British Journal of Dermatology (1991) 124, 361-364. ADONIS 000709639100084G Isotretinoin treatment alters steroid metabolism in women with acne M.RADKMAKER. M.WALLACE.* W.CUNLIFFEt AND N.B.SIMPSON Departments of Dermatologii and "Biochemistrii. Glasgow Roijal Inftrmarij. •^Department of Dermatology, Leeds General Infirmarij. l^eds. U.K. Glasgow Accepted for publication 1 October 1990 Summary The effect of isotretinoin (Roaccutane) on serum steroids and urinary steroid metabolites was investigated in seven female patients receiving the drug for treatment of severe acne over a 16-week period. Serum concentrations of deiiydroepiandrostcrone suiphate (DHAS). androstenedione (A2). and free androgen index (FAl) were not significantly altered. There was a significant fall in testosterone during treatment and a signiticant reduction in the 24 h urinary excretion of androsterone. tetrahydrocortisone (THE) and tetrahydrocortisol (THF) from week 8 onwards and for aetiocholanolone and allo-THF from week 12 (P<() 05). Although pretreatment levels of urinary steroid metabolites were not abnormal, the ratios of the 5a/5// metabolites (androsterone:aetiocholanolone and allo-THF:THF) were at the upper limit of the reference range and were lowered after treatment, suggesting that 5a-reductase activity is sensitive to isotretinoin. Tsotretinoin suppresses sebaceous gland activity by blocking the differentia lion of basal cells into sebocytes.' The exact mechanism is not known but because these glands are androgen-responsive the effects of isotretinoin on androgens have been investigated. A number of studies suggest that sebaceous gland inhibition is not hormonally related but may cause secondary changes in the activity of the skin steroid 5a-reductase.^ To obtain more information on the response of steroid Sa-reduction to treatment with isotretinoin we measured urinary steroid metabolites by capillary column gas liquid chromatography and serum androgen levels (testosterone, androstenedione (A2). and dehydroepiandrosterone sulphate (DHAS)) by radioimmunoassay during the course of 16 weeks of therapy with isotretinoin (Roaccutane). Methods Subjects Seven women, median age 26-7 years (range 18-44 years) with persistent acne that was non-responsive to antibiotics were studied. All were using barrier methods of contraception and had a normal menstrual pattern with regular cycles of between 21 and 35 days. There was no evidence of hirsutism, hair loss or virilism. Correspondence: Dr M.Rademaker. Department of Dennatology. Glasgow Royal Infirmary. (liasgow CA OSF. U.K. Pretreatment liver function and fasting serum lipids were normal and remained so during treatment. All seven women were given a 16-week course of isotretinoin (Roaccutane. Roche Products Ltd) at a dose of i mg/kg/body weight per day. The mean total acne grade' before starting was 3 5 (95% confidence interval, 0 3 6 6) with a mean facial gradeof 1 4 (01-2-7). Twentyfour-hour urine samples were collected Immediately before starting the drug and at 4-weekly intervals thereafter. Facial and total acne were also scored at monthly intervals.' Hormone analysis Sex hormone binding globulin (SHBG) was measured by time-resolved fluoroimmunoassay ('Delfia' SHBG kits. Pharmacia). Testosterone. DHAS and A2 were measured by conventional 'in house" radioimmunoassays. Derived free testosterone levels were calculated from the total testosterone and SHBG according to the method of Nanjee and Wheeler.'* Urinary steroid profiles analysis was performed by capillary column chromatography by a method similar to that of Bevan ct al.'' Separation of steroid methyloxime-trimethylsilyl ether derivatives was carried out on a model 438 gas chromatograph (PackerBecker BV. Delft. The Netherlands) fitted with a 'Flexsil' 2 5 mxO-52 mm capillary column coated with OV-1 (Phase-Sep. Queensferry. Clwyd). Measurements were made of the most abundant androgen metabolites 361 362 M.RADEMAKER et al common side-effects of isotretinoin (dry lips and eyes) but remained well throughout the treatment period and experienced no signiiicant alteration of their liver function tests or fasting serum lipids. Menstrual patterns did not change. The effects of isotretinoin treatment on serum androgens and SHBd concentrations are shown in Table 1. The mean baseline concentrations of testosterone. DHAS. and SHBG were normal while a modest elevation in A2 was observed (due to an abnormally high A2 level of 1 6 1 nmol/1 in one patient suspected of suffering from polycystic ovarian disease: others were all within the normal range 0-6-8-8 nmol/I). The mean androstenedione concentration fell during treatment: tbis fall was not significant and was largely due to normalization of serum A2 in the patient with an elevated pretreatment level. Over the 16-week treatment period tbere was a significant fall in serum testosterone at weeks 8 and 16 (P<0-05). (androsterone, aetiocholanoione) and glucocorticoid metabolites (telrahydrocortisone (THE), tetrahydrocortisol (THF). and allo-tetrahydrocortisol (allo-THF)). Ratios of 5a: 5/^ pairs (i.e. androsterone:aetiocholanoione and allo-THF:THF ratios) were calculated to provide an index of exogenous 5a-reductase activity. Statistics Results are presented as mean ± standard error of the mean (95% confidence interval). Statistical analyses were by the non-parametric tests of analysis of variance and by the Wilcoxon sign-rank test. Results Acne was virtually abolished in all patients by the end of the 4-month treatment period: the mean total acne score was 0-25 ( -O-O5-O-5) and the mean facial acne score was 0-07 (0()2-0-12). All patients experienced the Weeks Hormone (reference range) Baseline Testosterone ( 1 - 3 2 nmol/I) 1-9 ±0-3 l-7±O-2 I)ehydrt>epiandrosterone sulphate (2-11 |Umol/l) 7-4±l-8 Sex hormone binding globulin (30-120 nmol/n Androstenedione (nt»ol/l) (0-6-^8-8 nmol/1) 12 16 l-2±0-l' 1 5 ±0-2 l-3±01* 10-7 ±3-8 7-7±l-6 7-9 ±2-0 7-2±l-7 79±19 71±17 71±21 7O±21 71±2O 9 4±2 3 8 1 ±1-4 7-5±l-l 8-9±2 4 7-4±l-8 3-4±l-4 2-8 ±0-7 2-5±0-6 3-5 ±1-5 2-4±]l Table 1. Serum steroid concentrations (meaniSEM) of seven female patients with severe acne during a 16 week cour.se of isotrctinoin therapy (1 mg/kg/day). 'r<{)() compared with baseline Free androgen index Weeks Hormone (reference range) Baseline 12 16 Androsterone (!O29±457/(g) 1205±286 1090±226 596±12r 538±664' 664±194' Aetiocholanoione O335±525/ig) 7iO±l57 609 ±207* 74O±5O'' 1086±241 1175 ±288 Tetrabydrocortisone (THE) (1221±946/ig) 27O8±527 285S±759 I480±234' 1553±322 1587±292' Tetrahydroc-ortisol (THF) (16l7±525;jg) 1331 ±218 1298±246 778±161- 835±214 750±133" AIlo-Tetrahydrocortisol (allo-THF) (1008 ±491 ;ig) 1293 ±302 12}2±439 572 ±184 548 ±117" 450±10]- Table 2. Total 24 hour urinaty excretion of steroids (mean±SFAl. jUg/24 h) of seven female patients with severe acne during a 16-week course of isotretinoin therapy (1 mg/kg day). • p < 0 05 compared with baseline ISOTRETINOIN TREATMENT AND STEROID METABOLISM L2 1.1 1.0- S 0.8 • 0.7- 0.6 0.5-' 8 12 16 Week Figure 1. Ratio of 5a: 5^ urinary steroid metabolites (mean ± SEM) in .seven female patients with severe acne during a 16-week course of isotretinoin therapy U mg/kg/day) ( ' P < 0 - 0 5 from baseline). • . androsterone:aetiochoianolone; A, aUo-THF:THF. Total 24-hour excretion of the selected steroid metabolites are shown in Table 2: the baseline concentrations ofthe patients were within the expected limits for normal women. Over the study period, a marked reduction in urinary steroid metabolites was observed with significant falls of androsterone. THE and THF from week 8 onwards and aetiocholanolone and allo-THF from week 12 (P<nnO5). Baseline ratios of both androsterone: aetiocholanolone (M2±()-()9) and allo-THE:THF (0-89±0-n5) were at the upper limit of normal (normal mean values O-65±O2. range O - 3 5 - M 5 and ()-62±()2. range ( ) 2 - l - 0 . respectively). These high ratios fell significantly during treatment (Fig. 1). Discussion A number of studies suggest that sebaceous gland involution induced by isotretinoin is not androgenmediated. This conclusion is based on the lack of any dramatic effect of the drug on circulating precursor androgens. Lookingbill et al^ found that serum androgens testosterone. DHA and DHAS were not altered by treatment although an increase in free testosterone was found and Matsuoka et nl.^ found no change in circulating concentrations of cortisol. androstenedione. DHA and DHAS. Some of these findings are confirmed in this study where no significant change in DHAS. androstenedione and free androgen index occurred on treatment. 363 We did however find a small but significant fall in the serum level of testosterone. A more significant inhibitory effect was observed' on production of 5ci androgens (dihydrotestosterone and 3a-androstenediol glucuronide in women; 3a-androstenediol glucuronide in men) and this was thought to be due to the reduction in sii^e of the sebaceous gland. We have previously reported significant but small reductions in serum dihydrotestosterone in women on isotretinoin.' Whether or not isotretinoin has a direct effect on steroid 5a-reduction in vivo has. until now. been uncertain. In vitro studies of testosterone metabolism in hamster flank organ showed lack of inhibition of 5areductase by isotretinoin" but in female rats isotretinoin treatment caused a decrease in steroid Sa-reductase activity in both skin and liver.^ In cultured human prostatic cells 5a-reductase can be inhibited by retinoic acid through competitive inhibition of cofactor action (NADPH)'" yet in men circulating dihydrotestosterone is unchanged throughout isotretinoin therapy.In the present study marked reductions in the major androgen and glucocorticoid metabolites were found at the same time as decreased levels of 5a-reduction. 5areduction of androgens occurs in the peripheral tissues as well as the liver while glucocorticoids are mainly 5areduced in liver. It is therefore unlikely that these changes can be accounted for solely by drug-induced reduction in the size ofthe sebaceous gland and a direct effect on liver 5a-reduction is postulated. A clue as to how these aspects of steroid metabolism are related is given by recent reports on steroid metabolism in women with hirsutism and polycystic ovarian disease."'- In such patients it is postulated that increased 5a-reduction in the liver enhances hepatic cortisol metabolism and circulating cortisol concentrations are maintained within normal limits by increasing the secretion of corticotrophin which simulates adrenal production of both glucocorticoids and androgens. It may be that, by inhibiting 5a-reduction within the liver, isotretinoin reduces cortisol excretion, and thereby reduces corticotrophin secretion, the stimulus for adrenal steroid production. Alterations in steroid metabolism of a similar nature occur in patients suffering from acute intermittent porphyria but in this case 5a-reduction may be secondary to endogenous rather than exogenous factors.'^ Further work is required to verify and extend these findings. It is of course possible that the observed effects on steroid metabolism are related to the as yet unknown mechanism of action of retinoids in controlling cell differentiation. 364 M.RADEMAKER et al References 1 Landthaler M, Kummermehr J. Wagner A. Plewig G. Inhibitory effects of I i-(/.\ retinoic acid in human sebaceous glands. Arch Dermatol Res 19S(); 269: 297-^09. 2 Lookingbill DP. Hemers I,M. Tigelaar RE. Shalita AR. rJTect of isolretinoin on serum levels of precursor and peripherally derived androgens in patients with acne. Arch Dermatol 1988: 124: 540-J. 3 Burke BM. Cunliffe Wf.Theassessmentof acne vulgaris: the Leeds technique, Br I Dermaio! 1984: l i l : 8 J - 9 2 . 4 Nanjee MN. Wheeler MJ. Plasma free testosterone—is an index sufficient.^ Ann Clin Hiochem I98S: 22: i87-9(), 5 Bevan BR. Savvas M. Jenkins JM et al. Abnormal steroid excretion in gcstational trophobia.stic disease complicated by ovarian thecalutein cysts. / Clin Pathol 1986: 39: 6 2 7 - i 4 . (i Matsuoka LY. Wortsman J, Lifrak OT et al. Inflect ol' isotretinoin in atne is not mediated by adrenal androgens. / Am Acad Dermalol 1989:20: 128-9. 7 Simpson NB. Cunliffe WJ. Rademaker M el al. The sebaceous gland 8 9 10 11 12 13 as a source of androgen—an hypothesis. In: Acne and Re/atcd Disorders. (Marks R. Plewig G eds). I/indon: M Dunitz Ltd. 1989. Gomez EC. Moskowitz RJ. Effect of 11-cis-rt'tinoic acid on hamster flank organ. / Invest Dernmtol 1980: 74: 392-7. Gracf V. Ritter B. Goerz G. Eiffect of synthetic retinoids on 5areductasesin rat liver and skin. Proc of Sth Inl Cong of Endocrinologii {July 1988. Kyoto. Japan), p 423. HalgunsetJ, Sunde A. LundmoPI. Retinoic acid (RA): an inhibitor of 5a-reductase in human prostatic cancer cells. / .'iteroid Biochem 1987; 28: 731-6. Buchanan LM. Wallace AM. Thomson J. Abnormal steroid metabolism in hirsute women, Scott Med / 1990: 35: 155. Stewart PM, Shackleton CHL. Beastall GH. Inwards CRW, 5areductase activity in polycystic ovary syndrome, hincet 1990: 335:431-3. Herrick AL. Wallace AM. McCoU KEL et al. Association of elevated sex hormone binding globulin with abnormal steroid metabolism in acute inteimittant porphyria, / F.ndoiTinol 1988: Suppl 119: 114.
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