Hirsutism medical therapy: Difference between revisions

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__NOTOC__
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{{Hirsutism}}
{{Hirsutism}}
{{CMG}}: {{AE}}; {{Ochuko}} {{RHN}}
{{CMG}}; {{AE}}{{EG}}


==Overview==
==Overview==
Many women with unwanted hair seek methods of [[hair removal]] to control the appearance of hirsutism. But the actual causes should be evaluated by physicians, who can conduct blood tests, pinpoint the specific origin of the abnormal hair growth, and advise on the best course of treatment.


Pharmacologic medical therapies for hirsituism include [[oral contraceptives]], [[antiandrogen therapy|androgen receptor blockers]], [[5-alpha-reductase inhibitor|5-alpha reductase inhibitors]], [[GnRH|gonadotrophin-releasing hormone]] ([[GnRH agonist]]), [[adrenal]] suppressive [[glucocorticoids]], [[insulin]]-sensitising agents, and biological modifiers of hair follicular growth. Treatment options are [[systemic therapy]] and [[topical|topical therapy]].
==Medical Therapy==
==Medical Therapy==
===Pharmacologic Treatment===
*Pharmacologic medical therapies for hirsituism include:<ref name="pmid20418968">{{cite journal| author=Sachdeva S| title=Hirsutism: evaluation and treatment. | journal=Indian J Dermatol | year= 2010 | volume= 55 | issue= 1 | pages= 3-7 | pmid=20418968 | doi=10.4103/0019-5154.60342 | pmc=2856356 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20418968 }} </ref>  
====Hormonal Therapy====
**[[Oral contraceptives]]
* [[Oral contraceptives]] : Suppresses free [[testosterone]] level eg Yasmin which contains 30 microgram of [[estradiol]] and 3mg of drospirenone or Yaz (20microgram of estradiol and 3mg of drospirenone).
**[[Antiandrogen therapy|Androgen receptor blockers]]
* [[Gonadotropin-releasing hormone agonist]]<nowiki/>s :An  alternative to [[oral contraceptives]]<ref name="Rosenfield2005">{{cite journal|last1=Rosenfield|first1=Robert L.|title=Hirsutism|journal=New England Journal of Medicine|volume=353|issue=24|year=2005|pages=2578–2588|issn=0028-4793|doi=10.1056/NEJMcp033496}}</ref>
**[[5-alpha-reductase inhibitor|5-alpha reductase inhibitors]]
If a [[tumor]] of [[ovaries]] or [[adrenal gland]]<nowiki/>s is the underlying cause of hirsutism, surgery may be the treatment option.
**[[GnRH|Gonadotrophin-releasing hormone]] ([[GnRH agonist]])
* Parenteral long acting gonadotropin-releasing hormone analogues <ref name="pmid20198556">{{cite journal| author=Klotz RK, Müller-Holzner E, Fessler S, Reimer DU, Zervomanolakis I, Seeber B et al.| title=Leydig-cell-tumor of the ovary that responded to GnRH-analogue administration - case report and review of the literature. | journal=Exp Clin Endocrinol Diabetes | year= 2010 | volume= 118 | issue= 5 | pages= 291-7 | pmid=20198556 | doi=10.1055/s-0029-1225351 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20198556 }} </ref> combined with OCPs containing estrogen and progestin for severe hirsutism not respinding to OCPs and antiandrogen e.g Leuprolide.
**[[Adrenal]] suppressive [[glucocorticoids]]
**[[Insulin]]-sensitising agents
**Biological modifiers of hair follicular growth


====Adrenal Suppression====
===Hirsutism===
* Oral [[glucocorticoids]] : In patients with [[CAH]] eg Prednisone or Dexamethasone.
* Metformin for infertile women with [[PCOS]].


====Antiandrogens====
*1. '''Adult'''
* Finestride: A 5α-reductase inhibitor, 2.5mg daily. (this is rarely used because it causes fatal hepatitis with a high risk of being teratogenic.
**1.1 '''Systemic therapy'''
* Eflornithine hydrochloride cream (Vaniqa): Applied twice daily to the face.
*** Preferred regimen (1): [[Ethinyl estradiol]] 30 μg '''''PLUS''''' [[norethindrone]] 1 mg PO daily over a 9-month period<ref name="pmid2136834">{{cite journal |vauthors=Murphy A, Cropp CS, Smith BS, Burkman RT, Zacur HA |title=Effect of low-dose oral contraceptive on gonadotropins, androgens, and sex hormone binding globulin in nonhirsute women |journal=Fertil. Steril. |volume=53 |issue=1 |pages=35–9 |year=1990 |pmid=2136834 |doi= |url=}}</ref> 
*** Preferred regimen (2): [[Mestranol]] 100 μg '''''PLUS''''' [[norethindrone]] 2 mg PO daily for about 2 weeks<ref name="GivensAndersen1974">{{cite journal|last1=Givens|first1=James R.|last2=Andersen|first2=Richard N.|last3=Wiser|first3=Winfred L.|last4=Fish|first4=Stewart A.|title=Dynamics of Suppression and Recovery of Plasma FSH, LH, Androstenedione and Testosterone in Polycystic Ovarian Disease Using an Oral Contraceptive|journal=The Journal of Clinical Endocrinology & Metabolism|volume=38|issue=5|year=1974|pages=727–735|issn=0021-972X|doi=10.1210/jcem-38-5-727}}</ref>
*** Preferred regimen (3): [[Ethinyl estradiol]] 30 μg '''''PLUS''''' [[desogestrel]] 150 mcg PO daily for 4-7 months<ref name="pmid3156694">{{cite journal |vauthors=Dewis P, Petsos P, Newman M, Anderson DC |title=The treatment of hirsutism with a combination of desogestrel and ethinyl oestradiol |journal=Clin. Endocrinol. (Oxf) |volume=22 |issue=1 |pages=29–36 |year=1985 |pmid=3156694 |doi= |url=}}</ref>
*** Preferred regimen (4): [[Spironolactone]] starting dose of 50 mg PO q12h; may be increased to 200 mg PO daily.<ref name="pmid1826112">{{cite journal |vauthors=Shaw JC |title=Spironolactone in dermatologic therapy |journal=J. Am. Acad. Dermatol. |volume=24 |issue=2 Pt 1 |pages=236–43 |year=1991 |pmid=1826112 |doi= |url=}}</ref>
*** Alternative regimen (1): [[Cyproterone|Cyproterone Acetate]] 50-100 mg PO daily<ref name="pmid12749435">{{cite journal |vauthors=Lumachi F, Rondinone R |title=Use of cyproterone acetate, finasteride, and spironolactone to treat idiopathic hirsutism |journal=Fertil. Steril. |volume=79 |issue=4 |pages=942–6 |year=2003 |pmid=12749435 |doi= |url=}}</ref>
*** Alternative regimen (2): [[Cyproterone|Cyproterone Acetate]] 2 mg '''''PLUS''''' [[ethinyl estradiol]] 35 μg PO daily<ref name="pmid14583927">{{cite journal |vauthors=Van der Spuy ZM, le Roux PA |title=Cyproterone acetate for hirsutism |journal=Cochrane Database Syst Rev |volume= |issue=4 |pages=CD001125 |year=2003 |pmid=14583927 |doi=10.1002/14651858.CD001125 |url=}}</ref>
*** Alternative regimen (3): [[Finasteride]] 1-5 mg PO daily<ref name="pmid9854686">{{cite journal |vauthors=Faloia E, Filipponi S, Mancini V, Di Marco S, Mantero F |title=Effect of finasteride in idiopathic hirsutism |journal=J. Endocrinol. Invest. |volume=21 |issue=10 |pages=694–8 |year=1998 |pmid=9854686 |doi=10.1007/BF03350800 |url=}}</ref>
*** Alternative regimen (4): [[Flutamide]] 125-250 mg PO q12h
*** Alternative regimen (5): [[Bicalutamide ]] 25 mg PO daily<ref name="pmid20218823">{{cite journal |vauthors=Castelo-Branco C, Cancelo MJ |title=Comprehensive clinical management of hirsutism |journal=Gynecol. Endocrinol. |volume=26 |issue=7 |pages=484–93 |year=2010 |pmid=20218823 |doi=10.3109/09513591003686353 |url=}}</ref>
*** Alternative regimen (6): [[Metformin]] 500-1000 mg PO q12h<ref name="pmid21856600">{{cite journal |vauthors=Paparodis R, Dunaif A |title=The Hirsute woman: challenges in evaluation and management |journal=Endocr Pract |volume=17 |issue=5 |pages=807–18 |year=2011 |pmid=21856600 |doi=10.4158/EP11117.RA |url=}}</ref>
*** Alternative regimen (7): [[Rosiglitazone]] 4-8 mg PO daily
*** Alternative regimen (8): [[Pioglitazone]] 10-30 mg PO daily<ref name="pmid23159176">{{cite journal |vauthors=Blume-Peytavi U |title=How to diagnose and treat medically women with excessive hair |journal=Dermatol Clin |volume=31 |issue=1 |pages=57–65 |year=2013 |pmid=23159176 |doi=10.1016/j.det.2012.08.009 |url=}}</ref>
*** Alternative regimen (9): [[Leuprolide]] 7.5 mg IM '''''PLUS''''' [[estradiol]] 25-50 µg [[transdermal]] monthly<ref name="pmid22335316">{{cite journal |vauthors=Bode D, Seehusen DA, Baird D |title=Hirsutism in women |journal=Am Fam Physician |volume=85 |issue=4 |pages=373–80 |year=2012 |pmid=22335316 |doi= |url=}}</ref>
*** Alternative regimen (10): [[Prednisone]] 5-10 mg PO daily<ref name="pmid22064667">{{cite journal |vauthors=Escobar-Morreale HF, Carmina E, Dewailly D, Gambineri A, Kelestimur F, Moghetti P, Pugeat M, Qiao J, Wijeyaratne CN, Witchel SF, Norman RJ |title=Epidemiology, diagnosis and management of hirsutism: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome Society |journal=Hum. Reprod. Update |volume=18 |issue=2 |pages=146–70 |year=2012 |pmid=22064667 |doi=10.1093/humupd/dmr042 |url=}}</ref>
**1.2 '''Topical Therapy'''
*** Preferred regimen (1): [[Eflornithine|Eflornithine hydrochloride]] 13.9% cream topical q12h<ref name="pmid18252793">{{cite journal |vauthors=Martin KA, Chang RJ, Ehrmann DA, Ibanez L, Lobo RA, Rosenfield RL, Shapiro J, Montori VM, Swiglo BA |title=Evaluation and treatment of hirsutism in premenopausal women: an endocrine society clinical practice guideline |journal=J. Clin. Endocrinol. Metab. |volume=93 |issue=4 |pages=1105–20 |year=2008 |pmid=18252793 |doi=10.1210/jc.2007-2437 |url=}}</ref>
*** Preferred regimen (2): [[Finasteride]] 0.25% or 0.5% cream topical daily<ref name="pmid22658123">{{cite journal |vauthors=Farshi S, Mansouri P, Rafie F |title=A randomized double blind, vehicle controlled bilateral comparison study of the efficacy and safety of finasteride 0.5% solution in combination with intense pulsed light in the treatment of facial hirsutism |journal=J Cosmet Laser Ther |volume=14 |issue=4 |pages=193–9 |year=2012 |pmid=22658123 |doi=10.3109/14764172.2012.699680 |url=}}</ref>


===Non-Pharmacologic Treatment===
* Cosmetic therapy : Bleaching, shaving, depilating agents, plucking, waxing treatments.
* Electrosurgical methods include electrosurgical epilation and [[Laser therapy]] which can remove unwanted hair for some women specially for women with dark hair and light skin.<ref name="Franks2012">{{cite journal|last1=Franks|first1=Stephen|title=The investigation and management of hirsutism|journal=Journal of Family Planning and Reproductive Health Care|volume=38|issue=3|year=2012|pages=182–186|issn=1471-1893|doi=10.1136/jfprhc-2011-100175}}</ref>
Light-source-assisted hair reduction (photoepilation) is a common method in the treatment of unwanted hair and is more effective than shaving, waxing and electrolysis.<ref name="pmid9681347">{{cite journal |vauthors=Dierickx CC, Grossman MC, Farinelli WA, Anderson RR |title=Permanent hair removal by normal-mode ruby laser |journal=Arch Dermatol |volume=134 |issue=7 |pages=837–42 |year=1998 |pmid=9681347 |doi= |url=}}</ref>
{| class="wikitable"
{| class="wikitable"
!Skin/hair color 
!Group
!Choice of photoepilation device
!Medicine
!Dosage
!Mechanism of action
!Side effect
!Notes
|-
|-
|Light skin/dark hair 
| rowspan="3" |[[Oral contraceptive|Oral Contraceptive Pills (OCPs)]]
|Relatively short wavelength 
|[[Ethinyl estradiol]]/<br>[[Norethindrone]]
|30 μg /<br> 1.0 mg
| rowspan="3" |
* Inhibiting [[androgen]] secretion by the [[ovaries]]
* Increasing [[sex hormone binding globulin|sex hormone binding globulin (SHBG)]] production by the [[liver]]
* Inhibiting adrenal [[androgen]] production
| rowspan="3" |
* Increased risk of [[venous thromboembolism]]
* [[Breast]] tenderness
* [[Headache]]
* [[Gastrointestinal]] symptoms
| rowspan="3" |
*Absolute contraindications
**[[Smoking]] over the age of 35 (>15 cigarettes per day)
**[[Hypertension]]
**[[Ischemic heart disease]]
**[[Migraine]] headache with [[focal neurological symptoms]]
**[[Breast cancer]] (current)
**[[Diabetes]] with [[retinopathy]]/[[nephropathy]]/[[neuropathy]]
**Severe [[cirrhosis]]
**[[Liver tumour]] ([[adenoma]] or [[hepatoma]])
|-
|-
|Dark skin/dark hair 
|[[Mestranol]]/[[norethindrone]]
|Relatively long wavelength or IPL(intense pulsed light)
|100 μg / 2mg
|-
|-
|Light/white hair 
|[[Ethinyl estradiol]]/<br>[[desogestrel]]
|IPL + radiofrequency
|30 μg /<br> 150 mcg
|-
| rowspan="5" |[[Antiandrogens]]
|[[Spironolactone]]
|100-200 mg
|
* [[Antagonist]] of both [[aldosterone]] and [[androgen]] receptor
* Competes with [[Dihydrotestosterone|dihydrotestosterone (DHT)]] for binding to the [[androgen]] receptor
* Variable progestational activity
* Decreases production of [[ovarian]] [[androgens]]
* Inhibitory effect on 5 alpha-reductase activity (5-RA)
* Competes with [[androgens]] for binding to [[sex hormone binding globulin|SHBG]]
|
* [[Abnormal uterine bleeding|Irregular menstrual bleeding]]
* [[Headache]]
* [[Hypotension]]
* [[Nausea]]
* Decreased [[libido]]
|
*Contraindications
**[[Renal insufficiency]]
**[[Hyperkalaemia]]
|-
|[[Cyproterone|Cyproterone Acetate]] 
|50-100 mg
| rowspan="2" |
*Competes with [[dihydrotestosterone]] for the [[androgen]] receptor
*Inhibits 5α-reductase
*Decrease in circulating [[testosterone]] and [[androstenedione]] levels through a reduction in circulating [[luteinizing hormone|luteinizing hormone (LH)]]
| rowspan="2" |
*[[Liver]] toxicity
*[[Abnormal uterine bleeding|Irregular menstrual bleeding]]
*[[Nausea]]
*Decreased [[libido]]
| rowspan="2" |
-
|-
|[[Cyproterone|Cyproterone Acetate]]/<br>[[ethinyl estradiol]]
| 2 mg /<br> 35 μg
|-
|[[Flutamide]]
|125-250 mg
| rowspan="2" |
*Non-steroidal, [[competitive inhibitors]] of [[androgen]] receptor binding
| rowspan="2" |
*[[Hepatotoxicity]]
*[[Fulminant liver failure]]
| rowspan="2" |
* Contraindication
**[[Fulminant liver failure]]
|-
|[[Bicalutamide ]]
|25 mg
|-
| rowspan="2" |[[5-alpha-reductase inhibitor|5-alpha reductase inhibitors]]
|[[Finasteride]]
|1-5 mg
| rowspan="2" |
*Type II inhibitor of the [[5-alpha-reductase|5α-reductase enzyme]]
*Reduces the conversion of [[testosterone]] into [[dihydrotestosterone]]
| rowspan="2" |
*[[Feminisation]] of the male fetus
*[[Liver dysfunction]]
| rowspan="2" |
-
|-
|[[Dutasteride]]
|0.5 mg
|-
|[[GnRH|Gonadotrophin-releasing hormone]] ([[GnRH agonist]])
|[[Leuprolide]]
|7.5 mg
|
*Suppress the [[hypothalamic-pituitary-gonadalaxis|hypothalamic-pituitary-ovarian axis]]
*Inhibiting [[luteinising hormone|luteinising hormone (LH)]] and [[follicle-stimulating hormone|follicle-stimulating hormone (FSH)]]
*Decreasing the secretion of [[androgens]] by the [[ovaries]]
|
*If not combined with [[estrogen]]
**[[Menopausal]] symptoms
**[[Hot flushes]]
**[[Osteoporosis]]
|
*[[GnRH analogues]] not suggested for most women with hirsutism, because of:
**Not seem to have advantages over other therapies
**High price
**Need additional [[estrogen]] to prevent [[bone loss]] and [[menopausal]] symptoms
|-
|[[Adrenal]] suppressive [[glucocorticoids]]
|[[Prednisone]]
|5-10 mg
|
*Used in cases of non-classic [[congenital adrenal hyperplasia]]
*Suppress [[adrenocorticotropic hormone]] dependent [[adrenal]] [[androgen]] synthesis
|
*[[Weight gain]]
*[[Osteoporosis]]
*[[Adrenal suppression]]
|
-
|-
| rowspan="3" |[[Insulin]]-sensitising agents
|[[Metformin]]
|500-1000 mg
| rowspan="3" |
*Decrease [[hyperinsulinaemia]] by increasing [[insulin sensitivity]]
*Lower [[insulin]] levels result in an increase of [[sex hormone binding globulin|SHBG]], thereby reducing the levels of circulating free [[androgens]]
| rowspan="3" |
*[[Gastrointestinal]] distress
*Increased risk of [[cardiovascular events]]
*[[Liver dysfunction]]
*[[Lactic acidosis]]
| rowspan="3" |
*These are best choices for hirsutism along with [[insulin resistance]]
*It is not suggested to prescribe these [[drugs]] just for hirsutism
|-
|[[Rosiglitazone]]
|4-8 mg
|-
|[[Pioglitazone]]
|10-30 mg
|}
|}


Latest revision as of 22:59, 7 November 2017

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Overview

Pharmacologic medical therapies for hirsituism include oral contraceptives, androgen receptor blockers, 5-alpha reductase inhibitors, gonadotrophin-releasing hormone (GnRH agonist), adrenal suppressive glucocorticoids, insulin-sensitising agents, and biological modifiers of hair follicular growth. Treatment options are systemic therapy and topical therapy.

Medical Therapy

Hirsutism

Group Medicine Dosage Mechanism of action Side effect Notes
Oral Contraceptive Pills (OCPs) Ethinyl estradiol/
Norethindrone 		30 μg /
1.0 mg
Mestranol/norethindrone 100 μg / 2mg
Ethinyl estradiol/
desogestrel 		30 μg /
150 mcg
Antiandrogens Spironolactone 100-200 mg
Cyproterone Acetate 50-100 mg

-

Cyproterone Acetate/
ethinyl estradiol 		2 mg /
35 μg
Flutamide 125-250 mg
Bicalutamide 25 mg
5-alpha reductase inhibitors Finasteride 1-5 mg

-

Dutasteride 0.5 mg
Gonadotrophin-releasing hormone (GnRH agonist) Leuprolide 7.5 mg
Adrenal suppressive glucocorticoids Prednisone 5-10 mg

-

Insulin-sensitising agents Metformin 500-1000 mg
  • These are best choices for hirsutism along with insulin resistance
  • It is not suggested to prescribe these drugs just for hirsutism
Rosiglitazone 4-8 mg
Pioglitazone 10-30 mg

References

  1. ↑ Sachdeva S (2010). "Hirsutism: evaluation and treatment". Indian J Dermatol. 55 (1): 3–7. doi:10.4103/0019-5154.60342. PMC 2856356. PMID 20418968.
  2. ↑ Murphy A, Cropp CS, Smith BS, Burkman RT, Zacur HA (1990). "Effect of low-dose oral contraceptive on gonadotropins, androgens, and sex hormone binding globulin in nonhirsute women". Fertil. Steril. 53 (1): 35–9. PMID 2136834.
  3. ↑ Givens, James R.; Andersen, Richard N.; Wiser, Winfred L.; Fish, Stewart A. (1974). "Dynamics of Suppression and Recovery of Plasma FSH, LH, Androstenedione and Testosterone in Polycystic Ovarian Disease Using an Oral Contraceptive". The Journal of Clinical Endocrinology & Metabolism. 38 (5): 727–735. doi:10.1210/jcem-38-5-727. ISSN 0021-972X.
  4. ↑ Dewis P, Petsos P, Newman M, Anderson DC (1985). "The treatment of hirsutism with a combination of desogestrel and ethinyl oestradiol". Clin. Endocrinol. (Oxf). 22 (1): 29–36. PMID 3156694.
  5. ↑ Shaw JC (1991). "Spironolactone in dermatologic therapy". J. Am. Acad. Dermatol. 24 (2 Pt 1): 236–43. PMID 1826112.
  6. ↑ Lumachi F, Rondinone R (2003). "Use of cyproterone acetate, finasteride, and spironolactone to treat idiopathic hirsutism". Fertil. Steril. 79 (4): 942–6. PMID 12749435.
  7. ↑ Van der Spuy ZM, le Roux PA (2003). "Cyproterone acetate for hirsutism". Cochrane Database Syst Rev (4): CD001125. doi:10.1002/14651858.CD001125. PMID 14583927.
  8. ↑ Faloia E, Filipponi S, Mancini V, Di Marco S, Mantero F (1998). "Effect of finasteride in idiopathic hirsutism". J. Endocrinol. Invest. 21 (10): 694–8. doi:10.1007/BF03350800. PMID 9854686.
  9. ↑ Castelo-Branco C, Cancelo MJ (2010). "Comprehensive clinical management of hirsutism". Gynecol. Endocrinol. 26 (7): 484–93. doi:10.3109/09513591003686353. PMID 20218823.
  10. ↑ Paparodis R, Dunaif A (2011). "The Hirsute woman: challenges in evaluation and management". Endocr Pract. 17 (5): 807–18. doi:10.4158/EP11117.RA. PMID 21856600.
  11. ↑ Blume-Peytavi U (2013). "How to diagnose and treat medically women with excessive hair". Dermatol Clin. 31 (1): 57–65. doi:10.1016/j.det.2012.08.009. PMID 23159176.
  12. ↑ Bode D, Seehusen DA, Baird D (2012). "Hirsutism in women". Am Fam Physician. 85 (4): 373–80. PMID 22335316.
  13. ↑ Escobar-Morreale HF, Carmina E, Dewailly D, Gambineri A, Kelestimur F, Moghetti P, Pugeat M, Qiao J, Wijeyaratne CN, Witchel SF, Norman RJ (2012). "Epidemiology, diagnosis and management of hirsutism: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome Society". Hum. Reprod. Update. 18 (2): 146–70. doi:10.1093/humupd/dmr042. PMID 22064667.
  14. ↑ Martin KA, Chang RJ, Ehrmann DA, Ibanez L, Lobo RA, Rosenfield RL, Shapiro J, Montori VM, Swiglo BA (2008). "Evaluation and treatment of hirsutism in premenopausal women: an endocrine society clinical practice guideline". J. Clin. Endocrinol. Metab. 93 (4): 1105–20. doi:10.1210/jc.2007-2437. PMID 18252793.
  15. ↑ Farshi S, Mansouri P, Rafie F (2012). "A randomized double blind, vehicle controlled bilateral comparison study of the efficacy and safety of finasteride 0.5% solution in combination with intense pulsed light in the treatment of facial hirsutism". J Cosmet Laser Ther. 14 (4): 193–9. doi:10.3109/14764172.2012.699680. PMID 22658123.

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