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Estrogen Replacement in Turner Syndrome: Literature Review and Practical Considerations
Open accessAbstract
Context: Most girls with Turner syndrome (TS) have hypergonadotropic hypogonadism and need hormonal replacement for induction of puberty and then for maintaining secondary sex characteristics, attaining peak bone mass, and uterine growth. The optimal estrogen replacement regimen is still being studied. Evidence Acquisition: We conducted a systematic search of PubMed for studies related to TS and puberty. Evidence Synthesis: The goals of replacement are to mimic normal timing and progression of physical and social development while minimizing risks. Treatment should begin at age 11 to 12 years, with dose increases over 2 to 3 years. Initiation with low-dose estradiol (E2) is crucial to preserve growth potential. Delaying estrogen replacement may be deleterious to bone and uterine health. For adults who have undergone pubertal development, we suggest transdermal estrogen and oral progestin and discuss other approaches. We discuss linear growth, lipids, liver function, blood pressure, neurocognition, socialization, and bone and uterine health as related to hormonal replacement. Conclusion: Evidence supports the effectiveness of starting pubertal estrogen replacement with low-dose transdermal E2. When transdermal E2 is unavailable or the patient prefers, evidence supports use of oral micronized E2 or an intramuscular preparation. Only when these are unavailable should ethinyl E2 be prescribed. We recommend against the use of conjugated estrogens. Once progestin is added, many women prefer the ease of use of a pill containing both an estrogen and a progestin. The risks and benefits of different types of preparations, with examples, are discussed.
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“During adulthood the aim is to restore the physiological hormonal environment as closely as possible and HRT is important for continuing bone mass accrual to reach peak bone mass during the third decade and for further uterine growth and development.326,327”
From Clinical practice guidelines for the care of girls and women with Turner syndrome. (2024) · cites this paper as [326]
In the citing paper
“The deleterious role of hypogonadism on LFA has been emphasized in two review articles.326,719”
From Clinical practice guidelines for the care of girls and women with Turner syndrome. (2024) · cites this paper as [326]
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MethodMenopausal hormone therapy and breast cancer risk
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Clinical Indications for Growth Hormone Therapy
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“In Europe, several 2 mg containing E2 formulations are also available (Klein et al., 2018), combined with a progestin.”
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Society for endocrinology guideline for understanding, diagnosing and treating female hypogonadism
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“122 Current data suggest estrogen replacement is safe for the vast majority of women with TS.”
InfluentialViuff, M., & Gravholt, C. H. (2022) · Annales d Endocrinologie · doi:10.1016/j.ando.2022.06.001 · Cited by 36
Diagnostic and therapeutic use of oral micronized progesterone in endocrinology
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Delayed and Precocious Puberty: Genetic Underpinnings and Treatments
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Novel insights in Turner syndrome
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“Most commonly, low-dose estrogen therapy via estradiol patch is initiated between ages 11 and 12 years tomitigate fusion of epiphyseal growth plate [84].”
BackgroundChallenges Waiting for an Adult with DSD
Nowotny, H. F., & Reisch, N. (2022) · Hormone Research in Paediatrics · doi:10.1159/000527433 · Cited by 24
Puberty in the Female and Its Disorders
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Self-citationEstradiol matrix patches for pubertal induction: stability of cut pieces at different temperatures
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MANAGEMENT OF ENDOCRINE DISEASE: transition of care for young adult patients with Turner syndrome
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Human sex chromosome aneuploidies: The hypothalamic–pituitary–gonadal axis
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“The lifelong care of these girls and women often depends directly on these other comorbidities, especially after short stature and pubertal delay are addressed during infancy, childhood and adolescence (Gravholt et al., 2017; Kline et al., 2018).”
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Porcu, E., Cipriani, L., & Damiano, G. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1269009 · Cited by 17
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Whigham, C., Vollenhoven, B. J., & Vincent, A. J. (2022) · Prenatal Diagnosis · doi:10.1002/pd.6261 · Cited by 18
“HRT regime; however, the latest evidence suggests that a transdermal estrogen patch is effective for pubertal induction.(5) Caution must be exercised when choosing a route of administration, considering co‐morbidities.”
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Aversa, T., Pomi, A. L., Pepe, G., Corica, D., Messina, M. F., Coco, R., Sippelli, F., Ferraloro, C., Luppino, G., Valenzise, M., et al. (2023) · Clinical Therapeutics · doi:10.1016/j.clinthera.2023.12.004 · Cited by 17
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Kulkarni, M., Travers, J. B., & Rohan, C. A. (2021) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-021-08863-4 · Cited by 15
Less ready for adulthood?—Turner syndrome has an impact on transition readiness
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Rasouli, M. A., McDaniel, K. E., Awadalla, M. S., & Chung, K. (2019) · Case Reports in Obstetrics and Gynecology · doi:10.1155/2019/3719178 · Cited by 13
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Reversal Learning Performance in the XY∗ Mouse Model of Klinefelter and Turner Syndromes
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Disorders of Puberty: Pharmacotherapeutic Strategies for Management
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Distinct waves of ovarian follicles contribute to mouse oocyte production
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“Consistent with hormonal disruption, hormone replacement therapy significantly improves the development of individuals with Turner syndrome ( Klein et al., 2018 ).”
Dysgerminoma in a 10-Year Old with 45X/46XY Turner Syndrome Mosaicism
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MicroRNA-126-3p/5p and Aortic Stiffness in Patients with Turner Syndrome
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“As TS is closely linked to estrogen deficiency, due to ovarian failure, and endothelial dysfunction, further studies are required to evaluate the impact of miR-126-3p/5p on TS health [40,41].”
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Voutsadaki, K., Matalliotakis, M., & Ladomenou, F. (2022) · Acta bio-medica dell'Ateneo parmense/Acta biomedica · doi:10.23750/abm.v93i5.13719 · Cited by 13
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“However, more recent evidence in other congenital hypo-gonadal conditions such as Turner ’ s syndrome shows that low dose oestrogen started earlier at age 11 is used to achieve optimal uterine development (Klein et al., 2018).”
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Oestrogen treatment restores dentate gyrus development in premature newborns by IGF1 regulation
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Iron overload disorders: Growth and gonadal dysfunction in childhood and adolescence
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Approach to the Patient With Turner Syndrome
Turner, H. E., Johannsen, E. B., Smyth, A., Orchard, E., & Gravholt, C. H. (2025) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaf517 · Cited by 11
Turner Syndrome: Ocular Manifestations and Considerations for Corneal Refractive Surgery
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Gonadal dysgenesis: a clinical overview of Turner syndrome
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Adolescent brain development in girls with Turner syndrome
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“…most individuals with TS require estrogen replacement therapy in order to induce puberty, maintain secondary sex characteristics (e.g., breasts, menstrual cycle, increased body fat), achieve peak bone mass, and normalize uterine growth for possible pregnancy later in life (Klein et al., 2018).”
BackgroundCardiovascular Complications in Patients with Turner’s Syndrome
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Pubertal induction in girls with Turner Syndrome
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Backeljauw, P. F., Chernausek, S. D., Gravholt, C. H., & Kruszka, P. S. (2021) · Elsevier eBooks · doi:10.1016/b978-0-323-62520-3.00017-8 · Cited by 5
Witkowska-Krawczak, E., Erazmus, M., Majcher, A., Pyrżak, B., & Kucharská, A. (2023) · Frontiers in Pediatrics · doi:10.3389/fped.2023.1173419 · Cited by 5
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COVID-19 Pandemic: Mental Health in Girls With and Without Fragile X Syndrome
Jordan, T. L., Bartholomay, K. L., Lee, C. H.-Y., Miller, J. G., Lightbody, A. A., & Reiss, A. L. (2021) · Journal of Pediatric Psychology · doi:10.1093/jpepsy/jsab106 · Cited by 6
“Although there is a growing body of literature describing children’s responses to trauma, disasters, and adverse events in general, investigations of children’s responses to pandemics in particular remain relatively sparse (Klein et al., 2018).”
BackgroundManagement of a Girl With Delayed Puberty and Elevated Gonadotropins
McGlacken-Byrne, S. M., Achermann, J. C., & Conway, G. S. (2022) · Journal of the Endocrine Society · doi:10.1210/jendso/bvac108 · Cited by 6
“There are several pubertal induction regimens that vary by country [82-85].”
BackgroundHypogonadism in male and female: which is the best treatment?
BERTELLI, E., FRENNA, M. D., Cappa, M., SALERNO, M., WASNIEWSKA, M., BIZZARRI, C., & SANCTIS, L. D. (2021) · Minerva Pediatrics · doi:10.23736/s2724-5276.21.06534-4 · Cited by 7
Burt, E., Yasmin, E., Davies, M. C., Creighton, S. M., Brain, C. E., Ruff, C. F., Learner, H. I., Williams, L., Cameron‐Pimblett, A., Talaulikar, V. S., et al. (2022) · Clinical Endocrinology · doi:10.1111/cen.14740 · Cited by 5
“In the context of pubertal induction, studies have demonstrated development to Tanner stage 4 after an average of 2 years of treatment.(3,6,8) In our study it is apparent that the breast develops at a slower pace than the uterus during the initial phase of exogenous oestrogen treatment and change in breast volume did…”
BackgroundIdkowiak, J., Smyth, A., Mundy, L. R., Wanaguru, A., Gleeson, H. K., & Högler, W. (2022) · Clinical Endocrinology · doi:10.1111/cen.14755 · Cited by 4
Distinct waves of ovarian follicles contribute to mouse oocyte productionPreprint
Yin, Q., & Spradling, A. C. (2025) · eLife · doi:10.7554/elife.107352 · Cited by 6
Kim, J., Kim, M.-S., Suh, B., Ko, C. W., Lee, K., Yoo, H., Shin, C. H., Hwang, J. S., Kim, H.-S., Chung, W. Y., et al. (2021) · BMC Endocrine Disorders · doi:10.1186/s12902-021-00904-5 · Cited by 5
“estrogen treatment should began at 11 or 12 years of age in girls with high gonadotropin or low anti-Mullerian hormone [7, 31].”
BackgroundLifelong medical challenges and immunogenetics of Turner syndrome
Cho, W. K. (2024) · Korean Journal of Pediatrics · doi:10.3345/cep.2024.00430 · Cited by 5
“59) A 59-61 ) HRT initiation should be customized to each patient Infertility is prevalent in TS, and fertility and family planning are becoming increasingly important concerns.”
BackgroundEvolution of Health Care in Turner Syndrome
Shankar, R. K., Gravholt, C. H., & Backeljauw, P. F. (2024) · American Journal of Medical Genetics Part C Seminars in Medical Genetics · doi:10.1002/ajmg.c.32124 · Cited by 4
“In the past two decades, there is improved understanding of the prevalence of spontaneous thelarche and menarche in TS, and the neuropsychological, bone health and metabolic consequences of untreated estrogen deficiency in early adolescence (Klein et al. 2018).”
Intersex Bodies, Language, and Medical Authority
Civitello, A. D. (2022) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780190212926.013.75 · Cited by 4
Villasmil, M. G. P., Ryckman, K. K., Norris, A. W., & Pinnaro, C. T. (2023) · Hormone Research in Paediatrics · doi:10.1159/000534371 · Cited by 4
“Hypergonadotropic hypogonadism, which is expected in individuals with TS [53], necessitates treatment with estrogen beginning at age 11 – 12 [18].”
Amirkashani, D., Rohani, F., Khodadost, M., Hoseini, R., Alidoost, H., & Madani, S. (2022) · BMC Pediatrics · doi:10.1186/s12887-022-03406-y · Cited by 5
“According to the international Turner Syndrome guidelines, it is recommended to initiate estrogen therapy when patients are between 11 and 12 years of age, and then gradually increasing the external estrogen to adult dosage over 2 to 3 years [17].”
MethodGravholt, C. H. (2024) · Elsevier eBooks · doi:10.1016/b978-0-12-815234-8.00002-1 · Cited by 4
The effects of estrogen induction therapy on pubertal presentations in turner syndrome patients
Lee, Y., Huang, C., Lin, C., Cheng, B.-W., Huang, S.-K., Yeh, S.-N., Lee, Y., & Ting, W. (2022) · Taiwanese Journal of Obstetrics and Gynecology · doi:10.1016/j.tjog.2022.05.014 · Cited by 3
Howarth, S., & Quinton, R. (2022) · BMJ Case Reports · doi:10.1136/bcr-2022-250870 · Cited by 3
Januskaite, P., Goyanes, Á., Orlu, M., & Basit, A. W. (2025) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2025.114798 · Cited by 3
Aportes al estudio de las relaciones entre memoria episódica y teoría de la mente
Aguilar, M. J., Agulla, L., Said, A., & López, M. (2020) · Interdisciplinaria Revista de Psicología y Ciencias Afines · doi:10.16888/interd.2020.37.1.11 · Cited by 3
Skeletal Characteristics of Children and Adolescents with Turner Syndrome
Kawai, M., & Hasegawa, Y. (2022) · Endocrines · doi:10.3390/endocrines3030038 · Cited by 4
“These findings indicate that aBMD is decreased in adults with TS, which is partly attributable to insufficient ERT, as evidenced in multiple observational studies and metaanalyses [8,9].”
ResultBrander, E. P. A., Keenahan, L. A., Sangi‐Haghpeykar, H., Graham, M. E., & Dietrich, J. E. (2023) · Journal of Pediatric and Adolescent Gynecology · doi:10.1016/j.jpag.2023.03.007 · Cited by 3
Blanchett, R., Chen, H., Vlasova, R., Cornea, E. A., Maza, M. T., Davenport, M. L., Reinhartsen, D. B., DeRamus, M., Pretzel, R. E., Gilmore, J. H., et al. (2024) · Cerebral Cortex · doi:10.1093/cercor/bhae351 · Cited by 2
“If these differences do arise later in childhood, they could reflect postnatal deficiency in gonadal steroid hormones (Rubin et al. 1981; Schulz and Sisk 2016; Klein et al. 2018).”
BackgroundReich, J. A., Murthy, D. B., Coble, C., & Shah, B. C. (2024) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem-2024-0187 · Cited by 2
Turner syndrome: skin, liver, eyes, dental and ENT evaluation should be improved
Lam, J., Stoppa‐Vaucher, S., Αντωνίου, Μ., Bouthors, T., Arana, I. L. R., Sekarski, N., Rutz, T., Fries, S., Binz, P., Niel, F., et al. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1190670 · Cited by 3
Caracterización de una cohorte de pacientes pediátricas con Síndrome de Turner
Guzmán-Arias, E. C., Grajales-Restrepo, D. A., Zuluaga, N. A., Lopera-Cañaveral, M. V., & Niño-Serna, L. F. (2023) · Andes pediatrica · doi:10.32641/andespediatr.v94i5.4617 · Cited by 2
“El diagnóstico temprano de esta entidad ayuda a un adecuado manejo de las comorbilidades, además de lograr una talla más cercana a lo normal con el uso de hormona de crecimiento y el inicio oportuno de la inducción puberal 7,9,10 .”
BackgroundGrowth During Pubertal Induction in Girls With Turner Syndrome: A Retrospective Cohort Analysis
Nicholls, J., Harris, M. A., Hughes, I. P., Huynh, T., & McMahon, S. (2024) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae071 · Cited by 2
Distinct waves of ovarian follicles contribute to mouse oocyte productionPreprint
Yin, Q., & Spradling, A. C. (2025) · eLife · doi:10.7554/elife.107352.1 · Cited by 1
Challenges of Turner Syndrome Care in Adulthood: A Single Tertiary Center Experience
Robeva, R. N., Elenkova, A. P., & Zacharieva, S. (2023) · Clinical and Experimental Obstetrics & Gynecology · doi:10.31083/j.ceog5001022 · Cited by 1
Transition from pediatrics to adult health care in girls with turner syndrome
Sabbadin, C., Marin, L., Manso, J., Mozzato, C., Camozzi, V., Andrisani, A., Sacchetti, C., Mian, C., Scaroni, C. M., Guazzarotti, L., et al. (2024) · Expert Review of Endocrinology & Metabolism · doi:10.1080/17446651.2024.2347265 · Cited by 2
“TS is often accompanied by difficulties in achieving successful pregnancies due to a severe reduction of ovarian reserve with POI [76,77], and cardiac or cardiovascular issues related to TS can further complicate the pregnancy (hypertension, diabetes, cardiac malformations [2,36,78,79].”
BackgroundMethodInfluentialGender-Diverse Youth with Turner Syndrome: Special Management Considerations
Eitel, K. B., Zenno, A., Blasi, C. C. D., Fechner, P. Y., & Hodax, J. K. (2024) · JCEM Case Reports · doi:10.1210/jcemcr/luae076 · Cited by 1
Zhi, H., Xu, C., Yan, H., Liu, C., & Liu, L. (2025) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2025.1527887 · Cited by 1
“This condition is seen in most patients with TS and may occur at birth or gradually during childhood, adolescence, or early adulthood (18, 19).”
Metadata
- Authors
- Klein, K. O., Rosenfield, R. L., Santen, R. J., Gawlik, A. M., Backeljauw, P. F., Gravholt, C. H., Sas, T. C. J., & Mauras, N.
- Affiliations
- University of California San Diego (US)
- University of Chicago (US)
- University of Virginia (US)
- Medical University of Silesia (PL)
- Cincinnati Children's Hospital Medical Center (US)
- Aarhus University Hospital (DK)
- Erasmus MC (NL)
- Nemours Children's Health System (US)
- Corresponding author
- Klein, Karen O
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2018-02-08
- Volume
- 103
- Issue
- 5
- Pages
- 1790-1803
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2792324931
- Cited by
- 151
- References
- 107
- Citations by year
- 2026: 7 · 2025: 18 · 2024: 26 · 2023: 18 · 2022: 30 · 2021: 18 · 2020: 15 · 2019: 16 · 2018: 3
- FWCI
- 1.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- Funders
- Novo Nordisk Fonden (NNF13OC0003234, NNF15OC0016474)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Sexual Differentiation and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Keywords
- Turner syndrome, estrogen replacement therapy, puberty induction, estradiol, transdermal estradiol, micronized estradiol, ethinyl estradiol, progestins, bone health, uterine growth, peak bone mass, linear growth, lipid profile, liver function, blood pressure, neurocognitive function, socialization, conjugated estrogens
- MeSH terms
- Age Factors, Child, Estrogens, Female, Humans, Turner Syndrome, Estrogen Replacement Therapy, Time-to-Treatment
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