Turner syndrome medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Akash Daswaney, M.B.B.S[2]

Overview

Medical therapies include growth hormone, estrogen replacement therapy, oxandrolone (if growth hormone achieves suboptimal height), vitamin D supplementation, oral hypoglycemic agents and anti-hypertensives.

Medical Therapy

• The treatment of Turner syndrome requires a step wise multidisciplinary approach. Treatment of short stature (with growth hormone), pubertal delay (with estrogen replacement therapy and subsequent hormone replacement therapy) must work in conjunction with treatment of complications (coordinating between various departments to treat dermatological, otorhinolaryngological, cardiovascular, endocrinological, ophthalmological and embryological complications) and cognitive skill coping strategies.
• Decisions where treatment is concerned should be guided on a clinician’s correlation between the genotype and phenotype of the patient.
• Based on whether a diminished final height or pubertal development is the goal, growth hormone and estrogen replacement therapy doses need to be modified. It is not known whether either affects the efficacy of the other.

Growth Hormone

• Growth Hormone addresses the most common concern and phenotype seen in Turner syndrome patients ; short stature.
• Turner syndrome patients do not have growth hormone deficiency and neither does growth hormone cause an increase in bone mass or bone age. It however does lead to an increased final height.
• If not treated with growth hormone, it has been estimated that the final adult height would be 20 cm below the average adult female height.
• Initiation:
  • Growth hormone may be initiated as early as 4-6 years of age.
  • Some studies suggest that growth hormone should be initiated when the patient’s height falls below the fifth percentile. This would have taken place by 2 years of age.
• Preferred regimen–
  • Starting at 45–50 µg/kg/day and increasing (if the initial response is suboptimal) to a dose of 68 µg/kg/day, subcutaneously seven days a week, at night (preferably)
  • For the first year, height should me monitored ever 3-4 months.
  • Following which it should be monitored every 4-6 months.
• Escalating doses are often required as the effects of growth hormone start to decrease after the first couple of years. However, an increased sensitivity is seen in the first 1-2 years of treatment.
• Decision to stop growth hormone therapy is based on completion of linear growth (bone age of 13.5-14 years and height velocity <2cm/year)

• Efficacy depends on:
  1. Mid-parental height
  2. Age at which therapy is initiated
  3. Duration of GH therapy
  4. Dose of GH therapy
  5. Baseline height prior to initiation
  • In a study conducted in India, where growth hormone was administered to 16 Turner syndrome patients, a distinct benefit was gleaned from the patients’ height SD score and body mass index.
  • Long term treatment has shown to have the greatest impact on posterior facial height and height of the posterior mandibular ramus.
  • Another study showed that patients receiving growth hormone had a final height of -0.3 SD of the normal population, compared to -2.2 SD in individuals who did not.
• Complications:
  1. Increased risk of otitis media
  2. Increased risk of joint disorders
  3. Increased risk of colon cancer
  4. Increased risk of lymphatic cancer
  5. Decreased insulin sensitivity causing an increase in adipose tissue and may further increase the tendency for patients to develop type 2 diabetes mellitus
  6. May expose underlying scoliosis
  7. Enlarged hands and feet
  8. Intracranial hypertension
  9. Slipped capital femoral epiphyses
  10. Pancreatitis
• To prevent prolong exposure to insulin growth factor 1 (IGF-1), it is recommended to decrease the dosage of growth hormone if serum IGF-1 is 3 standard deviations for the person’s age.
  • IGF-1 levels should be constantly monitored and be kept below 2 standard deviations for a person’s age.

Estrogen replacement therapy

• Transdermal estradiol is the preferred form of estrogen due to it’s ability to avoid first pass metabolism and therefore, it has an increased bioavailability.
• Initiation:
  • Therapy started at 11-12 years of age (if no breast development takes place if elevated gonadotrophins are detected or anti-mullerian hormone is low).
  • Patches of a specific estradiol formulation are usually available and are sometimes cut in half according to the administration dose.
  • Some studies have tried starting therapy with oral estrogen and then transitioning to patches.
  • The rationale behind initiation of estrogen replacement therapy should be the timing of puberty induction such that it mimics normal pubertal development and at the same time allows for the patient to avoid social problems in school due to physical and psychological development delays.
• Preferred regimen:
  • Recommended starting dose for induction of puberty is 3-7 µg/day.
  • This is gradually increased at 6 month intervals and by 2-3 years of therapy, adult doses of 100 µg/day are administered.
• Progestin supplementation is required by 2 years of age to decrease the risk of endometrial cancer (due to the unopposed effect of estrogen) and as soon as withdrawal bleeding is noted.
• Benefits noted:
  1. Improvements in cognition, motor speed, nonverbal processing time and memory
  2. Improvements in growth velocity, prevents premature closure of the epiphysis
  3. Improvements in bone health and trabecular bone] volume.
  4. Cardiovascular protection
  5. Induction of puberty and uterine development
  6. Increased bone mineral density
  7. Decreases psychosocial stress related to pubertal delay

Oxandrolone

• Oxandrolone is added as an adjunct to growth hormone therapy to help achieve an adequate final height.
• This was indicated in a study which used oxandrolone in doses of 0.05mg/kg/day and found that patients taking oxandrolone had their final adult height increased by 4.5 cm.
• Initiation:
  • Turner syndrome patients greater than 10 years of age, who are receiving a growth hormone treatment regimen and with a poorly projected final adult height.
• Preferred regimen– 0.03-0.05mg/kg/day.
• Benefits:
  1. One study showed that oxandrolone helped improve working memory performance.
• Complications:
  1. Signs of virilization such as hirsutism, acne, enlarged clitoris, deeper voice.
  2. Delayed breast development
  3. Decrease in HDL

Hormone Replacement Therapy

• Serum levels for follicle stimulating hormone, lutenizing hormone, estradiol and anti Mullerian hormone provide an insight into the patient’s ovarian function.
• Depending on these levels, and whether or not the patient has completed their growth hormone regimen (final adult height has been achieved) , hormone replacement therapy may be given at 12 or 14 years of age.
• This includes a combination of estrogen and progesterone.

Treatment for type 2 Diabetes mellitus and Obesity

• Treatment of Diabetes Mellitus is the same in Turner syndrome patients and oral hypoglycemic agents such as metformin and thiazolidenodiones are employed.
• Furthermore, obesity which may be prevented by instituting a strict exercise regime (swimming, walking, cycling) at a very young age.

Nandrolone Phenylpropionate

• A study in China administered nandrolone phenylpropionate in the early stages of Tuner syndrome along with Liuwei Dihuang pills (a traditional Chinese medicine)
• The combination prompted the development of secondary sexual characteristics.

Vitamin D supplementation

• Low vitamin D levels are noted in Turner syndrome patients and therefore prophylactic vitamin D supplementation coupled with an active lifestyle which includes regular sports and weight bearing exercises should be employed.

Treatment for Hypertension

• Hypertension must be treated aggressively using beta blockers as first line followed by angiotensin converting enzyme inhibitors (ACE inhibitors) due to the risk of aortic dilation. "Turner Syndrome - StatPearls - NCBI Bookshelf".

References

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