JOURNAL OF ADOLESCENT HEALTH CARE 2:23-27, 1981

Treatment of Menstrual Irregularities with Dexamethasone in Congenital Adrenal Hyperplasia

ALICE BAGHDASSARIAN GRANOFF, M.D.

Abnormal menstrual patterns occur frequently in ado- lescent girls with congeriital adrenal hyperplasia (CAH). In this report, two sisters with CAH secondary to the 21- hydroxylase defect are described in whom the adminis- tration of dexamethasone, a long-acting glucocorticoid, initiated or regulated their menstrual cycles. Plasma lev- els of 17-hydroxyprogesterone and androstenedione were elevated while on therapy with 80 mg/day of hydrocor- tisone, and became normal after treatment with daily dexamethasone, 1.5 mg. Urinary excretion of 17-ketoste- roids and pregnanetriol showed a similar pattern. Plasma steroid levels remained suppressed after lowering the dexametllasone dose to 0.75 mg daily, an amount equiv- alent to less than the original hydrocortisone dose. These data suggest that dexamethasone has a potential role in the management of patients with CAH who have men- strual irregularities, particularly if conventional therapy does not suppress adrenal steroid production.

KEY WORDS:

Adrenal hyperplasia, congenital Dexamethasone Menstruation

A var ie ty of glucocort icoids have been used to treat congenital adrenal hyperp las ia (CAH). The d rug usual ly cons idered opt imal is the physiologic hor- m o n e cortisol because it is the principle glucocorti- coid secreted by the adrenal cortex (1). In addit ion, it has been r epor t ed that the synthet ic glucocorti- coids m a y have a dele ter ious effect on linear g rowth and skeletal ma tu ra t ion (2-4).

From the Valley Medical Center of Fresno, California. Direct repr!nt requests to: Alice B. Granoff, M.D., St. Louis Chil-

dren's Hospital, 500 South Kingshighway, P.O. Box 14871, St. Louis, MO 63178.

Manuscript accepted May 5. 1981.

Recently, Richards et al. admin i s t e red long-act ing glucocorticoids to four girls wi th CAH and men- strual irregularit ies (5) and m e n s e s began or became more regular dur ing t rea tment . The p u r p o s e of this repor t is to describe two sisters wi th C A H and men- strual irregularit ies w h o were successfully t reated with dexame thasone . P r o m p t initiation of men se s in one and regulat ion of m e n s e s in the other cor- related wi th enhanced suppres s ion of p l a sma 17- h y d r o x y p r o g e s t e r o n e (17-OHP), and ros t ened ione (A), and tes tos te rone (T).

Case Reports

Patient 1

The older of two sisters was seen at 19 years of age for amenorrhea. She was diagnosed as having CAH due to 21-hydroxylase deficiency without salt loss at two years of age. Treatment with hydrocortisone was initiated. Pu- berty began at 11 years of age, but menses did not follow. She received hydrocortisone, 40 mg in the morning and at night. On physical examination, she was 159 cm tall and weighed 76 kg. The blood pressure m the left arm was 135/80 mmHg. She had uniform obesity. Her face was rounded. She had striae on her abdomen which were not purple There were no signs of virilization and she had normal sexual maturation. Gynecologic examination was normal, with no evidence of enlarged ovaries or adnexal masses. By palpation, the uterus was small.

l

The patient repeatedly expressed concern about her lack of menstrual periods Accordingly, her hydrocorti- sone regimen was changed from 40 mg b.i.d to 20 mg at 0800, 20 mg at 1500, and 40 mg at 22~)0. Four weeks later, plasma specimens were obtained at 0800 on two consecutive days for 17-OHP, T, A, dehydroepiandios- terone (DHEA) and its sulfate (DHEAS), estradiol (Ea), luteinizing hormone (LH), and follicle stimulating hor- mone (FSH) These tests were performed by the Endocrine

© Society for Adolescent Medicine, 1981 23 Published by Elsevier North Holland, Inc., 52 Vanderbilt Ave., New York, NY 10017 ISSN 0197-0070/81/050023-05/$02.50

24 GRANOFF JOURNAL OF ADOLESCENT HEALTH CARE Vol. 2, No. 1

Science Laboratories, Tarzana, California. Twenty-four- hour urinary 17-ketosteroids (17-KS) and pregnanetriol (PNT) were obtained as well as a 24-hour urinary cortisol to assess compliance. The urinary tests were performed by Smith Kline Clinical Laboratories, Inc., Burlingame, California. Despite the higher doses of hydrocortisone, her plasma levels of 17-OHP, T, A, and urinary 17-KS and PNT levels continued to be markedly elevated (Table 1). The studies were repeated one month later and showed a similar pattern.

Patient 2

The younger sister was diagnosed and treated for CAH in early infancy. Menarche was at age 13 but her menstrual periods were scant and irregular. At 16 years of age, she was 157 cm tall and weighed 72 kg. Her blood pressur e in the left arm was 120/70 mmHg. On her usual dose of hydrocortisone (33 mg/m2/day: 15 mg at 0800, 15 mg at 1500, and 30 mg at 2200), she had elevated morning plasma levels of 17-OHP (9646, 4646 ng/dl), T (155, 150 ng/dl), and A (1126, 1076 ng/dl); and elevated 24-hour urinary 17-KS (18, 16 mg/24h) and PNT (8, 6.5 rag). Plasma DHEA (210 ng/dl), DHEAS (46 + g/dl), E2 (50, 80 pg/ml), LH (4.5, 6 mIU/ml), and FSH (9.0, 8 mIU/ml) were normal. All tests were performed by the above laboratories.

Methods Patient 1 was hospitalized; the hydrocor t i sone ther- apy was d iscont inued for the three days prior to admission. On the first day of hospitalization, base- line plasma and ur inary samples were obtained (Study 1). Plasma concentrat ions of 17-OHP, T, A,

DHEA, DHEAS, and E2 were moni tored every four hours. In addit ion, 24-hour ur inary levels of 17-KS and PNT were obtained. Following these studies, the pat ient Was given her usual doses of hydrocor- tisone (20 mg at 0800, 20 mg at 1500, and 40 mg at 2200). After four days of therapy, her plasma and ur inary steroid levels were repea ted (Study 2). Treat- ment was then initiated with dexamethasone (0.5 mg at 0900 and 1.0 mg at 2100). After four days, the steroid studies were repeated (Study 3).

Results

Testosterone

Plasma T was elevated w h e n glucocorticoid was wi thd rawn (Figure 1). After reinst i tut ion of hydro- cortisone, levels of T decreased to normal. However , a fur ther decrease in plasma T was found with dex- amethasone (Figure 1).

17-Hydroxyprogesterone

In the absence of glucocorticoid therapy, plasma 17- O H P levels were markedly elevated (11,956 to 23,028 ng/dl; Figure 1). Following administrat ion of her usual dose of glucocorticoid, the levels of 17-OHP decreased but her levels were still elevated in the samples obta ined at 0600, 1000, and 1400 hours. In contrast, after four days of dexamethasone therapy, plasma 17-OHP levels were normal t h roughou t the 24-hour period.

Table 1. Baseline Preadmission Laboratory Data ~

Normal premenopausal

Steroids women Day 1 Day 2

17 OHP (ng/dl) Follicular 15-70 Luteal 35-290 1092 2100

T (ng/dl) 10-55 220 150 A (ng/dl) 85-257 420 520 DHEA (ng/dl) 160-700 220 204 DHEAS (~g/dl) 60-230 50 54

Early follicular 10-150 E2 (pg/ml) Late follicular 5-300 48 40

Midcycle 250-600 Luteal 50-300

17-KS (mg/24 hr) 5-11 28 30 PNT (mg/24 hr) <3.5 20 21 Cortisol (~g/24 hr) 20-90 209

aPatient receiving usual dose of hydrocortisone--42 mg/m 2. 17 OHP = 17 hydroxyprogesterone; T = testosterone; A = androstenedione; DHEA = dehydroepiandrosterone; DHEAS =

dehydroepiandrosterone sulfate; E2 = estradiol; 17-KS = 17-ketosteroids; PNT = pregnanetriol.

September 1981 TREATMENT OF CONGENITAL ADRENAL HYPERPLASIA 25

Androstenedione

Baseline levels of plasma A were elevated (Study 1, Figure 1). After her usual dose of hydrocortisone, the levels obtained at 0600 hours remained elevated, but for the remainder of the 24-hour testing period, levels were within the normal range. Further low- ering of plasma A levels occurred with dexametha- sone, specifically at 0600 hours.

Dehydroepiandrosterone, Dehydroepiandrosterone Sulfate, and Estradiol

These levels were normal during all three studies (Table 2); but DHEA and DHEAS were generally lower during Studies 2 and 3.

Urinary 17-ketosteroids, Pregnanetriol

As expected, baseline levels of 17-KS and PNT were markedly elevated in the urine (Table 2). After administration of hydrocortisone, these urinary lev- els declined but remained above the normal range. Further suppression to normal levels occurred fol- lowing therapy with dexamethasone.

Clinical Follow-up Patient 1 at discharge was continued on 1.5 mg of dexamethasone daily. She had her first menstrual period one month later, then had none for two months. Plasma steroid levels remained normal, but in the interim, she developed purple striae Over her abdomen. Her dose was decreased to 0.75 mg daily (0.25 mg in the morning and 0.5 mg at night). On

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F i g u r e 1. Concentrationsofplasma17-OHPprogesterone, testosterone, and androstenedione prior to therapy, after four days of treatment with hydrocortisone (80 mg/day) and dexamethasone (1.5 mg/day) in patient No. 1. A = no medication; 0 = hydrocortisone; • = dexamethasone.

the lower dose, steroid levels of plasma specimens obtained in the morning remained normal (17-OHP, 239 ng/dl; A, 240 ng/dl; T, 39 ng/dl; 17-KS, 5.3 rag/ 24 hr; PNT, 0.9 mg/24 hr), and her menstrual periods resumed. These have remained regular for 30 months.

Table 2. Comparison of Therapy with Hydrocortisone and Dexamethasone: Effect on Plasma Concentration of DHEA, DHEAS, E2, and 24-Hour Urinary 17-KS and PNT

Normal Study No. premenopausal

Women 1 a 2 b 3"

DHEA (ng/dl) DHEAS (/~g/dl)

E2 (pg/ml)

17-KS (rag/24 hr) PNT (mg/24 hr)

Early follicular Late follicular Midcycle Luteal

160-700 282-428 176-221 120-176 60-230 55-65 40-60 20-40 10-150 5-300

250-600 51-54 32-43 48-62 50-300

5-11 55.1 27.4 3.7 <3.5 46.0 20.1 0.9

~Study 1: Baseline value obtained before therapy. ~Study 2: Values obtained after 4 days of therapy with hydrocortisone (80 mg/day). cStudy 3: Values obtained after 4 days of therapy with dexamethasone (1.5 mg/day). DHEA = dehydroepiandrosterone;. DHEAS = dehydroepiandrosterone sulfate; E2 = estradiol, 24-hour urinary 17-KS = 24 hour

urinary 17-ketosteroids; PNT = pregnanetriol. ~.

26 GRANOFF JOURNAL OF ADOLESCENT HEALTH CARE Vol. 2, No. 1

Patient 2 was started on 0.25 mg of dexametha- sone in the morning and 0.5 mg at night. Two weeks later, her plasma steroid levels obtained in the morn- ing were normal, except for a slightly elevated 17- OHP and A (17-OHP, 450 ng/dl; T, 35 ng/dl; A, 420 ng/dl). Menstrual periods became normal and reg- ular two months later and have remained regular for 24 months.

Discussion The main objectives in the treatment of CAH are suppression of virilization and achievement of an adult height compatible with the genetic potential. In postpubertal female patients, maintenance of nor- mal menses and fertility is also an important con- sideration. However, in large clinical series, as many as 25% of adolescent girls with CAH have bligo- menorrhea or amenorrhea (6-8). In addition, some patients with longstanding adrenal hyperplasia have hyperplastic adrenal glands, which are very sensi- tive to adrenocorticotropin. Prior to referral, the older patient in this study received her daily hydro- cortisone in two divided doses, a regimen that is usually not adequate for adrenal suppression. The same dosage of 80 mg/day was maintained but given in three divided doses, with 50% of the total dose at bedtime (2200-2300). Despite three months on this treatment, her adrenal steroid levels remained elevated. Twenty-four hour urinary cortisol as an outpatient was 160/~g. Poor compliance, therefore, did not appear to be a major factor, since her plasma and urinary levels remained elevated while she re- ceived the same dose and schedule in the hospita ! under supervision. It is possible that continuing hy- drocortis0ne therapy for a longer period in a super- vised clinical setting might have further suppressed the precursor steroids. This was, however, not prac- tical.

More recently (9), inadequate mineralq.corticoid replacement has been implicated as a factor in re- sistance to glucocorticoid therapy in "non-salt los- ers." Subclinical salt loss with kiypovolemia and hy- perreninemia may contribute to glucocorticoid resistance. Plasma renin activity was measured in both patients at 0800 while ambulatory and was found to be 5.2 ng/ml/hr in the older sister and 1.6 ng/ml/hr in the younger sister (normal up to 5 ng/ ml/hr). Thus, for unknown reasons, these patients remained refractorY to therapy even when hydro- cortisone was administered in a relatively high dose. It is known that dexamethasone shows enhanced adrenal suppressive potency; in one study, it was

estimated to be 80 times that of cortisol (range 30-200) (10) or approximately twice dexametha- sone's accepted antiinflammatory effect (11).

These experimental observations have not been widely applied to the clinical management of pa- tients with CAH, in part, because of the known del- eterious effect of even small doses of long-acting glucocorticoids on skeletal maturation and linear growth (2-4). However, once adult height is achieved, these considerations become less impor- tant.

Because of the wide variability in response to dex- amethasone, a relatively high dose (1.5 mg/day) was used initially for therapy but still within the same range used by Richards et al. (5). This dose resulted in prompt adrenal suppression (Figure 1) and initi- ation of menstrual periods in the first patient. Fur- thermore, adequate adrenal suppression and regular menses were maintained after lowering the dose to 0.75 rag/day. This lower dose was equally effective in the second patient. It is possible that an even lower dose of dexamethasone might have been ef- fective in these patients, but this has not been tried. Thus far, the only untoward effects of therapy were the appearance of some purple striae in t he first patient and a 2.7-3.6-kg weight gain in both sisters, but with no other cushingoid features. The striae diminished upon lowering the dose to 0.75 mg/day in the older sister, and she reports a 4-kg weigh t loss using dietary measures.

Data from the first patient suggest that in the presence of menstrual irregularities, plasma levels of DHEAS and T can be normal, despite other lab- oratory indications of suboptimal adrenal suppres- sion (Tables I and 2, Figure 1) (12-15). In the second patient, baseline plasma DHEAS levels were normal, despite marked elevations of other steroids, further confirmation that the measurement of DHEAS is an insensitive indicator of adequate adrenal suppres- sion (5,12). These and other observations (5,16) sug- gest that in patients with CAH, no single laboratory test can be relied on to assess the adequacy of ther- apy, but that the most helpful ones are plasma levels of 17-OHP and, if collected properly, 24-hour uri- nary 17-KS and PNT.

In summary, in postpubertal females with CAH, menstrual irregularities may result from failure of physiologic doses of hydrocortisone to completely suppress adrenal excess. The assessment of ade- quacy of adrenal suppression and prescription of a steroid replacement remains a difficult task. Dexa- methasone, because of its pharmacologic character- istics (biologic half-life, frequency of administration,

September 1981 TREATMENT OF CONGENITAL ADRENAL HYPERPLASIA 27

relatively greater potency as an adrenal suppressive agent), may offer an alternative to hydrocortisone in the treatment of menstrual irregularities.

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