Long-term treatment with RU486 and glucocorticoid receptor resistance Theoretical and therapeutic implications

ENDOCRINE ROUNDS Long-Term Treatment with RU486 and Glucocorticoid Receptor Resistance Theoretical and Therapeutic Implications Steven W.J. Lamberts, Jan W. Koper, and Frank H. de Jong

Glucocorticoid receptor resistance in humans occurs rarely in hereditary disorders. RU486 blocks progesterone receptors, but at higher doses also blocks glucocorticoid receptors. In this article, the clinical and biochemical effects of long-term treatment with RU486 ofpatients with meningiomas, breast cancer, and Cushing’s syndrome are compared with those present in patients with hereditary glucocorticoid receptor resistance. The potential use of RU486 outside the field of fertility regulation is discussed. (Trends Endocrinol Metab 1992;3:199-204).

and normokalemia. The hereditary pattern of the (partial) glucocorticoid receptor resistance in this family pointed to a dominant autosomal transfer. Glucocorticoid receptors were investigated in a whole cell dexamethasonebinding assay in mononuclear leukocytes in this patient as well as in her two afflicted brothers. The number of glucocorticoid receptors was lowered, while their affinity was normal (Figure la). As a “bioassay” for glucocorticoid action, dexamethasone suppressibilityof mitogenstimulated incorporation of [3H]thymidine into mononuclear leukocytes was also measured: both in this patient and in her two afflicted brothers, the concentration of dexamethasone needed to achieve 50% of the maximal inhibition of [3H]thymidine incorporation was higher than in healthy controls (Figure 1b). Case 2

??

Case Reports

Case 1 A 26-year-old woman presented with hirsutism, baldness, and menstrual irregularities (Lamberts et al. 1986). She had no hypertension and a normal serum potassium concentration, and there were no signs or symptoms related to long-standing exposure to excess glucocorticoids, such as centripetal obesity, moonface, muscle and skin atrophy, easy bruisability, or psychiatric abnormalities. Plasma cortisol levels were elevated (a value at 0800-0900 hours of 11 lo-1290 nmol/L) and were insufficiently suppressed in the overnight 1-mg dexamethasone suppression test to 580 nmol/L (normal, cl45 nmoY L). Further investigations showed an increased cortisol secretion rate, increased ACTH levels, a normal diurnal rhythm of cortisol at an elevated level,

Steven W.J. Lamberts, Jan W. Koper, and Frank H. de Jong are at the Department of Medicine, Erasmus University, Rotterdam, The Netherlands.

TEM Vol. 3, No. 6, I992

and a normal increase of serum ACTH, cortisol, PRL, and GH concentrations in response to insulin-induced hypoglycemia. These observations show that this patient had an intact hypothalamopituitary-adrenal axis set at an elevated level, with functioning feedback mechanisms. However, serum androstenedione and testosterone levels were considerably increased to 10.4 nmol/L (normal, 34.5 nmol/L) and 5.5 nmol/L (normal, ~3.0 nmol/L), respectively. These increases in androgen levels were interpreted as being of adrenal origin, secondary to chronic hyperstimulation by ACTH. Short-term therapy with dexamethasone (0.5-l .5 mg/day) resulted in a normalization of circulating ACTH, cortisol, androstenedione, and testosterone levels, while the diurnal rhythm of ACTH and cortisol and their response to hypoglycemia remained normal. Investigation of the family of this patient showed that both the father and two brothers had elevated morning serum cortisol concentrations, which suppressed insufficiently in response to 1-mg dexamethasone. These three men were asymptomatic, having a normal blood pressure 01992,

Elsevier Science Publishing Co., 1043-2760/92/$5.00

This 64-year-old woman had a meningioma (volume, 9.6 cm3) that was localized parasellarly at the apex of the left optic nerve. Slow but continuous growth of the tumor over the past 3 years had resulted in a progressive, complete loss of vision of the left eye, as well as in its propulsion. She had severe headaches and tension around the left eye socket. The tumor was not considered to be totally removable by surgical means. RU486 therapy (200 mg/day) initially caused nausea, anorexia, and increased tiredness, which diminished after 3-6 weeks of therapy. Thereafter she felt much better and the headaches and tension around the left eye diminished and/or disappeared completely during the course of the 12 months of RU486 therapy. Tumor size, which had increased significantly during the 6 months preceding RU486 therapy, stabilized during treatment, and the ultimate volume of the meningioma, as measured 10 months after ceasing RU486 administration, was 8.4 cm3. The course of endocrine variables before, during, and after RU486 treatment is shown in Table 1. RU486 resulted in increased circulating cortisol, deoxycortisol, androstenedione, dihydroepiandrosterone, as well as estradiol 199

1.80

0

r

controls 7191

7.7

(0)

(216)

(0.2)

patient 3183

7.1

(0) (253)

(1.5)

0.60

0

2

4

a

BOUND

a

6 (fmol/l

0’

10

12

14

CELLS)

80-

60-

2o

b

IC,,

Ml)

10.1

(1.1)

DEXAMETHASONE

(nM)

Figure 1. (a) Glucocorticoid receptors in mononuclear leukocytes of the patient (0) in comparison with controls (0). Numbers within parentheses represent SEM of four determinations in the patient and of the results obtained in 18 normal control individuals. (b) The inhibition by dexamethasone of mitogen-stimulated incorporation of [3H]thymidine into mononuclear leukocytes in the patient (0) in comparison with that in nine control subjects (mean f SEM). The study was performed twice in the patient.

levels 3 weeks after its start. Eventually there was some “adaptation,” during which these hormone levels did not further increase, with the exception of the serum testosterone concentrations. All hormone levels returned to pretreatment normal values 4 months after cessation of RU486 therapy.

200

??

Discussion

Glucocotiicoid Humans

Receptor Resistance in

Primary (partial) glucocorticoid receptor resistance in humans is a familial disease characterized by increased serum cortisol concentrations, a normal cir-

01992, Elsevier Science Publishing Co., 1043-2760/92/$5.00

cadian pattern of ACTH and cortisol set at a higher level, resistance to adrenal suppression by dexamethasone, and absence of the clinical signs and symptoms of Cushing’s syndrome (Chrousos et al. 1982). In its severe form, hypertension and hypokalemic alkalosis are present, secondary to an increased secretion of mineralocorticoids (Vingerhoeds et al. 1976). In women with glucocorticoid receptor resistance, the secondary overproduction of adrenal androgens results in acne, hirsutism, and irregular menstruation (Lamberts et al. 1986; see Figure 2). The disease has been considered to be extremely rare, and until recently only a total of seven symptomatic patients and 14 asymptomatic family members had been described. We reported on five further symptomatic patients with primary glucocorticoid receptor resistance with a wide variety in their clinical presentation (Lamberts et al. 1992a). After our first patient (case l), three additional young female patients were discovered who presented with hirsutism, acne, and/or irregular menstruation together with an abnormal response to 1 mg dexamethasone. Their increased adrenal androgen production was effectively suppressed by chronic treatment with low doses of dexamethasone (varying between 1 and 1.5 mg/day). There was an impressive clinical improvement with regard to hirsutism, while acne disappeared and menstruation normalized. The number of glucocorticoid receptors in these three additional patients decreased (in two) or the receptor showed a decreased affinity to dexamethasone (in one). Glucocorticoids are the oldest medical therapy for idiopathic hirsutism. They decrease hair growth in 30%50% of hirsute women, while reducing androgen levels (Perloff et al. 1957). Our observations suggest that among the group of women presenting with hirsutism, there is a subgroup of as yet unidentified size, which has increased adrenal androgen production secondary to partial cortisol resistance, recognizable by an insufficient suppression of cortisol in the overnight 1-mg dexamethasone test. The clinical signs and symptoms pointing to glucocorticoid receptor resistance in males are quite different. Increased adrenal androgen production only moderately adds to the high circulating tes-

TEM Vol. 3, No. 6, 1992

intact at

a

ity of mitogen-stimulated thymidine incorporation in his cultured leukocytes (Lamberts et al. 1992a). Recent indications have been that the altered properties of the glucocorticoid receptors in these patients have a genetic basis. For example, the defect in the original male Dutch patient described by Vingerhoeds et al. (1976) turned out to be a point mutation causing a single amino acid substitution in the hormone-binding domain of the glucocorticoid receptor (Hurley et al. 1991).

diurnal

rhythm

reset higher

hypothalamus

4

7 (?)

CRH

/

“decreased feedback effects”

pituitary

gland

cv+-

RlJ486 dImInIshed sensltlvtty to dexamethasone

I ;

cortlsol

-

‘T

-q--

adrenal androgens

no

peripheral

of

hypercortlsollsm

only

t

In

effects

women:

hlrsutlsm.

acne.

Irregular

menstruations -

+

adrenal T

mlneralocortlcoids

2. Schematic representation giucocorticoid receptor resistance.

Figure

-

hypokalemia hypertension

of the biochemical

of

and clinical consequences

The steroid RU486 (mifepristone) is an antiprogestagen that can interrupt pregnancy very early on by interfering with the process of implantation and decidual function. It also may facilitate surgical evacuation of the uterus and certain difficult deliveries that would otherwise end in cesarean section (Baulieu 1989). Apart from being a very potent progesterone receptor antagonist with little agonist activity, RU486 at higher concentrations also blocks glucocorticoid receptor activity (Moguilewsky et al. 1982). This unique combination of actions of the drug allows its use outside the field of fertility regulation. RU486 and Breast Cancer

tosterone

levels of testicular

origin

in

these patients, making the compensatory increase in mineralocorticoid production the diagnostic key. Indeed, all three symptomatic men described so far presented with hypertension and/or hypokalemia (Vingerhoeds et al. 1976; Lamberts et al. 1992a). Inappropriately elevated adrenal androgens had caused isosexual precocity in one boy, however (Malchoff et al. 1990).

Apart from a decreased number of glucocorticoid receptors or a decreased affinity of the receptors for dexamethasone, abnormal thermolability of the receptor has also been described in one patient (Br&meg&-d et al. 1986), and we described a male patient with cortisol resistance with normal numbers as well as a normal affinity of his glucocorticoid receptors in the whole cell assay, but a significant decrease in the suppressibil-

Therapy with progestins like medroxyprogesterone or megestrol acetate has previously been shown to be successful in the palliative treatment of some patients with metastatic breast cancer. At high concentrations, these drugs act as progesterone receptor antagonists, causing temporary blockage of further tumor growth. RU486 was shown to be very effective in inducing tumor growth inhibition in several animal models with

Table 1. The course of adrenocortical steroid and estradiol levels before, during, and after RU466 (200 mg/day) therapy for 12 months of a 64-year-old woman with a parasellar meningloma (normal values are given between parentheses)

Cortisol(200-3 80 nmol/L) Deoxycortisol (
TEM Vol. 3, No. 6, 1992

Before therupy

3

6

4

8

I2

weeks

weeks

months

months

months

3 months car therupy

371 25 6.3 6.1 16.3 1.1 87

1079 123 17.8 7.6 66.6 1.8 233

934 87 11.3 32.1 2.3 216

657 98 12.6 9.1 37.1 2.0 -

758 39 17.9 6.5 41.3 2.4 132

889 102 2.6 154

238 77 7.3 7.6 12.6 0.5 51

(sulfate).

01992,

Elsevier Science Publishing Co., 1043-2760/92/$5.00

201

(transplantable) progesterone receptorpositive breast and pituitary tumors (Lamberts et al. 1985a; Bakker et al. 1987). Studies in vitro with a variety of cultured tumor cells indeed showed that the antiproliferative effects of RU486 were mainly mediated by its progesterone receptor-blocking effects (Bardon et al. 1985; Lamberts et al. 1987). These experimental observations resulted in high expectations with regard to the potential use of RU486 in the treatment of women with metastatic progesterone receptor-positive breast cancer. In an initial study, 22 unselected patients with metastatic breast cancer were treated for 3 months with 200 mg RU486 per day: tumor growth was stabilized temporarily in about one-third of the patients (Romieu et al. 1987). In a subsequent study, Klijn et al. (1989) treated 11 postmenopausal patients with metastatic breast cancer with 2OwOO mg RU486 for a period of 3-34 weeks. Objective tumor shrinkage was seen in one, a short and transient period of stable disease was seen in six, and progressive tumor growth occurred in the other four patients. It was especially striking in this study that the period of stable disease during RU486 treatment was rather short. Endocrine studies carried out in these patients provided an explanation for this unusual clinical observation. Chronic therapy with RU486 caused, presumably via its glucocorticoid receptor-blocking activity, an increase in circulating ACTH and cortisol levels, and eventually also of serum androstenedione concentrations. After several weeks of RU486 therapy, circulating estradiol levels increased in all of these postmenopausal patients, reaching levels as high as in the early proliferative phase of the normal cycle. This increase in estradiol was probably a result of peripheral aromatization of the excess androstenedione. On the basis of these data, the initial growth-inhibitory actions of RU486 might have been counteracted by growth-stimulatory effects of the increased levels of estradiol. These rather unexpected observations seem to allow the preliminary conclusion that RU486, despite its promising anticancer effects in experimental conditions, cannot be used as a single therapy in the treatment of breast cancer. Future clinical trials with RU486

202

should only be carried out in combination with an antiestrogen. RU486 and Meningiomas Meningiomas are common brain tumors, originating from the leptomeninx. They occur at least three times more often in women than in men, and many clinical observations suggest an increased growth rate of meningiomas during pregnancy (Bickerstaff et al. 1958). Virtually all meningiomas obtained, from both female and male patients, contain high numbers of high-affinity progesterone receptors (Magdelenat et al. 1982; Blankenstein et al. 1983). Surprisingly, and in contrast to all other previously studied normal and tumor tissues, the presence of progesterone receptors in meningioma tissue is not accompanied by that of functional estradiol receptors. Both in vivo studies with transplanted human meningioma tissue in nude mice and in vitro studies with meningioma cells gave

MENINGIOMAS

OCCUR AT LEAST

THREE TIMES MORE OFTEN IN WOMEN THAN/N MEN.

initially mixed and contradictory results with regard to the role of progesterone and the potential use of RU486 in the regulation of tumor growth (Olson et al. 1987; Blankenstein et al. 1989). Our own studies showed that progesterone probably plays a permissive role in the regulation of the growth of meningioma cells, making the tumor cells more sensitive to the mitogenic effects of growth factors like epidermal growth factor and IGF-I. Interestingly, these mitosis-inducing effects could be blocked effectively in most tumors by the addition of RU486 to the culture medium (Koper et al. 1990). These in vitro observations of a direct antiproliferative effect of RU486 on cultured meningioma cells formed the basis for a clinical trial with the drug in patients with meningiomas (Lamberts et al. 1992b). Surgery is the treatment of choice in meningiomas: especially those tumors localized on the surface of the brain can be completely removed in most cases. However, meningiomas localized parasellarly, around the base of the skull or near the optic nerves, are much more difficult to remove, and

recurrences are frequently observed (Mirimanoff et al. 1985). We treated 10 patients with 12 recurrent or as yet untreated meningiomas for 12 months with 200 mg RU486 per day. All patients had been selected because their tumors had shown evidence of recent growth, while their localization did not allow complete surgical removal. Computed tomographic (CT) analysis of tumor size before, during, and after 12 months of RU486 therapy showed progressive growth in five meningioma patients, unchanged size in three tumor patients, and shrinkage in four tumor patients. In five patients, a subjective increase in well-being was observed, with a disappearance of headaches. Similar observations were made in two other studies involving 14 and two meningioma patients, respectively (Grunberg et al. 1991; Haak et al. 1990). All meningioma patients complained during the first days or weeks of RU486 therapy (200 mg/day) of nausea, vomiting, anorexia, and tiredness. Blood pressure remained constant. A transient increase in numbers of peripheral eosinophils was noted. In four patients, the subjective complaints increased to such an extent that prednisone (7.5 mgiday) was given in addition to RU486. This immediately alleviated all complaints, supporting the concept that these patients had transient (relative) adrenal insufficiency secondary to RU486-mediated glucocorticoid receptor blockade. Indeed, in retrospect, serum cortisol levels and urinary cortisol excretion had increased more rapidly in these four patients after the start of RU486 therapy than in the others (Lamberts et al. 199 1). RU486 administration to normal individuals activates the hypothalamopituitary-adrenal axis (Gaillard et al. 1984). In our meningioma patients, chronic RU486 therapy resulted in resetting of this system at a higher level, at which the diurnal variation of ACTH and cortisol remained intact. The system could still be normally stimulated by corticotropin- releasing hormone (CRH), but with a loss of the inhibitory feedback effects of a low dose (1 mg) of dexamethasone. The increased ACTH secretion resulted secondarily in increased adrenal androgen levels, as well as increased estradiol levels (>200 pmol/L) as observed previously in postmenopausal women with breast cancer. The estradiol

01992, Elsevier Science Publishing Co., 1043-2760/92/$5.00

TEA4 Vol. 3, No. 6, 1992

arose from peripheral aromatization of androstenedione, as evidenced by the close correlation between these levels in our patients (Lamberts et al. 1991). The similarity in these endocrine changes (see case 2) to those observed in the patient with primary glucocorticoidreceptor resistance (case 1) is clear. These observations also raise the question of safety of (chronic) use of RU486. The observed side effects of nausea, vomiting, anorexia, and tiredness, together with eosinophilia and the instant improvement after the simultaneous administration of low doses of prednisone, suggest that RU486 causes (relative) adrenal insufficiency in the presence of high circulating cortisol levels in most patients. A lowering of blood pressure is probably prevented by the simultaneous increase in mineralocorticoid production secondary to the RU486-mediated increase in ACTH secretion. This combination of events might also be the reason why the single oral administration of 600 mg RU486 for induction of abortion is safe, even in the few patients who experienced concurrent severe vaginal blood loss (Baulieu 1989). No lowering of blood pressure was observed in most studies. The place of medical therapy of surgically nonremovable and/or recurrent meningiomas with RU486 is not yet clear. As most meningiomas contain large numbers of progesterone receptors without functional estrogen receptors, chronic therapy with RU486 can be used safely without taking into account the secondary increase in estradiol levels. These might be even of clinical subjective benefit in postmenopausal women. The studies on RU486 treatment of meningioma patients published until now (Grunberg et al. 1991; Haak et al. 1990; Lamberts et al. 1992b) suffer from methodologic shortcomings that make them only “observational” ones. Apart from the small number of patients studied, the size, location, and duration of existence of the tumors varied considerably, while no data were available with regard to the

CRH WA)

0

1

1

1

1

1

DEX

0

0

10

10

10

10

0

0

0

10

100

1000

RU466

(nM) (IBM)

3. The effect of preincubation for 72 h with dexamethasone and RU486 on CR&stimulated ACTH release by cultured normal rat pituitary cells (n = 4; mean + SEM). CRH, corticotropin-releasing hormone; and DEX, dexamethasone.

Figure

and number of progesterone receptors in meningiomas in relation to their radiologic CT appearance (Huisman et al. 1991). Progesterone receptors were present in 16 of 21 meningiomas studied. A negative correlation was found between the number of progesterone receptors and “malignant” aspects of the tumors at CT (for example, the presence of necrosis, cyst formation, intratumoral hemorrhages, irregular surface, and/or heterogeneous attenuation of contrast). This suggests that especially the most “aggressive” meningiomas have relatively few or no progesterone receptors, making these tumors less attractive candidates for medical therapy with antiprogestins.

The Glucocorticoid Effects of RU486

Receptor-Blocking

The glucocorticoid receptor-blocking effects of RU486 can also be used in the therapy of different hypercortisolic states. In Figure 3, the direct interrelationship between the effects of dexa-

presence of progesterone receptors on these meningiomas. Most importantly,

methasone and RU486 on the pituitary gland are shown: increasing concentra-

there was no placebo group in this study, which makes definite conclusions with regard to potential beneficial effects attributed to RU486 at present uncertain. To try to predict which patients might benefit most, we studied the presence

tions of RU486 overcame the dexamethasone-induced inhibition of CRHstimulated ACTH release by cultured rat and human pituitary cells in a dosedependent manner (Lamberts et al. 1985a and b).

TEM Vol. 3, No. 6, 1992

01992,

Elsevier Science Publishing Co., 1043-2760/92/$5.00

In the clinical setting, chronic with RU486

mg/kg.day)

indeed

was shown to block effectively

the bio-

logic effects

(5-22

therapy

of hypercortisolism

tients with different syndrome

in pa-

forms of Cushing’s

(Nieman et al. 1985; Bertagna

et al. 1986). Both in patients with ectopic ACTH

secretion

and

adrenal

tumors,

clinical

conditions

tory increase

in patients

RU486

with

improved

the

without a compensa-

in ACTH and/or cortisol

secretion (Nieman et al. 1985; Bertagna et al. 1986). We especially considered the rapid disappearance within 24-72 administration Cushing’s

of acute psychosis

h after the start of RU486 in several patients

syndrome

caused

with

by adrenal

cancer and ectopic ACTH secretion major der

therapeutic

Lely

psychotic

as a

improvement

et al.

1991),

reactions

(Van

because

these

are very difficult

to

n-eat effectively otherwise (Haskett 1985). A major much

remaining

RU486

long. Excessive ceptors

will

problem

should

blockade

of cortisol

be eventually

because

of signs

nausea,

vomiting,

and

patient

therapy

ing’s syndrome

with RU486

like

and tiredof eosino-

in the circulation. of patients

re-

recognized

symptoms

anorexia,

ness as well as a reappearance philic leukocytes

is how

be given for how

Out-

with Cushseems

un-

safe at this time.

203

??

Conclusions

The discovery and synthesis of RU486, the first progesterone receptor-blocking drug, is a fundamental breakthrough in pharrnacotherapy. Because of the emotional reactions that surround especially its use in the induction of abortion, RU486 has been called the most controversial drug of the nineties (Coles 1988). Apart from its application in breast cancer, meningioma, and hypercortisolism, the use of RU486 in endometriosis and ovarian tumors is also being investigated. In addition, local applicapermitting a circumscribed tions, antiglucocot-ticoid effect (glaucoma, healing wounds, and burns), are also under study (Baulieu 1989).

References Bakker GH, Setyono-Han B, Henkelman MS, et al.: 1987. Comparison of the actions of the antiprogestin mifepristone (RU486), the progestin megestrol acetate, the LHRH analog buserelin, and ovariectomy in treatment of rat mammary tumors. Cancer Treat Rep 71:1021-1027. Bardon S, Vignon F, Chalbos D, Rochefort H: 1985. RU486, a progestin and glucocorticoid antagonist inhibits the growth of breast cancer cells via the progesterone receptor. J Clin Endocrinol Metab 50:692697. Baulieu EE: 1989. RU-486 as an antiprogesterone steroid: from receptor to contragestion and beyond. JAMA 262:1808-1813. Bertagna X, Bertagna C, Laudat MH, Husson JM, Girard F, Luton JP: 1986. Pituitaryadrenal response to the antiglucocorticoid action of RU486 in Cushing’s syndrome. J Clin Endocrinol Metab 63:639-642. Bickerstaff ER, Small JM, Guest IA: 1958. The relapsing course of certain meningiomas in relation to pregnancy and menstruation. J Neurol Neurosurg Psychiatry 21:89-91. Blankenstein MA, Blaauw G, Lamberts SWJ, et al.: 1983. Presence of progesterone receptors and absence of oestrogen receptors in human intracranial meningioma cytosols. Eur J Cancer Clin Oncol 19:365-370. Blankenstein MA, Van ‘t Verlaat JW, Croughs RJM: 1989. Hormone dependency of meningiomas [Letter]. Lancet 1: 138 1. Briinnegard M, Werner S, Gustafsson J-A: 1986. Primary cortisol resistance associated with a thermolabile glucocorticoid receptor in a patient with fatigue as the only symptom. J Clin Invest 78: 1270-l 278. Chrousos GP, Vingerhoeds ACM, Brandon D, et al.: 1982. Primary cortisol resistance in 204

man: a glucocorticoid receptor-mediated disease. J Clin Invest 69:1261-1269. Coles P: 1988. French government approves abortion pill for commercial use. Nature 335:486-487. Gaillard R, Riondel A, Muller AF, Herrmann W, Baulieu EE: 1984. RU486: a steroid with 9 antiglucocorticosteroid activity that only disinhibits the human pituitary-adrenal system at a specific time of day. Proc Nat1 Acad Sci USA 81~3879-3884. Grunberg S, Weiss M, Spitz I, et al.: 1991. Treatment of unresectable meningiomas with the antiprogesterone agent mifeptistone. J Neurosurg 74:861-866. Haak HR, De Keizer RJ, Hagenouw-Taal JC, Van Seters AP, Vielvoye GJ, Van Dulken H: 1990. Successful mifepristone treatment of recurrent, inoperable meningioma. Lancet 1:124. Haskett R: 1985. Diagnostic categorization of psychiatric disturbance in Cushing’s syndrome. Am J Psychiatry 142:911-916. Huisman TWA, Tanghe HLJ, Koper Jw, et al.: 199 1. Progesterone, estradiol, somatostatin and epidermal growth factor receptors on human meningiomas and their CT characteristics. Eur J Cancer 27:1453-1457. Hurley DM, Accili D, Stratakis A, et al.: 1991. Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance. J Clin Invest 87:680-686. Klijn JGM, De Jong FH, Bakker GH, Rodenburg CJ, Alexieva-Figusch J: 1989. Antiprogestins, a new form of endocrine therapy for human breast cancer. Cancer Res 49:2851-2856. Koper JW, Foekens JA, Braakman R, Lamberts SWJ: 1990. Effects of progesterone on the response to epidermal growth factor and other growth factors in cultured human meningioma cells. Cancer Res SO:2604 2607. Lamberts SWJ, Uitterlinden P, Bons EG, Verleun T: 1985a. Comparison of the actions of RU38486 and megestrol acetate in the model of a transplantable adrenocorticotropin- and prolactin-secreting rat pituitary tumor. Cancer Res 45:1015-1019. Lamberts SWJ, Bons EG, Uitterlinden P: 1985b. Studies on the glucocorticoidreceptor blocking action of RU38486 in cultured ACTH-secreting human pituitary tumour cells and normal rat pituitary cells. Acta Endocrinol (Copenh) 108:64-69. Lamberts SWJ, Poldermans D, Zweens M, De Jong FH: 1986. Familial cortisol resistance: differential diagnostic and therapeutic aspects. J Clin Endocrinol Metab 63:13281333. Lamberts SWJ, Van Koetsveld P, Verleun T:

01992,

Elsevier Science Publishing Co., 1043-2760/92/$5.00

1987. Prolactin release-inhibitory effects of progesterone, megestrol acetate, and mifepristone (RU38486) by cultured rat pituitary tumor cells. Cancer Res 47~3667-3671. Lamberts SWJ, Koper JW, De Jong FH: 199 1. The endocrine effects of long-term treatment with mifepristone (RU486). J Clin Endocrinol Metab 73:187-191. Lamberts SWJ, Koper Jw, Biemond P, Den Holder FH, De Jong FH: 1992a. Cortisol receptor resistance: the variability of its clinical presentation and response to treatment. J Clin Endocr Metab 74:3 13-32 1. Lamberts SWJ, Tanghe HLJ, Avezaat CJJ, et al.: 1992b. Mifeptistone (RU486) treatment of meningiomas. J Neurol Neurosurg Psychiatry (in press). Magdelenat H, Pertuiset BF, Poisson M, et al.: 1982. Progestin and oestrogen receptors in meningiomas: biochemical characterization, clinical and pathological correlations in 42 cases. Acta Neurochir (Wien) 64: 199-2 13. Malchoff CD, Javier EC, Malchoff DM, et al.: 1990. Primary cortisol resistance presenting as isosexual precocity. J Clin Endocrinol Metab 70:503-507. Mirimanoff RO, Dosoretz DE, Longgood RM, Ojeman RG, Martuza RL: 1985. Meningioma: analysis of recurrence and progression following neurosurgical resection. J Neurosurg 62: 18-24. Moguilewsky M, Deraedt R, Teutsch G, Philibert D: 1982. RU38486: an antiglucocorticoid with a new mechanism of antihormonal therapy [abst]. J Steroid Biothem 17:68. Nieman LK, Chrousos GP, Kellner C, et al.: 1985. Successful treatment of Cushing’s syndrome with the glucocorticoid antagonist RU486. J Clin Endocrinol Metab 61:536540. Olson JJ, Beck DW, Schlechte JA, Lob PM: 1987. Effect of the antiprogesterone RU38486 on meningioma implanted into nude mice. J Neurosurg 66:584-587. Perloff WH, Hadd HE, Channick BJ, Nodine EH: 1957. Hirsutism. Arch Intern Med 100:981-992. Romieu G, Maudelonde T, Ulmann A, et al.: 1987. The antiprogestin RU486 in advanced breast cancer: preliminary clinical trial. Bull Cancer (Paris) 74:455-461. Van der Lely AJ, Foeken K, Van der Mast RC, Lamberts SWJ: 1991. Rapid reversal of acute psychosis with the cortisol receptor blocking agent RU486 (mifepristone) in two patients with the Cushing syndrome caused by metastatic adrenal cancer. Ann Intern Med 114:143-144. Vingerhoeds ACM, Thijssen JHH, Schwartz FJ: 1976. Spontaneous hypercortisolism without Cushing’s syndrome. J Clin EndoTEM crinol Metab 43:1128-l 133. TEM Vol. 3, No. 6, 1992