About
The Journal "Obstetrics and Gynecology"Journal HistoryAims and ScopePolicies on Conflict of Interest, Human and Animal Rights, and Informed ConsentEditorial ProcessData sharing statementAdvertising PolicyThe Process for Handling Cases Requiring Corrections, Retractions, and Editorial Expressions of ConcernEditorial BoardEditorial CounsilInformation for ProfessionalsNewsContacts
ArchiveEthical StandardsSubscription
For authors
InstructionsInformed consent policyContract offerEASE GuidelinesICJME CriteriaWAME Recommendations on ChatGPT and Chatbots in Relation to Scholarly Publications
Reviewing
Procedure for reviewingReviewers 2023-2024
About
The Journal "Obstetrics and Gynecology"Journal HistoryAims and ScopePolicies on Conflict of Interest, Human and Animal Rights, and Informed ConsentEditorial ProcessData sharing statementAdvertising PolicyThe Process for Handling Cases Requiring Corrections, Retractions, and Editorial Expressions of ConcernEditorial BoardEditorial CounsilInformation for ProfessionalsNewsContacts
ArchiveEthical StandardsSubscription
For authors
InstructionsInformed consent policyContract offerEASE GuidelinesICJME CriteriaWAME Recommendations on ChatGPT and Chatbots in Relation to Scholarly Publications
Reviewing
Procedure for reviewingReviewers 2023-2024
Logout
Obstetrics and Gynegology2022№5
Functional hypothalamic amenorrhea in clinical...

Functional hypothalamic amenorrhea in clinical practice: medical and diagnostic features

DOI
https://dx.doi.org/10.18565/aig.2022.5.149-156

Bondarenko K.R., Kazantseva V.D., Dobrokhotova Yu.E.

Pirogov Russian National Research Medical University, Ministry of Health of Russia, Moscow, Russia
The paper presents the current data on the epidemiology, causes, and pathogenesis of functional hypothalamic amenorrhea (FHA). The authors highlight the current therapeutic approaches aimed at eliminating the cause of the disease and at preventing long-term consequences associated with hypoestrogenism in the presence of hypogonadotropic hypogonadism in FHA. The paper describes a clinical case that is used by the authors to analyze the most common diagnostic and therapeutic errors in the management of patients with FHA. The patients with this disease may be effectively treated provided that there is interdisciplinary involvement by professions in mental health and in dietology to normalize eating behavior and to ensure a positive energy balance. According to international and Russian clinical practice guidelines, to restore and maintain bone mineral density, patients with FHA require hormone replacement therapy with transdermal estrogens (for example, as a patch, 0.1% estradiol gel (Divigel), and others) in combination with progestins to protect the endometrium.
Conclusion: Implementation of consistent diagnostic measures, adherence to the clear algorithms that can timely verify FHA, and correctly selected hormone replacement therapy with transdermal estrogens will be able to level off the symptoms of the disease and to prevent long-term complications as osteoporosis and cardiovascular diseases.

Keywords

amenorrhea
functional hypothalamic amenorrhea
replacement hormone therapy
transdermal estrogens
Full text (in Russian)

References

  1. Gordon C.M., Ackerman K.E., Berga S.L., Kaplan J.R., Mastorakos G., Misra M. et al. Functional hypothalamic amenorrhea: An Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 2017; 102(5): 1413-9. https://dx.doi.org/10.1210/jc.2017-00131.
  2. Lippincott M.F., True C., Seminara S.B. Use of genetic models of idiopathic hypogonadotrophic hypogonadism in mice and men to understand the mechanisms of disease. Exp. Physiol. 2013; 98(11): 1522-7. https://dx.doi.org/10.1113/expphysiol.2013.071910.
  3. Castinetti F., Taieb D., Henry J.F., Walz M., Guerin C., Brue T. et al. MANAGEMENT OF ENDOCRINE DISEASE: Outcome of adrenal sparing surgery in heritable pheochromocytoma. Eur. J. Endocrinol. 2016; 174(1): R9-18. https://dx.doi.org/10.1530/EJE-15-0549.
  4. Gordon C.M. Clinical practice. Functional hypothalamic amenorrhea. N. Engl. J. Med. 2010; 363(4): 365-71. https://dx.doi.org/10.1056/NEJMcp0912024.
  5. Caronia L.M., Martin C., Welt C.K., Sykiotis G.P., Quinton R., Thambundit A. et al. A genetic basis for functional hypothalamic amenorrhea. N. Engl. J. Med. 2011; 364(3): 215-25. https://dx.doi.org/10.1056/NEJMoa0911064.
  6. Practice Committee of the American Society for Reproductive Medicine. Current evaluation of amenorrhea. Fertil. Steril. 2006; 86(5, Suppl. 1): S148-55. https://dx.doi.org/10.1016/j.fertnstert.2006.08.013.
  7. Бондаренко К.Р., Доброхотова Ю.Э. Клинические маски вторичной аменореи: лечение заболевания, а не симптома. Акушерство и гинекология. 2021; 8: 206-18. [Bondarenko K.R., Dobrokhotova Yu.E. Clinical masks of secondary amenorrhea: treatment of the disease rather than its symptom. Obstetrics and Gynecology. 2021; 8: 206-18. (in Russian)]. https://dx.doi.org/10.18565/aig.2021.8.206-218.
  8. Silveira L.G., Noel S.D., Silveira-Neto A.P., Abreu A.P., Brito V.N., Santos M.G. et al. Mutations of the KISS1 gene in disorders of puberty. J. Clin. Endocrinol. Metab. 2010; 95(5): 2276-80. https://dx.doi.org/10.1210/jc.2009-2421.
  9. Jayasena C.N., Abbara A., Veldhuis J.D., Comninos A.N., Ratnasabapathy R., De Silva A. et al. Increasing LH pulsatility in women with hypothalamic amenorrhoea using intravenous infusion of Kisspeptin-54. J. Clin. Endocrinol. Metab. 2014; 99(6): E953-61. https://dx.doi.org/10.1210/jc.2013-1569.
  10. Carr B.R., Blackwell R.E., Azziz R. Essential reproductive medicine. McGraw-Hill Medical; 2015: 276-7.
  11. Loucks A.B., Thuma J.R. Luteinizing hormone pulsatility is disrupted at a threshold of energy availability in regularly menstruating women. J. Clin. Endocrinol. Metab. 2003; 88(1): 297-311. https://dx.doi.org/10.1210/jc.2002-020369.
  12. Loucks A.B., Kiens B., Wright H.H. Energy availability in athletes. J. Sports Sci. 2011; 29(Suppl. 1): S7-15. https://dx.doi.org/10.1080/02640414.2011.588958.
  13. Reame N.E., Sauder S.E., Case G.D., Kelch R.P., Marshall J.C. Pulsatile gonadotropin secretion in women with hypothalamic amenorrhea: evidence that reduced frequency of gonadotropin-releasing hormone secretion is the mechanism of persistent anovulation. J. Clin. Endocrinol. Metab. 1985; 61(5): 851-8. https://dx.doi.org/10.1210/jcem-61-5-851.
  14. De Souza M.J., Miller B.E., Loucks A.B., Luciano A.A., Pescatello L.S., Campbell C.G., Lasley B.L. High frequency of luteal phase deficiency and anovulation in recreational women runners: blunted elevation in follicle-stimulating hormone observed during luteal-follicular transition. J. Clin. Endocrinol. Metab. 1998; 83(12): 4220-32. https://dx.doi.org/10.1210/jcem.83.12.5334.
  15. Misra M., Miller K.K., Bjornson J., Hackman A., Aggarwal A., Chung J. et al. Alterations in growth hormone secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism. J. Clin. Endocrinol. Metab. 2003; 88(12): 5615-23. https://dx.doi.org/10.1210/jc.2003-030532.
  16. De Souza M.J., Nattiv A., Joy E., Misra M., Williams N.I., Mallinson R.J. et al. 2014 Female Athlete Triad Coalition consensus statement on treatment and return to play of the female athlete riad: 1st International Conference held in San Francisco, California, May 2012 and 2nd International Conference held in Indianapolis, Indiana, May 2013. Br. J. Sports Med. 2014; 48(4): 289. https://dx.doi.org/10.1136/bjsports-2013-093218.
  17. Meczekalski B., Katulski K., Czyzyk A., Podfigurna-Stopa A., Maciejewska-Jeske M. Functional hypothalamic amenorrhea and its influence on women's health. J. Endocrinol. Invest. 2014; 37(11): 1049-56. https://dx.doi.org/10.1007/s40618-014-0169-3.
  18. Podfigurna-Stopa A., Pludowski P., Jaworski M., Lorenc R., Genazzani A.R., Meczekalski B. Skeletal status and body composition in young women with functional hypothalamic amenorrhea. Gynecol. Endocrinol. 2012; 28(4):299-304. https://dx.doi.org/10.3109/09513590.2011.613972.
  19. Drinkwater B.L., Nilson K., Chesnut C.H.I., Bremner W.J., Shainholtz S., Southworth M.B. Bone mineral content of amenorrheic and eumenorrheic athletes. N. Engl. J. Med. 1984; 311(5): 277-81. https://dx.doi.org/10.1056/NEJM198408023110501.
  20. Friday K.E., Drinkwater B.L., Bruemmer B., Chesnut C. 3 rd, Chait A. Elevated plasma low-density lipoprotein and high-density lipoprotein cholesterol levels in amenorrheic athletes: effects of endogenous hormone status and nutrient intake. J. Clin. Endocrinol. Metab. 1993; 77(6): 1605-9. https://dx.doi.org/10.1210/jcem.77.6.8263148.
  21. O'Donnell E., De Souza M.J. The cardiovascular effects of chronic hypoestrogenism in amenorrhoeic athletes: a critical review. Sports Med. 2004; 34(9): 601-27. https://dx.doi.org/10.2165/00007256-200434090-00004.
  22. Hoch A.Z., Papanek P., Szabo A., Widlansky M.E., Schimke J.E., Gutterman D.D. Association between the female athlete triad and endothelial dysfunction in dancers. Clin. J. Sport Med. 2011; 21(2): 119-25. https://dx.doi.org/10.1097/JSM.0b013e3182042a9a.
  23. Kaplan J.R., Manuck S.B. Ovarian dysfunction and the premenopausal origins of coronary heart disease. Menopause. 2008; 15(4, Pt 1): 768-76. https://dx.doi.org/10.1097/gme.0b013e31815eb18e.
  24. Чернуха Г.Е., Гусев Д.В., Табеева Г.И., Прилуцкая В.Ю. Современные обоснования терапии функциональной гипоталамической аменореи. Акушерство и гинекология. 2018; 6: 11-7. [Chernukha G.E., Gusev D.V., Tabeeva G.I., Priluckaya V.Yu. Current principles of therapy for functional hypothalamic amenorrhea. Obstetrics and Gynecology. 2018; 6: 11-7. (in Russian)]. https://dx.doi.org/10.18565/aig.2018.6.11-17.
  25. Bulun S. Physiology and pathology of the female reproductive axis. In: Melmed S., Kenneth S., Larsen P.R., Kronenberg H., eds. Williams textbook of endocrinology. 13th ed. Philadelphia, PA: Elsevier; 2016: 590-664.
  26. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Washington, DC: American Psychiatry Association; 2013.
  27. Kopp-Woodroffe S.A., Manore M.M., Dueck C.A., Skinner J.S., Matt K.S. Energy and nutrient status of amenorrheic athletes participating in a diet and exercise training intervention program. Int. J. Sport Nutr. 1999; 9(1): 70-88. https://dx.doi.org/10.1123/ijsn.9.1.70.
  28. De Souza M.J., Nattiv A., Joy E., Misra M., Williams N.I., Mallinson R. et al. 2014 Female Athlete Triad Coalition consensus statement on treatment and return to play of the female athlete triad: 1st International Conference held in San Francisco, CA, May 2012, and 2nd International Conference held in Indianapolis, IN, May 2013. Clin. J. Sport Med. 2014; 24(2): 96-119. https://dx.doi.org/10.1097/JSM.0000000000000085.
  29. Arends J.C., Cheung M.Y., Barrack M.T., Nattiv A. Restoration of menses with nonpharmacologic therapy in college athletes with menstrual disturbances: a 5-year retrospective study. Int. J. Sport Nutr. Exerc. Metab. 2012; 22(2): 98-108. https://dx.doi.org/10.1123/ijsnem.22.2.98.
  30. Cialdella-Kam L., Guebels C.P., Maddalozzo G.F., Manore M.M. Dietary intervention restored menses in female athletes with exercise-associated menstrual dysfunction with limited impact on bone and muscle health. Nutrients. 2014; 6(8): 3018-39. https://dx.doi.org/10.3390/nu6083018.
  31. Golden N.H., Jacobson M.S., Schebendach J., Solanto M.V., Hertz S.M., Shenker I.R. Resumption of menses in anorexia nervosa. Arch. Pediatr. Adolesc. Med. 1997; 151(1): 16-21. https://dx.doi.org/10.1001/archpedi.1997.02170380020003.
  32. Muñoz M.T., Morandé G., García-Centenera J.A., Hervás F., Pozo J., Argente J. The effects of estrogen administration on bone mineral density in adolescents with anorexia nervosa. Eur. J. Endocrinol. 2002; 146(1): 45-50. https://dx.doi.org/10.1530/eje.0.1460045.
  33. Golden N.H., Lanzkowsky L., Schebendach J., Palestro C.J., Jacobson M.S., Shenker I.R. The effect of estrogen-progestin treatment on bone mineral density in anorexia nervosa. J. Pediatr. Adolesc. Gynecol. 2002; 15(3): 135-43. https://dx.doi.org/10.1016/s1083-3188(02)00145-6.
  34. Rickenlund A., Carlström K., Ekblom B., Brismar T.B., Von Schoultz B., Hirschberg A.L. Effects of oral contraceptives on body composition and physical performance in female athletes. J. Clin. Endocrinol. Metab. 2004; 89(9): 4364-70. https://dx.doi.org/10.1210/jc.2003-031334.
  35. Warren M.P., Brooks-Gunn J., Fox R.P., Holderness C.C., Hyle E.P. Hamilton W.G., Hamilton L. Persistent osteopenia in ballet dancers with amenorrhea and delayed menarche despite hormone therapy: a longitudinal study. Fertil. Steril. 2003; 80(2): 398-404. https://dx.doi.org/10.1016/s0015-0282(03)00660-5.
  36. Bachrach L.K., Guido D., Katzman D., Litt I.F., Marcus R. Decreased bone density in adolescent girls with anorexia nervosa. Pediatrics. 1990; 86(3): 440-7.
  37. Weissberger A.J., Ho K.K., Lazarus L. Contrasting effects of oral and transdermal routes of estrogen replacement therapy on 24-hour growth hormone (GH) secretion, insulin-like growth factor I, and GH-binding protein in postmenopausal women. J. Clin. Endocrinol. Metab. 1991; 72(2): 374-81. https://dx.doi.org/10.1210/jcem-72-2-374.
  38. Cardim H.J., Lopes C.M., Giannella-Neto D., da Fonseca A.M., Pinotti J.A. The insulin-like growth factor-I system and hormone replacement therapy. Fertil. Steril. 2001; 75(2): 282-7. https://dx.doi.org/10.1016/s0015-0282(00)01691-5.
  39. Kam G.Y., Leung K.C., Baxter R.C., Ho K.K. Estrogens exert route- and dose-dependent effects on insulin-like growth factor (IGF)-binding protein-3 and the acid-labile subunit of the IGF ternary complex. J. Clin. Endocrinol. Metab. 2000; 85(5): 1918-22. https://dx.doi.org/10.1210/jcem.85.5.6527.
  40. Министерство здравоохранения Российской Федерации. Клинические рекомендации. Аменорея и олигоменорея. 2021. [Ministry of Healthcare of the Russian Federation. Oligomenorrhea and amenorrhea. Clinical guidelines. 2021. (in Russian)].
  41. Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum. Reprod. 2004; 19(1): 41-7. https://dx.doi.org/10.1093/humrep/deh098.
  42. Peña A.S., Witchel S.F., Hoeger K.M., Oberfield S.E., Vogiatzi M.G., Misso M. et al. Adolescent polycystic ovary syndrome according to the international evidence-based guideline. BMC Med. 2020; 18(1): 72. https://dx.doi.org/10.1186/s12916-020-01516-x.
  43. Lauritsen M.P., Pinborg A., Loft A., Petersen J.H., Mikkelsen A.L., Bjerge M.R. et al. Revised criteria for PCOS in WHO Group II anovulatory infertility – a revival of hypothalamic amenorrhoea? Clin. Endocrinol. (Oxford). 2015; 82(4): 584-91. https://dx.doi.org/10.1111/cen.12621.

Received 26.04.2022

Accepted 06.05.2022

About the Authors

Karina R. Bondarenko, Dr. Med. Sci., Associate Professor at the Department of Obstetrics and Gynecology of the Faculty of Medicine, Pirogov Russian National Research Medical University, Ministry of Health of Russia, karinabond@mail.ru , https://orcid.org/0000-0003-4147-1151 , SPIN code: 9976-0735, AuthorID: 798660, 117997, Russia, Moscow, Ostrovityanova str., 1.
Valeria D. Kazantseva, PhD student of the Department of Obstetrics and Gynecology of the Faculty of Medicine, Pirogov Russian National Research Medical University, Ministry of Health of Russia, shapee08@mail.ru, https://orcid.org/0000-0002-4011-3195, 117997, Russia, Moscow, Ostrovityanova str., 1.
Yulia E. Dobrokhotova, Dr. Med. Sci., Professor, Head of the Department of Obstetrics and Gynecology of the Faculty of Medicine, Pirogov Russian National Research Medical University, Ministry of Health of Russia, pr.dobrohotova@mail.ru, https://orcid.org/0000-0002-7830-2290, SPIN-code: 2925-9948, AuthorID: 312767,
117997, Russia, Moscow, Ostrovityanova str., 1.
Corresponding author: Karina R. Bondarenko, karinabond@mail.ru

Authors' contributions: Bondarenko K.R. – development of the idea of the article, writing the article, development of the diagnostic algorithm; Dobrokhotova Yu.E., Kazantseva V.D. – information collection, writing the article.
Conflicts of interest: The authors declare that there are no possible conflicts of interest.
Funding: The investigation has not been sponsored.
For citation: Bondarenko K.R., Kazantseva V.D., Dobrokhotova Yu.E. Functional hypothalamic amenorrhea in clinical practice: medical and diagnostic features.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2022; 5: 149-156 (in Russian)
https://dx.doi.org/10.18565/aig.2022.5.149-156

Similar Articles

№2 / 2018
Chernukha G.E., Tabeeva G.I., Gusev D.V., Kuznetsov S.Yu.
Estimation of adipose tissue indicators in functional hypothalamic amenorrhea
№3 / 2016
Podzolkova N.M., Puchkov K.V., Korennaya V.V.
Experience with ulipristal acetate in patients with uterine myoma
№3 / 2019
Chernukha G.E., Gusev D.V., Tabeeva G.I., Marchenko L.A.
New opportunities of clomiphene citrate treatment for functional hypothalamic amenorrhea
№6 / 2015
Yureneva S.V.
Optimization of menopausal hormone therapy-related risks: Therapy with transdermal estrogens alone or in combination with micronized progesterone
№5 / 2015
Yureneva S.V.
Optimization of menopausal hormone therapy-related risks: Monotherapy with transdermal estrogens or in combination with micronized progesterone. Advantages against venous thromboembolism and breast cancer
By continuing to use our site, you consent to the processing of cookies that ensure the proper functioning of the site.