The use of cyproterone acetate/ethinyl estradiol in hyperandrogenic skin symptoms – a review

Figures & data

Figure 1. Literature selection process for review.

Figure 2. Use of CPA/EE in the treatment of hyperandrogenic skin symptoms.

Table

Author (date)	n	Outcome measures (inc. assessment tools used where available)
Large, placebo-controlled studies (n≥ 100)
Palombo-Kinne et al. [28]	1326	Change (%) from baseline in inflammatory and total lesion count at cycle 6 in women receiving EE/DNG (n = 525); EE/CPA (n = 537); or placebo (n = 264). Proportion (%) of patients with acne improvement according to the Investigator Global Assessment
Large (n ≥ 100) comparator studies (t ≥ 3 months)
Vartiainen et al. [29]	172	Clinical assessment of improvement in the number of comedones, papules, pustules and nodules at six months in women receiving either combiphasic EE/DSG (25 μg DSG and 40 μg EE for 7 days followed by 125 μg DSG and 30 μg EE for 15 days) or EE35/CPA (2 mg CPA and 35 μg EE for 21 days)
Carlborg [30]	133	Clinical assessment of change in number of acne lesions at six months in women receiving CPA 2 mg/EE 50 μg (Diane); CPA 2 mg/EE 35 μg (Diane mite); or LNG 50 μg/EE 30 μg (Neovletta)
Dieben et al. [32]	183	Clinical and photographic evaluation of change in number of acne lesions and severity at end of cycle 4 in women receiving CTR-24 and Diane-35. Laboratory assessment of changes in testosterone, 3 alpha-17 beta-androstanediol glucuronide and SHBG at baseline and end of cycle 4
Small (n ≤ 100) comparator studies (t ≥ 3 months)
Charoenvisal et al. [64]	34	Change in mean objective acne score at six months in women receiving low-dose oral contraceptive containing DSG (Marvelon) or an antiandrogenic preparation containing CPA (Diane)
Miller et al. [65]	90	Clinical and photographic assessment of change in acne severity (visual analogue scale) and lesion count bimonthly at six months in women receiving with Diane; high-dose CPA regimen with EE; or Minovlar. Bacteriological sampling and sebum excretion rate (SER) measurements were also carried out
Small (n ≤ 100) dosing studies (t ≥ 3 months)
Fugere et al. [59]	40	Improvement in acne lesions (Cook score) at 3, 6 9 and 12 months in women receiving 2 mg CPA in combination with either 35 μg or 50 μg EE2 (Diane-35 versus Diane-50). Changes in lipid levels were also assessed
Colver et al. [66]	96	Assessment of improvement in acne (visual analogue scale) at nine months in women receiving CPA 2 mg in combination with either 35 μg or 50 μg EE
Small (n ≤ 100) combination studies (t ≥ 3 months)
Carmina and Lobo [33]	48	Change in Cook scores at 12 months in women receiving CPA 2 mg with 35 μg EE; CPA 50 mg with 25 μg EE (reverse sequential regimen); flutamide 250 mg daily; or finasteride 5 mg daily
Greenwood et al. [31]	62	Clinical assessment of improvement in acne lesions (severity and number) at six months in women receiving tetracycline alone; oestrogen-CPA; or a combination of these agents. Sebum excretion rates and bacterial counts were also assessed at six months

CPA: cyproterone acetate; EE: ethinylestradiol; SHBG: sex hormone-binding globulin; DHEAS: dihydroepiandrosterone sulphate; HDL: high density lipoprotein; LDL: low density lipoprotein.

Table

Author (date)	n	Outcome measures (inc. assessment tools used where available)
Comparator studies (t ≥ 6 months)
Porcile and Gallardo [38]	26	Change in hirsutism score, plasma testosterone, and lipids at 24 months in women with IH and/or PCOS receiving DSG 150 μg/30 μg EE; DSG 150 μg/50 μg EE; or CPA 2 mg/35 μg EE
Batukan et al. [67]	91	Change in hirsutism score (mF–G) and serum total testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate and SHBG levels at 6 and 12 months in women receiving either 3 mg DRSP/30 μg EE or 2 mg CPA/35 μg EE
Carmina and Lobo [33]	60	Decrease in hirsutism score (Ferriman–Gallwey–Lorenzo [FGL] index), anagen hair shaft diameters, serum LH and testosterone in hirsute hyperandrogenic women receiving CPA 2 mg/35 μg EE for 21 days each month (Diane group); CPA 50 mg (days 5–15) and EE 50 μg (days 5–25 each month) (CPA group); or decapeptyl 3.75 mg im every 28 days plus conjugated oestrogen 0.625 mg (days 1–21) and MPA 10 mg (days 12–21) (GnRHa group) at 3, 6, 9 and 12 months
Ibanez et al. [39]	34	Changes in hirsutism and acne scores; androgen excess; fasting insulin, lipid profile, C-reactive protein, high molecular-weight adiponectin, leptin, follistatin; carotid intima-media thickness; body composition (absorptiometry); and abdominal fat partitioning (magnetic resonance imaging) at six months in adolescent women receiving EE–CPA or a low-dose combination of pioglitazone, flutamide and metformin (PioFluMet)
Small dosing (n ≤ 100) studies (t ≥ 6 months)
Belisle and Love [34]	158	Change in mean hirsutism total index and distribution (facial, bust or abdomen) of hair in women with severe hirsutism receiving either low dose CPA (Diane, 2 mg) or a high dose (Androcur, 100 mg)
Small (n ≤ 100) studies (t ≥ 6 months)
Barth et al. [68]	21	Decrease in hair growth, as measured by F–G scores, direct measurement of hair shaft diameter and linear growth of hair on the face, forearm, abdomen and thigh at 12 months in women receiving Dianette (35 μg EE/2 mg CPA); Dianette plus 20 mg CPA; or Dianette plus 100 mg CPA administered on days 1–10 of the birth control pill cycle (as described by Hammerstein)
Small (n ≤ 100) combination studies (t ≥ 6 months)
Sert et al. [35]	79	Change in serum FSH, LH, testosterone and DHEAS levels; decrease in hirsutism score (F–G), and frequency of shaving/hot wax treatment at 6 and 12 months in women receiving Diane 35 plus CPA; Diane 35 plus spironolactone (100 mg); or spironolactone (100 mg) alone
Keleştimur et al. [37]	50	Change in hirsutism score (mF–G) and hormone levels (total and free T, androstenedione, DHEAS, SHBG and prolactin (PRL) at six-month intervals in women receiving either Diane 35 alone or Diane 35 plus spironolactone
Sahin et al. [36]	40	Change in hirsutism score (F–G) and total and free testosterone (T), androstenedione, DHEAS, and SHBG at 6 and 12 months in women receiving either Diane-35 alone or Diane-35 plus finasteride
Inal et al. [65]	80	Change in hirsutism score (mF–G) and hormonal profile at nine months in women receiving flutamide (250 mg/d for the first 10 days of the cycle) or spironolactone (100 mg/d) plus Diane 35
Taner et al. [69]	84	Change in hirsutism score (F–G) and serum hormones at 1, 3 and 6 months in women receiving either 250 mg flutamide per day or 250 mg flutamide plus 35 μg EE and 2 mg CPA per day
Tartagni et al. [55]	50	Change in hirsutism score (mF–G) and serum hormone levels (LH, FSH, free testosterone, DHT, DHEAS, androstenedione and SHBG at 3 and 6 months in women with either IH or hirsutism in PCOS receiving either Diane 35 or Diane 35 plus finasteride at six months
Vegetti et al. [70]	41	Decrease in mean diameter of hair from three different areas and one control area and subjective evaluation of improvement by physician and patient in women with severe hirsutism receiving GnRH analogue (goserelin) plus an OC containing EE and CPA and the same OC alone
Karakurt et al. [71]	29	Change in hirsutism score (mF–G), hormonal and lipid profiles at six months in women receiving either 250 mg/day flutamide alone or 100 mg/day spironolactone plus a combination tablet of 2 mg CPA/35 μg EE
Falsetti et al. [49]	25	Changes in androgen plasma levels, hair diameter and hirsutism score in women with moderate-severe PCOS-dependent hirsutism receiving either GnRH-A (group A) or combined pill and GnRH (group B) for six months

IH: idiopathic hirsutism; PCOS: polycystic ovary syndrome; CPA: cyproterone acetate; EE: ethinylestradiol; F–G: Ferriman–Gallwey; mF–G: modified Ferriman–Gallwey; SHBG: sex hormone-binding globulin; DHT: dihydrotestosterone; DHEAS: dihydroepiandrosterone sulphate; HDL: high-density lipoprotein; LDL: low-density lipoprotein; GnRH: gonadotrophin releasing hormone.

Table

Author (date)	n	Outcome measures (inc. assessment tools used where available)
Large (n ≥ 100) comparator studies (t ≥ 6 months)
Van Vloten et al. [40]	128	Changes in median total acne lesion count, sebum production, and hair growth on the upper lip, chin, and chest, levels of SHBG, androgens and LH over nine treatment cycles in women with mild-to-moderate facial acne, with or without seborrhea and/or hirsutism receiving 30 EE/3 mg DRSP or 35 μg EE/2 mg CPA

CPA: cyproterone acetate; EE: ethinylestradiol; DRSP: drosperinone; SHBG: sex hormone-binding globulin; LH: luteinising hormone.

Table

Author (date)	n	Outcome measures (inc. assessment tools used where available)
Large (n ≥ 100) comparator studies (t ≥ 6 months)
Bhattacharya and Jha [10]	171	Change in the free androgen index score and clinical, hormonal and biochemical parameters at 6 and 12 months in women receiving pills containing DSG (Novelon; 30/0.15 mg); CPA (Krimson 35; 35/2 mg); or DRSP (Yasmin; 30/3 mg)
Gokmen et al. [43]	141	Changes in hirsutism score (F–G) and lipid and hormonal levels in women receiving low-dose combined oral contraceptive, CPA 100 mg daily for the first 10 days of a 21-day cycle with an oral contraceptive containing 2 mg CPA; spironolactone (100–200 mg daily); or ketoconazole (400 mg daily)
Meyer et al. [61]	100	Decrease in hirsutism score (F–G) at 12 months in women receiving metformin (starting dose 500 g bd titrated upwards to 1 g bd over 4 weeks); high-dose OCP (35 μg EE/2 mg CPA); or low-dose OCP (20 μg EE/100 μg LNG) combined with an antiandrogen (spironolactone 50 mg bd). Hirsutism was not a primary outcome measure. Insulin resistance and surrogate markers of cardiovascular disease including arterial stiffness (pulse wave velocity [PWV]) and endothelial function were assessed as primary endpoints
Small (n < 100) studies (t ≥ 6 months)
Kahraman et al. [45]	52	Change in clinical features: mF–G; BMI, WHR and biochemical parameters (androgen profile, carbohydrate metabolism, lipid profile and oxidative stress) at 12 months in women with PCOS receiving 35 μg EE/2 mg CPS; or 30 μg EE/3 mg DRSP-containing OCs
Chung et al. [57]	76	Change in clinical and biochemical features of hyperandrogenism and quality of life in women receiving oral MPA for four months, followed by a washout period of four months and then Diane-35 for another four months (group 1) at 12 months. Group 2 received the same combination but in the reverse order
Harborne et al. [44]	52	Change in hirsutism assessed by patient self-assessment and F–G score in women receiving either metformin (500 mg, three times daily) or Dianette (EE, 35 μg; CPA, 2 mg) treatment for 12 months
Mastorakos et al. [54]	36	Change in hirsutism score, lipid, androgen, and sex hormone-binding globulin (SHBG) levels in women receiving 0.15 mg of DSG/30 μg of EE daily; or 2 mg of CPA/35 μg of EE daily for 21 days followed by a 7-day rest for a period at 12 months. An OGTT and metabolism indices, based on previously studied mathematical formulas, were also assessed
Creatsas et al. [46]	24	Change in hirsutism score (F–G) and blood levels of SHBG, total cholesterol (TC), LDL cholesterol, HDL cholesterol, TGs, apolipoproteins A–I, A–II, B, and lipoprotein (a) (Lp(a)) measurements at 3, 6, 9 and 12 months in women receiving either 2 mg CPA/35 μg EE or 0.150 mg DSG/30 μg EE for 12 months
Luque-Ramírez et al. [47]	34	Assessment of hyperandrogenism, lipid profiles, and indexes of glucose tolerance and insulin sensitivity at 12 and 24 weeks in women receiving oral treatment with metformin (850 mg twice daily) or with the Diane(35) Diario pill (35 μg EE/2 mg CPA)
Erkkola et al. [52]	83	Change in severity of hyperandrogenic symptoms at nine months in women with acne, seborrhea and hirsutism receiving 2 mg CPA/35 μg EE (Diane 35) and 0.150 mg DSG/30 μg EE (Marvelon)
Morin-Papunen et al. [41]	32	Change in hirsutism score (F–G) at six months in women receiving metformin (500 mg bd for three months, then 1000 mg bd for three months); or EE (35 μg)/CPA (2 mg) oral contraceptive pills (Diane Nova). WHR, serum testosterone, fasting free fatty acid, and insulin concentrations and improved oxidative glucose utilization and menstrual cyclicity were also assessed
Dahlgren et al. [42]	32	Change in hirsutism score (F–G), insulin sensitivity (estimated by glucose clamp technique), blood lipids and hormones at six months in women receiving either EE/CPA cyclically for six months or GnRH analogue (goserelin)
Lemay et al. [48]	28	Decrease in hirsutism score (F–G), plasma lipids and OGTT at six months in women receiving either rosiglitazone 4 mg/day or EE 35 μg/CPA 2 mg (21/28 days cycle) followed by both medications for another six months
Couzinet et al. [72]	10	Changes in severity of acne and seborrhea in women receiving 50 mg/day CPA (orally) and 3 mg DTrp6-LHRH (im), approximately once a month) for three months followed by cross-over treatment after a six-month break
Combination (t ≥ 6 months) studies
Acién et al. [56]	12	Change in symptoms (hirsutism [F–G score], weight) and hormonal and biochemical analyses at three and six months in women receiving either GnRH-a plus an OC pill containing EE CPA or EE–CPA alone
De Leo et al. [51]	35	Change in hirsutism score (F–G) in women receiving GnRH agonist; GnRH agonist plus COC; or GnRH agonist plus flutamide for six months. Ovarian and adrenal androgens, gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH), estradiol and oestrone plasma levels were also assessed at six months
Falsetti et al. [49]	25	Changes in androgen plasma levels, hair diameter and hirsutism score in women with moderate-severe PCOS-dependent hirsutism receiving either GnRH-A or combined pill and GnRH-A for six months
Open-label study
Golland and Elstein [50]	32	Changes in hirsutism score (F–G), hormone serum concentrations, ovarian volume, stromal density, and follicle number and size at 3, 6, 9 and 12 months in women receiving Diane-35

CPA: cyproterone acetate; EE: ethinylestradiol; F–G: Ferriman–Gallwey; mF–G: modified Ferriman–Gallwey; SHBG: sex hormone-binding globulin; DHEAS: dihydroepiandrosterone sulphate; HDL: high-density lipoprotein; LDL: low-density lipoprotein.

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