Clinical Endocrinology (1978) 9,389-399.

E N D O C R I N E E F F E C T S O F S P I R O N O L A C T O N E IN MAN

M . J . T I D D , C. E. H O R T H , L. E. RAMSAY, J. R. SHELTON A N D R. F . PALMER Research and Development Division, G. D. Searle & Co. Ltd., Lane End Road, High Wycombe, Bucks (Received 17 November 1977; revised 31 Jonuory I 9 78: revised 7 April 19 78;accepted 20 April 19 78)

SUMMARY

A double blind, controlled study was carried out in order to investigate the effects of administering spironolactone, 200 mg daily, to five healthy male volunteers. The patterns of change in plasma testosterone (T) and luteinizing hormone (LH) after spironolactone were significantly different from placebo and there were significant increases in the urinary excretion of androsterone (A), aetiocholanolone (EC) and total oestrogen. Urinary dehydroepiandrosterone (DHA) excretion, after an initial rise, declined progressively during the treatment period relative to controls. The results are discussed in the light of previous observations. It is concluded that treatment with spironolactone for 2-4 days will lead to a transient rise in plasma T and urinary DHA. Continued treatment (4-10 days) is thought to cause increased LH secretion, with normalization of plasma T and DHA excretion. These changes are accompanied by increased androgen catabolism and a slightly increased conversion of androgens t o oestrogens. Healthy men may therefore show alterations in sex steroid metabolism if treated for several days with high doses of spironolactone. Spironolactone, (SC-9420) (7a-acetylthio-l7~-hydroxy-3-oxo-l7a-pregn-4-ene-2 1-carboxylic acid-y-lactone) is an antagonist of aldosterone and other mineralocorticoids (Kagawa, 1960). Reports have appeared associating its use in the management of hypertension and the oedema of cardiac, renal and hepatic disorders with the occasional occurrence of gynaecomastia (Smith, 1962; Mann, 1963; Sussman, 1963; Williams, 1962; Clark, 1965) and loss of potency in men and menstrual irregularity, amenorrhoea, breast engorgement and chloasma in women (Greenblatt & Koch-Weser, 1973; Spark & Melby, 1968; Levitt, 1970). Gynaecomastia can develop within one month(Clark, 1965; Oleson & SandQe, 1962). The side-effects regress on withdrawal of the drug (Smith, 1962; Sussman, 1963;Clark, 1965; Levitt, 1970; Greenblatt & Koch-Weser, 1973). The mechanism by which spironolactone may produce these effects is not understood Correspondence: C. E. Horth, Metabolic Studies Dept, G . D. Searle & C o . Ltd., Lane End Road, High Wycombe, Bucks HP12 4HL. 0300-0664/78/1100-0389$02.00 01978 Blackwell Scientific Publications

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although it is known that the compound possesses activities other than mineralocorticoid antagonism. It has weak progestational activity (Hertz & Tullner, 1958) and is anti-androgenic in some animal tests (Jones & Woodbury, 1964; Hamrick e f al., 1973; Steelman et al., 1969; Basinger & Gittes, 1974; Rasmussen er d.,1972), and in man as demonstrated by its effect in benign prostatic hyperplasia (Castro et al., 1971). There have been few systematic laboratory investigations into the endocrine effects of spironolactone in man. This study was designed to investigate the effects of 10 days of spironolactone administration on plasma testosterone, luteinizing hormone, follicle stimulating hormone and oestradiol-170and on the urinary excretion of fractionated 17-oxosteroids, gonadotrophins and total oestrogens. MATERIALS AND METHODS

Clinical Ten healthy male subjects aged 18-31 years were admitted to the study after medical history and physical examination. Alcohol and medication were forbidden throughout the study. Five subjects were randomly assigned to placebo treatment and five to spironolactone treatment. On days 1 to 5 and days 16 to 23, all subjects received placebo medication in the form of 2 X 25 mg placebo spironolactone tablets at 10.00, 14.00., 18.00 and 22.00. On the intervening days (6 to 15) the treated group received spironolactone (200 mg per day) and the control group continued on placebos. Treatments were given double blind. At approximately 09.00 on each week day, prior to taking the first dose of the day, venous blood samples were taken with minimal stasis into blood tubes containing lithium heparin which were then centrifuged. The plasma was separated within 1 h after collection. Urine samples were collected for each successive 24 h period starting at 09.00 each day. All samples were stored at -20°C until analysed. Biochemical Plasma testosterone (T) was measured by radioimmunoassay (Williams et al., 1974). Significant interference in this assay by canrenone, (SC-9376) (17P-hydroxy-3-oxo-17a-pregn4, 6-diene-21-carboxylic acid-y-lactone), the principal plasma metabolite of spironolactone was excluded in a separate investigation. Plasma oestradiol (E,) was extracted with dichloromethane and measured by radioimmunoassay using an antiserum specific for oestradiol-170 (Wilson et al., 1974). The luteinizing hormone (LH) radioimmunoassays were carried out using an antiserum raised in rabbits to human chorionic gonadotrophin by a modification of the method of Midgley (1 966) and Stevens (1 969). The plasma LH standard was calibrated against the M.R.C. pituitary LH preparation 68/40. The standard used for urinary LH assays was the 2nd International Reference Preparation of Human Menopausal Gonadotrophin. This same preparation was used as a standard for the plasma and urinary follicle stimulating hormone (FSH) radioimmunoassays (Stevens, 1969) using antiserum raised against purified human pituitary FSH in rabbits and preabsorbed with HCG (Odell et al., 1969). Urine for LH and FSH assays was extracted by the double ethanolic precipitation procedure (Raiti & Blizzard, 1968). Urinary total oestrogen was quantitated by the method of Brown et al., (1968). Significant interference in this assay by potassium canrenoate (SC-14266) (potassium 170-hydroxy-3-0x0-17a-pregn-4,6-diene-21-carboxylate), the water soluble hydrolysed form of canrenone, was excluded in a separate investigation. The 17-oxosteroids (17-0s) dehydroepiandrosterone (DHA), androsterone (A) and aetio-

(5) (5) (5) (1) (5) (5) 0.32 3.60 2.32 21.0 8.9 10.9

8.47 17.2 0.732 7.44 60.8 (10) (10) (10) (6) (10) (10)

(6) (5) (5) (2) (5) 0.22 3.19 2.07 27.7 6.6 11.2

(8) (8) (8) (2) (8) (8)

7.28 (5) 16.3 (4) 0.632 (4) 5.34 (4) 49.2 (3)

Mean

No. of Subjects

0.30 f 0.08 2.80 i 0.26 2.01 f 0.30 19.2 f 4.4 5.6 f. 1.0 13.2 i 1.4

7.72 f 0.47 4.5 f 0.8 0.625 i 0.076 3.89 f 0.34 48.8 f 2.5

(5) (5) (5) (1) (5) (5)

(4) (4) (4) (2) (2)

Mean f SEM

0.20 2.93 1.92 37.1 7.5 12.4

7.99 3.9 0.572 3.50 51.1

(10) (10) (10) (6) (10) (10)

(2) (5)

(5)

(6) (5)

Mean

During

0.18 3.00 1.96 15.3

8.37 4.6 0.624 3.71 52.1

(2)

(8)

(8) (8)

(5) (4) (4) (4) (3)

Mean

After

0

2._

.;

Endocrine effects of spironolactone in man.

Clinical Endocrinology (1978) 9,389-399. E N D O C R I N E E F F E C T S O F S P I R O N O L A C T O N E IN MAN M . J . T I D D , C. E. H O R T H ,...
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