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Insulin receptor defect — Clinical Guidelines

Overview

Insulin receptor defects can contribute to hyperinsulinemia, which may exacerbate conditions like polycystic ovary syndrome (PCOS) characterized by hyperandrogenism, leading to symptoms such as hirsutism, acne, and menstrual irregularities. 8 19

Diagnosis

Clinical Presentation: Presence of excessive terminal hair growth in androgen-sensitive areas (e.g., face, chest, abdomen).

Hormonal Assessment: Elevated serum testosterone and/or other androgens (e.g., androstenedione, DHEA-S).

Insulin Resistance Testing: Fasting insulin levels, HOMA-IR index, or OGTT to assess for hyperinsulinemia.

Grading: Ferriman-Gallwey (FG) scale for hirsutism severity 7.

Management

First-Line Treatments:

- Anti-Androgens: Spironolactone (50-200 mg/day) to reduce androgen effects 18 4 5 9 10 11. - Combined Oral Contraceptives (COCs): Containing cyproterone acetate or other anti-androgenic progestins for androgen suppression 12 25 26.

Adjunctive Treatments:

- Insulin Sensitizers: Metformin to improve insulin resistance and reduce hyperinsulinemia 27. - Mechanical Hair Removal: Electrolysis, laser therapy, or waxing for cosmetic management 1.

Special Populations

Pregnancy: Avoid anti-androgens like spironolactone; COCs can be used cautiously under strict supervision 1 25.

Pediatrics: Use of anti-androgens should be approached cautiously due to potential side effects; COCs may be considered in adolescents with severe symptoms 2 18.

Elderly: Similar management principles apply, focusing on symptom control and minimizing side effects 18.

Comorbidities: Consider impact of treatments on existing conditions; monitor for interactions (e.g., St. John's wort with OCPs) 6.

Key Recommendations

Initiate Anti-Androgen Therapy: Use spironolactone (100-200 mg/day) for hirsutism and acne management (Evidence: Moderate) 18 4 5 9 10 11.

Combined Oral Contraceptives for Androgen Suppression: Prescribe COCs containing anti-androgenic progestins for women with hyperandrogenism (Evidence: Moderate) 12 25 26.

Consider Metformin for Insulin Resistance: In patients with concurrent PCOS, metformin can improve insulin sensitivity and reduce androgen levels (Evidence: Moderate) 27.

Monitor for Side Effects: Regularly assess for side effects of anti-androgens, particularly menstrual disturbances and breast changes (Evidence: Expert opinion) 15.

Avoid Certain Herbal Supplements: Discourage concurrent use of St. John's wort with hormonal therapies due to potential efficacy reduction (Evidence: Weak) 6.

References

1 Elliott J, Liu K, Motan T. Guideline No. 444: Hirsutism: Evaluation and Treatment. Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC 2023. link 2 Fuchs A, Matonóg A, Sieradzka P, Pilarska J, Hauzer A, Czech I et al.. Anti-androgenic therapy in young patients and its impact on intensity of hirsutism, acne, menstrual pain intensity and sexuality - a preliminary study. Ginekologia polska 2019. link 3 Słopień R, Pawlak M, Warenik-Szymankiewicz A, Sajdak S. The improvement of hirsutism and the decrease of testosterone concentration in the peripheral blood serum after removing an endometrioid ovarian cyst. Clinical and experimental obstetrics & gynecology 2016. link 4 Rathnayake D, Sinclair R. Use of spironolactone in dermatology. Skinmed 2010. link 5 Brown J, Farquhar C, Lee O, Toomath R, Jepson RG. Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne. The Cochrane database of systematic reviews 2009. link 6 Fogle RH, Murphy PA, Westhoff CL, Stanczyk FZ. Does St. John's wort interfere with the antiandrogenic effect of oral contraceptive pills?. Contraception 2006. link 7 Sagsoz N, Kamaci M, Orbak Z. Body hair scores and total hair diameters in healthy women in the Kirikkale Region of Turkey. Yonsei medical journal 2004. link 8 Orio F, Palomba S, Cascella T, Tauchmanovà L, Di Biase S, Labella D et al.. Adrenal adenoma and normal androgen levels in a young woman with polycystic ovaries: a case of idiopathic hirsutism?. Journal of endocrinological investigation 2004. link 9 Farquhar C, Lee O, Toomath R, Jepson R. Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne. The Cochrane database of systematic reviews 2003. link 10 Farquhar C, Lee O, Toomath R, Jepson R. Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne. The Cochrane database of systematic reviews 2001. link 11 Lee O, Farquhar C, Toomath R, Jepson R. Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne. The Cochrane database of systematic reviews 2000. link 12 Vegetti W, Testa G, Maggioni P, Motta T, Falsetti L, Crosignani PG. An open randomized comparative study of an oral contraceptive containing ethinyl estradiol and cyproterone acetate with and without the GnRH analogue goserelin in the long-term treatment of hirsutism. Gynecologic and obstetric investigation 1996. link 13 Moghetti P, Castello R, Negri C, Tosi F, Magnani CM, Fontanarosa MC et al.. Flutamide in the treatment of hirsutism: long-term clinical effects, endocrine changes, and androgen receptor behavior. Fertility and sterility 1995. link57785-1) 14 Fiet J, Gosling JP, Soliman H, Galons H, Boudou P, Aubin P et al.. Hirsutism and acne in women: coordinated radioimmunoassays for eight relevant plasma steroids. Clinical chemistry 1994. link 15 Hughes BR, Cunliffe WJ. Tolerance of spironolactone. The British journal of dermatology 1988. link 16 Barth JH, Dawber RP. Pili torti and hirsuties: are twisted hairs a normal variant?. Acta dermato-venereologica 1987. link 17 Parr JH, Seed M, Godsland I, Wynn V. The effects of reverse sequential anti-androgen therapy (cyproterone acetate and ethinyl estradiol) on hematological parameters. Journal of endocrinological investigation 1987. link 18 Ylöstalo P, Heikkinen J, Kauppila A, Pakarinen A, Järvinen PA. Low-dose spironolactone in the treatment of female hirsutism. International journal of fertility 1987. link 19 Reingold SB, Rosenfield RL. The relationship of mild hirsutism or acne in women to androgens. Archives of dermatology 1987. link 20 Schmidt JB, Spona J, Huber J. Androgen receptor in hirsutism and acne. Gynecologic and obstetric investigation 1986. link 21 Mauvais-Jarvis P. Regulation of androgen receptor and 5 alpha-reductase in the skin of normal and hirsute women. Clinics in endocrinology and metabolism 1986. link80027-5) 22 Rosenfield RL. Pilosebaceous physiology in relation to hirsutism and acne. Clinics in endocrinology and metabolism 1986. link80029-9) 23 Seed M, Godsland IF, Wynn V, Jacobs HS. The effects of cyproterone acetate and ethinyl oestradiol on carbohydrate metabolism. Clinical endocrinology 1984. link 24 Willingham MC, Pastan IH, Sahagian GG. Ultrastructural immunocytochemical localization of the phosphomannosyl receptor in Chinese hamster ovary (CHO) cells. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 1983. link 25 Lachnit-Fixson U. The development and evaluation of an ovulation inhibitor (DIAne) containing an antiandrogen. Acta obstetricia et gynecologica Scandinavica. Supplement 1979. link 26 Cremoncini C, Vignati E, Libroia A. Treatment of hirsutism and acne in women with two combinations of cyproterone acetate and ethinylestradiol. Acta Europaea fertilitatis 1976. link 27 Casey JH. Chronic treatment regimens for hirsutism in women: effect on blood production rates of testosterone and on hair growth. Clinical endocrinology 1975. link

Insulin receptor defect