Effectiveness of a differentiated approach to the treatment of patients with polycystic ovary syndrome using inositols and combined oral contraceptives in early reproductive age

Khashchenko E.P., Nadzharyan A.G., Uvarova E.V.

1) Academician V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, Moscow, Russia; 2) M.V. Lomonosov Moscow State University, Moscow, Russia; 3) I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia
Objective. To evaluate the effectiveness of treatment of girls aged 15–18 years with different phenotypes of polycystic ovary syndrome (PCOS) using combined oral contraceptives (COCs) and inositols depending on overweight and insulin resistance in girls. Materials and methods. The study included 153 patients aged 15–18 years with PCOS and 32 healthy controls; girls of the study group had oligo/amenorrhea, hyperandrogenism, and polycystic ovarian morphology revealed by the ultrasound assessment. The comparative analysis of clinical and anamnestic data of patients with PCOS (n=153) and the control group (n=32) was performed at the first stage of the study. Depending on the PCOS phenotype, overweight, and insulin resistance, there were groups of hormonal and non-hormonal management; the results of the clinical examination were compared before the administration of therapy and 6 months after it. The groups were compared with each other and with the control group; the results obtained after receiving the treatment were compared with the baseline values and with the group of healthy girls. Results. Before the therapy, the patients with PCOS showed a significant increase in the level of luteinizing hormone (LH), testosterone (T), androstenedione, anti-Müllerian hormone (AMH), and free androgen index (FIA) accompanied by low levels of sex hormone-binding globulin (SHBG) (p<0.0001 for all indicators) as well as significantly higher levels of 17-OHP, DHEA-S, and cortisol (p<0.005). Phenotypes B and D differed from phenotype A having higher levels of LH, T, androstenedione, and FIA (p<0.005 for all indicators). After the therapy with combined oral contraceptives, patients with phenotype A showed a significant decrease in LH, T, FIA, DHEA-S, androstenedione (p<0.005 for all indicators) and ovarian volume (p<0.005), but it was necessary to continue administering therapy, as the main hormonal and ultrasound characteristics were not normalized. A half of the patients with phenotypes B and D who received non-hormonal treatment with inositols showed a clinical effect after 6 months; their menstrual cycle restored and the main hormonal parameters were normalized according to the levels of LH, T, FIA, and SHBG. As the result did not demonstrate statistical significance and normative values, it was necessary to continue administering the non-hormonal therapy. There was no clinical effect of non-hormonal therapy in 13.6% of patients with PCOS, therefore, the therapy was changed. Conclusion. The administration of microdosed COCs with drospirenone for 6 months demonstrated its clinical effectiveness in the treatment of teenagers with classic PCOS, however, this period of administration was not sufficient for the clinical effect. It is recommended to continue the treatment of PCOS with COCs in teenagers for more than 6 months, and assess the hormonal parameters and the degree of hyperandrogenism before withdrawal of the drugs. The clinical effect was also observed in patients with non-classical PCOS after receiving non-hormonal combined therapy, namely the 5:1 ratio of myoinositol and D-chiroinositol. There was a tendency for normalization of hormonal and ultrasound parameters, which did not reach the standard values, so the therapy should be continued. However, the treatment had to be changed in 13% of the patients as they did not respond to the therapy.

Keywords

polycystic ovary syndrome
overweight
insulin resistance
hyperandrogenism
hyperglycemia
myo-inositol
D-chiroinositol
combined oral contraceptives

References

  1. Teede H.J., Misso M.L., Costello M.F., Dokras A., Laven J., Moran L. et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil. Steril. 2018; 110(3): 364-79. https://dx.doi.org/10.1016/j.fertnstert.2018.05.004.
  2. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil. Steril. 2004; 81(1): 19-25. https://dx.doi.org/10.1016/j.fertnstert.2003.10.004.
  3. Хащенко Е.П., Уварова Е.В., Мамедова Ф.Ш. Фенотипические особенности синдрома поликистозных яичников у девочек подросткового возраста. Репродуктивное здоровье детей и подростков. 2017; 1: 37-50. [Khashchenko E.P., Uvarova E.V., Mamedova F.Sh. Phenotypic features of polycystic ovary syndrome in adolescent girls. Reproductive health of children and adolescents. 2017; 1: 37-50. (in Russian)].
  4. Legro R.S., Arslanian S.A., Ehrmann D.A., Hoeger K.M., Murad M.H., Pasquali R. et al. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 2013; 98(12): 4565-92. https://dx.doi.org/10.1210/jc.2013-2350.
  5. Fenton C., Wellington K., Moen M.D., Robinson D.M. Drospirenone/ethinylestradiol 3mg/20microg (24/4 day regimen): a review of its use in contraception, premenstrual dysphoric disorder and moderate acne vulgaris. Drugs. 2007; 67(12): 1749-65. https://dx.doi.org/10.2165/00003495-200767120-00007.
  6. Bhattacharya S.M., Jha A., DasMukhopadhyay L. Comparison of two contraceptive pills containing drospirenone and 20 μg or 30 μg ethinyl estradiol for polycystic ovary syndrome. Int. J. Gynaecol. Obstet. 2016; 132(2): 210-3. https://dx.doi.org/10.1016/j.ijgo.2015.06.065.
  7. Vitek W., Hoeger K.M. Treatment of polycystic ovary syndrome in adolescence. Semin. Reprod. Med. 2014; 32(3): 214-21. https://dx.doi.org/10.1055/s-0034-1371093.
  8. Bachmann G., Kopacz S. Drospirenone/ethinyl estradiol 3 mg/20 mug (24/4 day regimen): hormonal contraceptive choices - use of a fourth-generation progestin. Patient Prefer. Adherence. 2009; 3: 259-64. https://dx.doi.org/10.2147/ppa.s3901.
  9. Kouzi S.A., Yang S., Nuzum D.S., Dirks-Naylor A.J. Natural supplements for improving insulin sensitivity and glucose uptake in skeletal muscle. Front. Biosci. (Elite Ed). 2015; 7: 94-106.
  10. Genazzani A.D., Shefer K., Della Casa D., Prati A., Napolitano A., Manzo A. et al. Modulatory effects of alpha-lipoic acid (ALA) administration on insulin sensitivity in obese PCOS patients. J. Endocrinol. Invest. 2018; 41(5): 583-90. https://dx.doi.org/10.1007/s40618-017-0782-z.
  11. Genazzani A.D., Despini G., Santagni S., Prati A., Rattighieri E., Chierchia E. et al. Effects of a combination of alpha lipoic acid and myo-inositol on insulin dynamics in overweight/obese patients with PCOS. Endocrinol. Metab. Synd. 2014; 3: 3. https://dx.doi.org/10.4172/2161-1017.1000140.
  12. Rago R., Marcucci I., Leto G., Caponecchia L., Salacone P., Bonanni P. et al. Effect of myo-inositol and alpha-lipoic acid on oocyte quality in polycystic ovary syndrome non-obese women undergoing in vitro fertilization: a pilot study. J. Biol. Regul. Homeost. Agents. 2015; 29(4): 913-23.
  13. Morgante G., Cappelli V., Di Sabatino A., Massaro M.G., De Leo V. Polycystic ovary syndrome (PCOS) and hyperandrogenism: the role of a new natural association. Minerva Ginecol. 2015; 67(5): 457-63.
  14. Cianci A., Panella M., Fichera M., Falduzzi C., Bartolo M., Caruso S. D-chiro-inositol and alpha lipoic acid treatment of metabolic and menses disorders in women with PCOS. Gynecol. Endocrinol. 2015; 31(6): 483-6. https://dx.doi.org/10.3109/09513590.2015.1014784.
  15. Masharani U., Gjerde C., Evans J.L., Youngren J.F., Goldfine I.D. Effects of controlled-release alpha lipoic acid in lean, nondiabeticpatients with polycystic ovary syndrome. J. Diabetes Sci. Technol. 2010; 4(2): 359-64. https://dx.doi.org/10.1177/193229681000400218.
  16. Bene J., Hadzsiev K., Melegh B. Role of carnitine and its derivatives in the development and management of type 2 diabetes. Nutr. Diabetes. 2018; 8(1): 8. https://dx.doi.org/10.1038/s41387-018-0017-1.
  17. Pekala J., Patkowska-Sokoła B., Bodkowski R., Jamroz D., Nowakowski P., Lochyński S. et al. L-carnitine-metabolic functions and meaning in humans life. Curr. Drug Metab. 2011; 12(7): 667-78. https://dx.doi.org/ 10.2174/138920011796504536.
  18. Salehpour S., Nazari L., Hoseini S., Moghaddam P.B., Gachkar L. Effects of L-carnitine on polycystic ovary syndrome. JBRA Assist. Reprod. 2019; 23(4): 392-5. https://dx.doi.org/10.5935/1518-0557.20190033.
  19. Samimi M., Jamilian M., Ebrahimi F.A., Rahimi M., Tajbakhsh B., Asemi Z. Oral carnitine supplementation reduces body weight and insulin resistance in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. Clin. Endocrinol. (Oxf). 2016; 84(6): 851-7. https://dx.doi.org/10.1111/cen.13003.
  20. El Sharkwy I., Sharaf El-Din M. l-carnitine plus metformin in clomiphene-resistant obese PCOS women, reproductive and metabolic effects: a randomized clinical trial. Gynecol. Endocrinol. 2019; 35(8): 701-5. https://dx.doi.org/10.1080/09513590.2019.1576622.
  21. Ismail A.M., Hamed A.H., Saso S., Thabet H.H. Adding L-carnitine to clomiphene resistant PCOS women improves the quality of ovulation and the pregnancy rate. A randomized clinical trial. Eur. J. Obstet. Gynecol. Reprod. Biol. 2014; 180: 148-52. https://dx.doi.org/10.1016/j.ejogrb.2014.06.008.
  22. Vigerust N.F., Bohov P., Bjørndal B., Seifert R., Nygård O., Svardal A. et al. Free carnitine and acylcarnitines in obese patients with polycystic ovary syndrome and effects of pioglitazone treatment. Fertil. Steril. 2012; 98(6): 1620-6. e1. https://dx.doi.org/10.1016/j.fertnstert.2012.08.024.
  23. Fenkci S.M., Fenkci V., Oztekin O., Rota S., Karagenc N. Serum total L-carnitine levels in non-obese women with polycystic ovary syndrome. Hum. Reprod. 2008; 23(7): 1602-6. https://dx.doi.org/10.1093/humrep/den109.
  24. Laganà A.S., Garzon S., Casarin J., Franchi M., Ghezzi F. Inositol in polycystic ovary syndrome: restoring fertility through a pathophysiology-based approach. Trends Endocrinol. Metab. 2018; 29(11): 768-80. https://dx.doi.org/10.1016/j.tem.2018.09.001.
  25. Zeng L., Yang K. Effectiveness of myoinositol for polycystic ovary syndrome: a systematic review and meta-analysis. Endocrine. 2018; 59(1): 30-8. https://dx.doi.org/10.1007/s12020-017-1442-y.
  26. Facchinetti F., Orrù B., Grandi G., Unfer V. Short-term effects of metformin and myo-inositol in women with polycystic ovarian syndrome (PCOS): a meta-analysis of randomized clinical trials. Gynecol. Endocrinol. 2019; 35(3): 198-206. https://dx.doi.org/10.1080/09513590.2018.1540578.
  27. Pundir J., Psaroudakis D., Savnur P., Bhide P., Sabatini L., Teede H. et al. Inositol treatment of anovulation in women with polycystic ovary syndrome: a meta-analysis of randomised trials. BJOG. 2018; 125(3): 299-308. https://dx.doi.org10.1111/1471-0528.14754.
  28. Pkhaladze L., Barbakadze L., Kvashilava N. Myo-inositol in the treatment of teenagers affected by PCOS. Int. J. Endocrinol. 2016; 2016: 1473612. https://dx.doi.org/10.1155/2016/1473612.

Received 11.03.2021

Accepted 18.03.2021

About the Authors

Elena P. Khashchenko, PhD, senior researcher, 2nd Gynecological Department (children and adolescent gynecology), V.I. Kulakov National Medical Research Center
for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia. Tel.: +7(495)438-85-42. Е-mail: khashchenko_elena@mail.ru. ORCID: 0000-0002-3195-307X.
117997, Russia, Moscow, Ac. Oparina str., 4.
Ani G. Nadzharyan, student of the Faculty of Fundamental Medicine, Lomonosov Moscow State University. E-mail: ani_nad@list.ru.
119991, Russia, Moscow, Leninskiye Gory, д. 1.
Elena V. Uvarova, Dr. Med. Sci., Professor, Head of the 2nd Gynecological Department (children and adolescent gynecology), V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia; Professor of the Department of Obstetrics, Gynecology, Perinatology and Reproductology, Institute of Professional Education, Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University). E-mail: elena-uvarova@yandex.ru. ORCID: 0000-0002-3105-5640. 117997, Russia, Moscow, Ac. Oparina str., 4.

For citation: Khashchenko E.P., Nadzharyan A.G., Uvarova E.V. Effectiveness of a differentiated approach to the treatment of patients with polycystic ovary syndrome using inositols and combined oral contraceptives in early reproductive age.
Akusherstvo i Ginekologiya / Obstetrics and gynecology. 2021; 3: 154-166 (in Russian)
https://dx.doi.org/10.18565/aig.2021.3.154-166

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