Chlormadinone Acetate As a Possible Effective Agent for Congenital Adrenal Hyperplasia to Suppress Elevated ACTH and Antagonize Masculinization

Endocrine Journal 1995, 42(4), 505-508

Chlormadinone Acetate as a Possible Effective Agent for Congenital Adrenal Hyperplasia to Suppress Elevated ACTH and Antagonize Masculinization

YUKIo KAGEYAMA, SATOSHIKITAHARA, TETSUROTSUKAMOTO, TOsHIHIKOTSUJII, SYUITIGOTO ANDHIROYUKI OSHIMA

Department of Urology, Tokyo Medical and Dental University School of Medicine, Tokyo 113, Japan

Abstract. We report two cases of congenital adrenal hyperplasia (CAH) in which administration of chlormadinone acetate (CMA), a substituted progestational agent for prostatic disease, suppressed ACTH hypersecretion and lowered plasma testosterone levels. Case 1 was 83-year-old male with advanced prostatic carcinoma and CAH due to 21-hydroxylase deficiency. His plasma testosterone did not decrease in spite of a bilateral orchiectomy. Case 2 was 40-year-old female with CAH due to 21- hydroxylase deficiency suffering from virilization after the cessation of cortisol supplement therapy because of her breast carcinoma. In these two cases, 'ral administration of CMA at a daily dose of 75- 100 mg suppressed ACTH and cortisol to subnormal levels and reduced testosterone levels. With the suppressive effect on ACTH excess and antiandrogenic action, CMA may be suitable for patients with CAH suffering from symptoms due to overproduced ACTH or adrenal androgen.

Key words: Chlormadinone acetate , Congenital adrenal hyperplasia, ACTH suppression (Endocrine Journal 42: 505-508,1995)

CHLORMADINONE acetate (17u-acetoxy-6-chlo- adrenal hyperplasia (CAH). Chlormadinone ace- ro-4,6-pregnadiene-3,20-dione; CMA), a substituted tate, administered for the prostatic carcinoma, progestational agent, has been used in the treat- suppressed hypersecretion of ACTH and lowered ment of benign prostatic hyperplasia (BPH) and plasma testosterone levels. With this experience prostatic carcinoma because of its anti-androgenic in mind, we administered CMA to a female pa- properties. In animal experiments, CMA has been tient with CAH suffering from virilization and reported to have suppressive effects on hypothala- general skin pigmentation after the cessation of cor- mo-pituitary-adrenal axis at high doses [1-4]. No tisol supplement therapy because of her breast remarkable change in adrenal function has how- carcinoma. CMA again suppressed ACTH hyper- ever been recognized during the treatment of secretion and improved her condition. We patients with prostatic disease with CMA. described these two cases and suggest that CMA A male patient with advanced prostatic carcino- may be a suitable drug for patients with CAH suf- ma, whose plasma testosterone did not decrease in fering from symptoms caused by oversecreted spite of bilateral orchiectomy, underwent hormon- adrenal androgen. al evaluation and was found to have congenital

Determination of Hormonal Values Received: December 8, 1993 Accepted: April 5, 1995 Correspondence to: Dr. Yukio KAGEYAMA, Department Levels of plasma ACTH, plasma cortisol, serum of Urology, Tokyo Medical and Dental University, 1-5-45, dehydroepiandrosterone sulfate (DHEA-S), serum Yushima, Bunkyo-ku, Tokyo 113, Japan 17c -hydroxyprogesterone (17a-OHP), plasma al- 506 KAGEYAMA et al. dosterone, plasma renin activity, serum LH, serum FSH and plasma testosterone were determined by Patients radio immunoassay at Mitsubishi Yuka Bioclinical Laboratory (Tokyo). ACTH, cortisol and some oth- Case 1 er hormones were measured at least twice, on different occasions, to determine their values be- An 83-year-old male visited our clinic complain- fore and after CMA administration. ing of nocturnal urinary frequency. He had no Antibodies and kits used to determine hormon- offspring and one of his sisters had been suspect- al values were as follows: anti-ACTH monoclonal ed to have had hermaphroditism although the antibody and ACTH-I IRMA kit (Mitsubishi Yuka) precise clinical data was not available. He was for plasma ACTH; anti-hydrocortisone rabbit se- 153 cm tall, weighed 51 kg and had mild skin pig- rum and gammacoat cortisol (Baxter) for cortisol; mentation even at sites covered by clothes. Except anti-DHEA-S-Succ-BSA (rabbit) for DHEA-S; anti for the above, no obvious symptoms were recog- 17a-OHP antibody (rabbit) and DPC 17a-OHP kit nized. A standard urological examination and a for 17a-OHP; anti-aldosterone rabbit antibody and biopsy of the prostate determined our diagnosis of aldosterone RIA kit (Dynabott) for aldosterone, advanced prostatic carcinoma. Despite a bilateral anti-angiotensin antibody and renir~ RIA beads orchiectomy as a hormonal tharapy, the patient's (Dynabott) for plasma renin activity; anti-LH mon- prostatic carcinoma continued to progress and the oclonal antibody and Spac-S LH kit (Dai-ichi RI) level of his plasma testosterone remained un- for LH; and anti-testosterone antibody (rabbit) and changed. In addition, his plasma ACTH and serum DPC total testosterone kit for testosterone. DHEA-S were extremely high while his plasma cortisol levels were within normal limits (Table 1). The patient's plasma testosterone levels remained at non-castration levels in spite of serum LH being at the lower limit of the normal range for his advanced age. His blood pressure was 148/78 mmHg

Table 1. Basal levels of hormones and electrolytes in two cases of CAH without glucocorticoid supplement therapy and the effects of CMA (100 mg/day for 4 weeks) on hormones SUPPRESSION OF ACTH BY CHLORMADINONE ACETATE IN CAH 507 in the morning and bilaterally enlarged adrenal symptoms suggesting a salt loosing tendency. The glands were diagnosed from CT scans (Fig. 1). patient had received no previous treatment for From these clinical and endocrinological results, a CAH, and oral administration of CMA at the daily diagnosis of CAH due to steroid 21 hydroxylase dose of 100 mg was started as an anti-androgen deficiency was established. Although the data for therapy for prostatic carcinoma, which resulted in the accumulation of 17a-OHP or its metabolites a marked improvement of the patient's condition. was absent, the patient's electrolytes were within Initially, the improvement was regarded as the anti- normal limits and he had not experienced any androgenic activity of the agent, but the plasma levels of testosterone were also found to decrease to castration levels. The plasma ACTH and cortisol levels also decreased to subnormal ranges while the plasma aldosterone levels remained within normal limits (Table 1). The suppression of ACTH has been maintained since the initiation of CMA administration (Table 2) and the patient's prostate cancer has been managed well without progres- sion. There has been no signs or symptoms suggesting adrenal insufficiency during the entire period.

Case 2

Patient 2 was a 40-year-old female. She was 144 cm tall and weighed 44.5 kg. At the age of 13 all of her siblings including herself were diagnosed as having CAH due to steroid 21-hydroxylase deficiency on the basis of virilization and the elevated excretion of pregnanetriol in the urine. At that time, she underwent plastic repair of the external genitalia and received glucocorticoid supplement therapy with a daily dose of 0.5 mg dexametha- sone until the age of 38, when she was found to have breast carcinoma. Following cessation of the supplement therapy, her plasma ACTH level was elevated but her plasma cortisol levels were within normal limits (Table 1), after a while she began suffering from acne and general pigmentation of Fig. 1. Abdominal CT scans in case 1. White arrows the skin. The oral administration of CMA at a indicate enlarged adrenal glands.

Table 2. Changes of plasma ACTH and serum cortisol after CMA administration 508 KAGEYAMA et al. daily dose of 100 mg suppressed the patient's plas- that CMA has a rather weak ability to exert a sup- ma ACTH and cortisol to subnormal levels and pressive effect on the hypothalamus, which results reduced her plasma testosterone levels (Table 1) in suppression of the elevated secretion of ACTH improving her condition. The ACTH suppression in the current CAH cases but has no significant and the patient's improved condition were main- effect on a normal hypothalamo-pituitary function. tained by a daily dose of 75 mg CMA without The assumption is consistent with previous find- adrenal insufficiency (Table 2). ings that no significant elevation of LH levels has been observed during the blocking of androgen action by CMA in the treatment of prostatic carci- Discussion noma [5]. The reason for the elevated levels of plasma aldosterone in our two patients is unclear, The current cases demonstrate that CMA is ca- but might be attributable to a mild salt loosing pable of suppressing elevated secretions of ACTH tendency resulting in secondary hyperaldoster- and reducing the production of adrenal androgens onism. After CMA administration, the elevated in patient's with CAH. plasma aldosterone level became normal in case 1 CMA, like other 17a-acetoxyprogesterones such but remained high in case 2. The difference might as medroxyprogesterone acetate or cyproterone reflect the degree of deficiency of 21-hydroxylase. acetate, has caused adrenal atrophy in experimen- The principle of the medical treatment of CAH tal animals at high doses [1-4]. Although the is to supply glucocorticoids to prevent manifesta- mechanism of adrenal suppression by CMA is un- tions of adrenal insufficiency and to suppress a clear, the structural similarity between CMA and hyperactive hypothalamo-pituitary function which corticosteroids leads us to the assumption that leads to overproduction of adrenal androgens. CMA has glucocorticoid-like effects and suppress- Cyproterone acetate has been administered to some es ACTH secretion by a negative feedback patients with CAH as an anti-androgenic agent to mechanism. Some of the 17a-acetoxyprogester- antagonize virilization by overproduced adrenal ones, including cortisol and CMA, have been androgens [6, 7]. The present results indicate that reported to cause thymus involution in rats [2], CMA is a suitable agent for antagonizing viriliza- suggesting a similarity in the pharmacological action due to CAH as an anti-androgen, as well as tion in part of CMA and cortisol. Since neither being an agent for suppressing the hyperactive ACTH suppression nor adrenal hypofunction has hypothalamo-pituitary axis. It is therefore, an agent been reported in patient's treated with CMA for suitable for patient's with CAH who need high prostatic diseases, the pituitary adrenal function doses of glucocorticoids to suppress overproduc- may not be suppressed to subnormal levels by tion of adrenal androgen. CMA in cases with a normal hypothalamo-pituitary-adrenal axis. Therefore, it appears most likely

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