB, Barfield WE, Lampros CP: Cortisone in the treatment of infertility. Fertil Steril 7:203, Ferriman D, Purdie AW, Tendall WJ: Use of corticosteroids in infertility associated with hirsutism and oligomenorrhea. Br Med J 1: 1006, 1961, 12. Smith KD, Steinberger E, PerlotT WH: Polycystic ovarian disease: a report of 501 patients. Am J Obstet Gynecol 93:994, Abraham GE, Maroulis GB: Effect of exogenous estrogen on serum pregnenolone, cortisol, and androgens in postmenopausal women. Obstet Gynecol 45:271, Shearman RP: Treatments: surgery, corticosteroids, gonadal steroids. In Induction of Ovulation. Springfield lll, Charles C Thomas, 1969, p Abraham GE, Chakmakjian ZH, Buster JE, Marshall JR: Ovarian and adrenal contributions to peripheral androgens in hirsute women. Obstet Gynecol 46:169, Roy S, Mahesh VB, Greenblatt RB: Effect of dehydroepiandrosterone and a'-androstenedione on the reproductive organs of female rats: production of cystic changes in the ovary. Nature 196:42, Singer EL, Seelig LL Jr, Rennels EG: Effects of dehydroepiandrosterone and cyanoketone on ovarian weight, cholesterol content, and ultrastructure in PMS-HCG treated, immature rats. Endocrinology 89:1223, Knudsen JF, Costoff A, Mahesh VB: Dehydroepiandrosterone-induced polycystic ovaries and acyclicity in the rat. Fertil Steril.26: 807, Siiteri PK: The importance of prohormones in estrogen metabolism in anovulatory women. Upjohn Lecture, Presented at the Twenty-Third Anual Meeting of The Pacific Coast Fertility Society, October, 1975, Palm Springs Calif 20. Dupon C, Rosenfield RL, Cleary RE: Sequential changes in total and free testosterone and androstenedione in plasma during spontaneous and Clomid-induced ovulatory cycles.,am. J Obstet GynecoI115:478, 1973 '

THE RELATION BETWEEN PLASMA TESTOSTERONE LEVELS AND THE LENGTHS OF PHASES OF THE MENSTRUAL CYCLE*

FERTILITY AND STERILITY Copyright 1979 The American Fertility Society Vol. 32, No.4, October 1979 Printed in U.s.A. THE RELATION BETWEEN PLASMA TESTOSTERONE LEVELS AND THE LENGTHS OF PHASES OF THE MENSTRUAL