Hypogonadism in adolescent girls: treatment and long-term effects

Hypogonadism in adolescent girls: treatment and long-term effects

Authors

  • Kleanthi Voutsadaki Department of Pediatrics, Venizeleion General Hospital Heraklion, Crete, Greece
  • Michail Matalliotakis Obstetrics and Gynecology Department of Venizeleion General Hospital Heraklion, Crete, Greece https://orcid.org/0000-0002-2967-184X
  • Fani Ladomenou Department of Pediatrics, Venizeleion General Hospital Heraklion, Crete, Greece

Keywords:

Hypogonadism, adolescent girls, treatment, long-term effects

Abstract

Background and aim: Hypogonadism in adolescent females presents as delayed puberty or primary amenorrhea. Constitutional delay of growth and puberty, hypogonadotropic hypogonadism and hypergonadotropic hypogonadism represent the principal differential diagnosis of delayed puberty. Girls with hypogonadism require hormone replacement therapy to initiate and sustain puberty. We aimed to provide a brief review concerning treatment for female adolescents with hypogonadism and further to focus on current data regarding long-term effects of therapy.

Methods: The published studies and articles of the international literature were used regarding the approach to adolescent girls with hypogonadism.

Results: The aim of therapy is the development of secondary sexual characteristics and achievement of target height, body composition and bone mass, to promote psychosexual health and, finally, to maximize the potential for fertility. Hypogonadal females need long-term HRT, so it is of great importance to fully define risks and benefits of therapy.

Conclusions: The optimal pubertal induction in women contains both estrogens and progesterone regimens.  Different therapeutic options have been described over the years in the literature, but larger randomized trials are required in order to define the ideal approach. The latest acquisitions in the field seem to propose that transdermal 17β-estradiol and micronized progesterone present the most physiological formulations available for this purpose. Further studies and follow up are needed concerning the long-term effects of HRT in adolescents.

References

Howard SR, Dunkel L. Delayed puberty - phenotypic diversity, molecular genetic mechanisms, and recent discoveries. Endocr Rev 2019; 40: 1285–1317.

Parent AS, Teilmann G, Juul A, Skakkebaek NE, Toppari J, Bourguignon JP. The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration. Endocr Rev 2003; 24: 668–93.

Young J, Xu C, Papadakis GE et al. Clinical management of congenital hypogonadotropic hypogonadism. Endocr Rev 2019; 40: 669–710.

Nordenström A, Ahmed S F, Van den Akker E, et al. Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline. Eur J Endocrinol 2022;186: G9–49.

Dunkel L, Quinton R. Transition in endocrinology: induction of puberty. Eur J Endocrinol 2014;170:R229-39.

Palmert MR, Dunkel L. Clinical practice. Delayed puberty. N Engl J Med 2012; 366:443-53.

Sedlmeyer IL, Palmert MR. Delayed puberty: analysis of a large case series from an academic center. J Clin Endocrinol Metab 2002;87:1613–20.

Varimo T, Miettinen PJ, Känsäkoski J, Raivio T, Hero M. Congenital hypogonadotropic hypogonadism, functional hypogonadotropism or constitutional delay of growth and puberty? An analysis of a large patient series from a single tertiary center. Hum Reprod 2017; 32:147–53.

Boehm U, Bouloux PM, Dattani MT, et al. Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism: pathogenesis, diagnosis and treatment. Nat Rev Endocrinol 2015; 11: 547–64.

Hietamäki J, Hero M, Holopainen E, et al. GnRH receptor gene mutations in adolescents and young adults presenting with signs of partial gonadotropin deficiency. PLOS ONE 2017; 12: e0188750.

Seppä S, Kuiri-Hänninen T, Holopainen E, Voutilainen R. Diagnosis and management of primary amenorrhea and female delayed puberty. Eur J Endocrinol 2021;184: R225-42.

Silveira LFG, Latronico AC. Approach to the patient with hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2013; 98: 1781–8.

Higham CE, Johannsson G, Shalet SM. Hypopituitarism. Lancet 2016; 388: 2403–2415.

Gordon CM, Ackerman KE, Berga SLm et al. Functional hypothalamic amenorrhea: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2017;102: 1413–39.

Kanner L, Hakim JCE, Davis Kankanamge Cm et al. Noncytotoxic-related primary ovarian insufficiency in adolescents: multicenter case series and review. J Pediatr Adolesc Gynecol 2018; 31: 597–604m

Kanj RV, Ofei-Tenkorang NA, Altaye M, Gordon CM. Evaluation and management of primary ovarian insufficiency in adolescents and young adults. J Pediatr Adolesc Gynecol 2018;31:13–8.

Huhtaniemi I, Hovatta O, La Marca A, et al. Advances in the molecular pathophysiology, genetics, and treatment of primary ovarian insufficiency. Trends Endocrinol Metab 2018; 29: 400–19.

Auchus RJ. Steroid 17-hydroxylase and 17,20-lyase deficiencies, genetic and pharmacologic. J Steroid Biochem Mol Biol 2017; 165: 71–8.

Berglund A, Viuff MH, Skakkebæk A, Chang S, Stochholm K ,Gravholt CH. Changes in the cohort composition of Turner syndrome and severe non-diagnosis of Klinefelter, 47,XXX and 47,XYY syndrome: A nationwide cohort study. Orphanet J Rare Dis 2019; 14: 16.

Khater D, De Sanctis V. Autoimmune diseases in Turner syndrome: an overview. Acta Biomed 2019; 90:341-4.

Klein KO, Phillips SA. Review of Hormone Replacement Therapy in Girls and Adolescents with Hypogonadism, J Pediatr Adolesc Gynecol 2019; 32:460-8.

Matthews D, Bath L, Högler W, Mason A, Smyth A, Skae M. Hormone supplementation for pubertal induction in girls. Arch Dis Child 2017;102:975-80.

Rosenfield RL, Devine N, Hunold JJ, Mauras N, Moshang Jr T, Root AW. Salutary effects of combining early very low-dose systemic estradiol with growth hormone therapy in girls with Turner syndrome. J Clin Endocrinol Metab 2005; 90:6424-30.

Howard SR, Dunkel L. Management of Hypogonadism From Birth to Adolescence, Best Pract Res Clin Endocrinol Metab 2018;32:355-72.

Ankarberg-Lindgren C, Kristrom B, Norjavaara E. Physiological estrogen replacement therapy for puberty induction in girls: a clinical observational study. Horm Res Paediatr 2014;81:239-44.

Shifren JL, Gass ML, NAMS Recommendations for Clinical Care of Midlife Women Working Group. The North American Menopause Society recommendations for clinical care of midlife women. Menopause 2014;21:1038–62.

Lee AJ, Cai MX, Thomas PE, Conney AH, Zhu BT. Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Endocrinology 2003; 144:3382-98.

Lepine J, Bernard O, Plante M, et al. Specificity and regioselectivity of the conjugation of estradiol, estrone, and their catecholestrogen and methoxyestrogen metabolites by human uridine diphospho-glucuronosyltransferases expressed in endometrium. J Clin Endocrinol Metab 2004; 89:5222-32.

Levesque E, Turgeon D, Carrier JS, Montminy V, Beaulieu M, Bélanger A. Isolation and characterization of the UGT2B28 cDNA encoding a novel human steroid conjugating UDP glucuronosyltransferase. Biochemistry 2001; 40:3869-81.

Federici S, Goggi G, Quinton R, et al. New and Consolidated Therapeutic Options for Pubertal Induction in Hypogonadism: In-depth Review of the Literature. Endocr Rev 2021:bnab043.

Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ 2019;364:k4810,

Smith NL, Blondon M, Wiggins KL, et al. Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens. JAMA Intern Med 2014;174:25-31.

O’Donnell RL, Warner P, Lee RJ, et al. Physiological sex steroid replacement in premature ovarian failure: randomized crossover trial of effect on uterine volume, endometrial thickness and blood flow, compared with a standard regimen. Hum Reprod 2012;27:1130-8.

Asscheman H, Giltay EJ, Megens JA, de Ronde WP, van Trotsenburg MA, Gooren LJ. A long-term follow-up study of mortality in transsexuals receiving treatment with cross-sex hormones. Eur J Endocrinol 2011;164:635-42.

Schierbeck LL, Rejnmark L, Tofteng CL et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ 2012; 345:e6409.

Nabhan Z, Eugster EA. Hormone replacement therapy in children with hypogonadotropic hypogonadism: where do we stand? Endocr Pract 2013;19:968-71.

Zacharin M. Disorders of puberty: pharmacotherapeutic strategies for management. Handb Exp Pharmacol 2020;261:507-38.

Davenport ML. Approach to the patient with Turner syndrome. J Clin Endocrinol Metab 2010;95:1487-95.

Torres-Santiago L, Mericq V, Taboada M, et al. Metabolic effects of Oral vs. Transdermal 17beta Estradiol (E2): a randomized clinical trial in girls with Turner Syndrome. J Clin Endocrinol Metab 2013; 98: 2716–24.

Taboada M, Santen R, Lima J, et al. Pharmacokinetics and pharmacodynamics of oral and transdermal 17β estradiol in girls with Turner syndrome. J Clin Endocrinol Metab 2011; 96:3502–10.

Mohammed K, Abu Dabrh AM, Benkhadra K, et al. Oral vs transdermal estrogen therapy and vascular events: a systematic review and meta-analysis. J Clin Endocrinol Metab 2015; 100: 4012–20.

Canonico M, Carcaillon L, Plu-Bureau, et al. Postmenopausal hormone therapy and risk of stroke: impact of the route of estrogen administration and type of progestogen. Stroke 2016; 47: 1734–41.

Shah S, Forghani N, Durham E, Neely EK. A randomized trial of transdermal and oral estrogen therapy in adolescent girls with hypogonadism. Int J Pediatr Endocrinol 2014; 2014:12.

Nabhan ZM, Dimeglio LA, Qi R, Perkins SM, Eugster EA. Conjugated oral versus transdermal estrogen replacement in girls with Turner syndrome: a pilot comparative study. J Clin Endocrinol Metab 2009; 94:2009-14.

Piippo S, Lenko H, Kainulainen P, Sipilä I. Use of percutaneous estrogen gel for induction of puberty in girls with Turner syndrome. J Clin Endocrinol Metab 2004; 89:3241-7.

Gawlik AM, Hankus M, Szeliga K, et al. Late-onset puberty induction by transdermal estrogen in turner syndrome girls-a longitudinal study. Front Endocrinol (Lausanne). 2018; 9:23.

Zacharin M. Pubertal induction in hypogonadism: current approaches including use of gonadotrophins. Best Pract Res Clin Endocrinol Metab 2015;29:367-83.

Delemarre EM, Felius B, Delemarre-van de Waal HA. Inducing puberty. Eur J Endocrinol 2008;159 (Suppl 1):S 9-15.

Labarta JI, Moreno ML, López-Siguero JP, et al.; Spanish Turner working group. Individualised vs fixed dose of oral 17β-oestradiol for induction of puberty in girls with Turner syndrome: an open-randomised parallel trial. Eur J Endocrinol 2012;167:523-9.

Stanczyk FZ, Hapgood JP, Winer S, Mishell DR Jr. Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects. Endocr Rev 2013;34:171-208.

Donaldson M, Kristrom B, Ankarberg-Lindgren C, et al. on behalf of the European Society for Paediatric Endocrinology Turner Syndrome Working Group. Optimal pubertal induction in girls with Turner syndrome using either oral or transdermal estradiol: a proposed modern strategy. Horm Res Paediatr 2019; 91:153–63.

Klein KO, Rosenfield RL, Santen, RJ et al. Estrogen Replacement in Turner Syndrome: Literature Review and Practical Considerations. J Clin Endocrinol Metab 2018; 103:1790-1803.

Stute P, Wildt L, Neulen J. The impact of micronized progesterone on breast cancer risk: a systematic review. Climacteric 2018; 21:111-22.

Casanova G, Spritzer PM. Effects of micronized progesterone added to non-oral estradiol on lipids and cardiovascular risk factors in early postmenopause: a clinical trial. Lipids Health Dis 2012;11:133.

Gravholt CH, Andersen NH, Conway GS, et al.; International Turner Syndrome Consensus Group. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrino. 2017;177:G1-70.

Pfeifer S, Butts S, Dumesic D, et al: Combined hormonal contraception and the risk of venous thromboembolism: a guideline. Fertil Steril 2017; 107:43-51.

Weber DR, Boyce A, Gordon C, et al. The utility of DXA assessment at the forearm, proximal femur, and lateral distal femur, and vertebral fracture assessment in the pediatric population: 2019 ISCD Official Position. J Clin Densitom 2019;22:567-89.

Phelan N, Conway SH, Llahana S, Conway GS. Quantification of the adverse effect of ethinylestradiol containing oral contraceptive pills when used in conjunction with growth hormone replacement in routine practice. Clin Endocrinol (Oxf) 2012;76:729-33.

Mauras N, Shulman D, Hsiang HY, Balagopal P,Welch S. Metabolic effects of oral versus transdermal estrogen in growth hormone-treated girls with turner syndrome. J Clin Endocrinol Metab 2007; 92: 4154–60.

Bakalov VK, Shawker T, Ceniceros I, Bondy CA. Uterine development in Turner syndrome. J Pediatr 2007;151:528-31.

Cleemann L, Holm K, Fallentin E, et al. Effect of dosage of 17β-estradiol on uterine growth in Turner syndrome – a randomized controlled clinical pilot trial. J Clin Endocrinol Metab 2020; 105:716-24.

Bannink EM, van Sassen C, van Buuren S, et al: Puberty induction in Turner syndrome: results of oestrogen treatment on development of secondary sexual characteristics, uterine dimensions and serum hormone levels. Clin Endocrinol (Oxf) 2009 ;70:265-73.

Paterson WF, Hollman AS, Donaldson MD. Poor uterine development in Turner syndrome with oral oestrogen therapy. Clin Endocrinol (Oxf) 2002; 56:359-77.

Rodrigues EB, Braga J, Gama M, Guimaraes MM. Turner syndrome patients’ ultrasound profile. Gynecol Endocrinol 2013; 29:704-6.

Elsedfy HH, Hamza RT, Farghaly MH, et al: Uterine development in patients with Turner syndrome: relation to hormone replacement therapy and karyotype. J Pediatr Endocrinol Metab 2012; 25:441-5.

Burt E, Davies MC, Yasmin E, et al. Reduced uterine volume after induction of puberty in women with hypogonadism. Clin Endocrinol (Oxf) 2019;91:798-804.

Ziglar S, Hunter TS. The effect of hormonal oral contraception on acquisition of peak bone mineral density of adolescents and young women. J Pharm Pract 2012; 25:331– 40.

Marino R, Misra M: Bone health in primary ovarian insufficiency. Semin Reprod Med 2011; 29:317–327.

Crofton PM, Evans N, Bath LE, et al. Physiological versus standard sex steroid replacement in young women with premature ovarian failure: effects on bone mass acquisition and turnover. Clin Endocrinol 2010; 73:707–14.

Guttmann H, Weiner Z, Nikolski E, et al. Choosing an oestrogen replacement therapy in young adult women with Turner syndrome. Clin Endocrinol 2001;54:159–64.

Alves ST, Gallichio CT,Guimarães MM. Insulin resistance and body composition in Turner syndrome: effect of sequential change in the route of estrogen administration. Gynecol Endocrinol 2006; 22: 590–4.

Reinehr T, Lindberg A, Toschke C, Cara J, Chrysis D & Camacho Hübner C. Weight gain in Turner syndrome: association to puberty induction? Longitudinal analysis of KIGS data. Clin Endocrinol (Oxf) 2016; 85: 85–91.

Shah S, Forghani N, Durham E, Neely EK. A randomized trial of transdermal and oral estrogen therapy in adolescent girls with hypogonadism. Int J Pediatr Endocrinol 2014; 2014:12.

Kalantaridou SN, Naka KK, Papanikolaou E, et al. Impaired endothelial function in young women with premature ovarian failure: normalization with hormone therapy. J Clin Endocrinol Metab 2004; 89: 3907–13.

Langrish JP, Mills NL, Bath LE, et al. Cardiovascular effects of physiological and standard sex steroid replacement regimens in premature ovarian failure. Hypertension 2009; 53: 805–11.

Zaiem F, Alahdab F, Al Nofal A, Murad MH, Javed A. Oral versus transdermal estrogen in turner syndrome: a systematic review and meta-analysis. Endocr Pract 2017;23:408-21.

Kuhl H. Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric 2005;8 (Suppl 1): S3-63.

Renoux C, Dell’aniello S, Garbe E, Suissa S. Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study. BMJ 2010;340:c2519.

Sweetland S, Beral V, Balkwill A, et al: Venous thromboembolism risk in relation to use of different types of postmenopausal hormone therapy in a large prospective study. J Thromb Haemost 2012; 10:2277-86.

Modena MG, Sismondi P, Mueck AO, et al. New evidence regarding hormone replacement therapies is urgently required transdermal postmenopausal hormone therapy differs from oral hormone therapy in risks and benefits. Maturitas 2005;52:1-10.

Scarabin PY, Oger E, Plu-Bureau G. Estrogen and Thrombo Embolism Risk Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 2003;362:428-32.

Ichikawa J, Sumino H, Ichikawa S, Ozaki M. Different effects of transdermal and oral hormone replacement therapy on the renin-angiotensin system, plasma bradykinin level, and blood pressure of normotensive postmenopausal women. Am J Hypertens 2006;19:744-9.

Yilmazer M, Fenkci V, Fenkci S, et al. Hormone replacement therapy, C-reactive protein, and fibrinogen in healthy postmenopausal women. Maturitas 2003;46:245-53.

Viuff MH, Stochholm K, Lin A, Berglund A, Juul S, Gravholt CH. Cancer occurrence in Turner syndrome and the effect of sex hormone substitution therapy. Eur J Endocrinol 2021; 184:79–88.

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26-10-2022

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PEDIATRIC AND ADOLESCENT ENDOCRINOLOGY UPDATE

How to Cite

1.
Voutsadaki K, Matalliotakis M, Ladomenou F. Hypogonadism in adolescent girls: treatment and long-term effects. Acta Biomed [Internet]. 2022 Oct. 26 [cited 2024 Jul. 18];93(5):e2022317. Available from: https://mattioli1885journals.com/index.php/actabiomedica/article/view/13719