Overview

Turner syndrome 

Turner syndrome is a rare genetic disorder characterised by the partial or complete absence of the second sex chromosome. The common genetic formula for people assigned female at birth (AFAB), is 46, XX, but in Turner syndrome, the affected people AFAB lack one of the X chromosomes, having the genetic formula as 45, X.

Individuals with Turner syndrome share common physiological defects including cardiovascular, renal, endocrine, reproductive and/or psychosocial abnormalities. Particularly, the mortality risk is increased due to cardiovascular complications. The mechanisms that result in these manifestations are still unclear and require further studies due to the absence of a consistent correlation between the karyotype and phenotype.^1,2 

Children AFAB with Turner syndrome

Most children AFAB with Turner syndrome have disrupted hormonal balance due to problems with the hypothalamus or pituitary gland. As a result, these individuals experience low levels of sex hormones also known as hypogonadism due to the ovary dysfunction associated with high levels of gonadotropin hormones which are responsible for the stimulation of the primary reproductive organs or gonads (hypergonadotropic), this condition is known as hypergonadotropic hypogonadism. Therefore, these cases require sex steroid hormonal therapy replacement.²

Diagnosis

Turner syndrome can be suspected by using a routine ultrasound scan to examine internal gonads (e.g., ovaries) and check for any abnormalities. Karyotype testing is the initial confirmatory diagnostic test for Turner syndrome which is conducted through chorionic villus sampling (from the placenta) or amniocentesis (amniotic fluid from the uterus). Karyotyping is done by taking a blood sample to analyse the individual’s chromosomes. Turner syndrome is usually confirmed by the detection of a complete or partial absence of one of the X chromosomes which is designated as 45, X.^1,2

Background on oestrogens and progestins

Oestrogens

Estradiol is the endogenous natural form of oestrogen, a female sex hormone, secreted in the human body, it acts through binding to oestrogen receptors. However, ethinyl estradiol is the synthetic form of oestrogen characterised by its extensive potency and is not metabolised to estradiol itself, this high potency is due to the more prolonged retention in its unaltered form by the target tissue compared to estradiol itself.

Moreover, there are more than 100 types of estrogens known as equine estrogens which are still prescribed, these types are not estradiol precursors, however, they are conjugated forms of estrogens of different receptor potency and affinity.^1,2

Progestins

Another steroid sex hormone which is considered for hormonal replacement therapy (HRT) in Turner syndrome individuals, is known as progestin. Unlike estrogens, progestins can bind to different types of receptors, this is explained by the binding to the progesterone receptor itself overlapping with binding to other receptors which are androgen-, glucocorticoid-, and mineralocorticoid receptors. There are four different main types of progestin, each having different potency on these receptors.¹

Oral contraceptive agents (OCPs) are formed by progestins combined with estrogens, knowing that all these types of agents have an increased risk for venous thromboembolism episodes. However, combinations of ethinyl estradiol plus third or fourth generations of progestins pose a slightly higher risk of thrombotic episodes compared to OCPs of first and second-generation progestins.

Lastly, crystalline micronised progesterone is mostly recommended during the pubertal induction process in girls with ovarian dysfunction or failure and appears to be at low risk of developing venous thromboembolic events.¹ 

Laboratory markers of ovarian function

Follicle-stimulating hormone (FSH) and luteinising hormone (LH)

Gonadotropins play a main role in detecting ovarian failure, particularly follicle-stimulating hormone(FSH). Thus, children AFAB with 45, X karyotype show higher concentrations of FSH compared to those with mosaic karyotype. Luteinising hormone (LH) and FSH demonstrate variable concentrations across different age stages, LH and FSH levels begin to elevate after birth, decrease during mid-childhood, and rise again following ovarian dysfunction.¹

Anti-müllerian hormone (AMH) and inhibin B

Low levels of anti-müllerian hormone (AMH) below 4 pmol/L and undetectable inhibin B suggest ovarian failure in Turner syndrome, knowing that undetectable levels of inhibin B could be a sign of absence of spontaneous puberty, though with limited accuracy.¹

Management 

Growth hormone therapy (GH)

Growth hormone therapy (GH) is the main treatment for individuals with Turner syndrome through sustaining body stature. It acts by increasing the height of patients, however, some variables affect GH efficacy that should be taken into consideration such as late use of the treatment and dosing.^2,3

Oestrogen replacement therapy

Children AFAB with Turner syndrome are at high risk for developing premature ovarian failure, thus, oestrogen replacement therapy is essential in the initiation of puberty and maintaining the secondary sexual features. Otherwise, if the treatment is not prescribed or delayed, patients with Turner syndrome will experience late puberty and amenorrhea.

Even after reaching puberty, these patients face a higher risk for early menopause due to premature ovarian dysfunction. Therefore, they can benefit from extended hormone replacement therapy in terms of symptom management and hormonal balance maintenance.^1,2

The majority of patients who wish to get pregnant require oocyte donation. Even though some of the patients are fertile, their pregnancies will be at high risk, due to cardiovascular factors.²

Exogenous estrogens exhibit protective effects on cardiovascular health, bone density, neurocognition, blood pressure, and reproductive function. Despite receiving GH and/or HRT, patients with Turner syndrome still require close monitoring and regular multidisciplinary follow-ups because of the elevated risk in terms of cardiovascular, renal, orthopaedic, neurophysiological, and metabolic complications.^1,2

The most recommended way to replace the oestrogen deficiency

Recent studies propose that systemically administered oestrogen is the most optimal route and biological approach to puberty induction. Endogenous estradiol is secreted directly into the systemic circulation. However, if we administer oral oestrogen, it will pass through different stages starting from the absorption through the gastrointestinal tract, passing the liver for metabolism until reaching the systemic circulation.

This oral administration of estrogens exposes the body organs, particularly the liver to high doses of estrogens compared to systemic administration. Orally administered estrogens, especially ethinyl estradiol, the most commonly used oral form of oestrogen, need to be metabolised in the liver to several metabolites. Oral estrogens are linked to elevated risks of development of high blood pressure (hypertension), pro-coagulation state, and venous thromboembolism.²

Oestrogen examples

• Transdermal estradiol
• Micronized 17β oral estradiol
• Ethinyl estradiol
• Depot estradiol¹ 

Use of progestins

To avoid the risk of development of endometrial cancer and endometrial hyperplasia due to the prolonged use of oestrogen therapy, patients should be guided about the benefits of adding on progestin therapy as a part of a cyclic hormone replacement therapy which begins after two years of initiating oestrogen therapy, unless menstrual bleeding or spotting take place, in this case it is recommended to be prescribed and administered earlier. Progestin therapy, particularly crystalline micronized progesterone, which is the optimal option due to the lower risks of breast cancer and venous thromboembolism, is administered for 10 days monthly.¹

Timing and dosing guidelines for oestrogen/progestin therapies

Lower doses of estradiol are recommended for puberty induction to preserve growth potential, in terms of practice and efficacy transdermal applications are preferred over oral or depot injections. Dose adjustments are required every 6 months to mimic normal puberty progression, this goes on for 2-3 years until achieving the adult replacement levels. According to a study comparing oral and transdermal oestrogen, no significant change was observed in bone density over 12 months.

Moreover, another study on children aged 5 to 13 gave them a low dose of oestrogen, resulting in an extra 2.1 cm in adult height and earlier breast development compared to those who were given the placebo. Therefore, this proposed that a low dose of oestrogen during childhood may ease a more natural puberty progression. Furthermore, maintaining oestrogen therapy and healthy habits can sustain bone density in adult Turner syndrome women over 5-6 years.¹

Risks of oestrogen therapy

Studies show that women treated with oral oestrogen have twice the risk of thromboembolism events compared to those treated with transdermal estrogens, showing that transdermal formulations did not increase the risk of thromboembolism.¹

Summary

• Turner syndrome is a rare genetic disorder characterised by partial or complete absence of the second chromosome and is designated by X, 45
• Children AFAB with Turner syndrome have low levels of sex hormones such as oestrogen and elevated levels of gonadotropic hormones such as follicle-stimulating hormones (FSH) which causes hormonal disturbance and defective loop feedback
• Karyotyping is the confirmatory test of Turner syndrome through withdrawing a blood sample, it is confirmed by detection of a complete or partial absence of one of the X chromosomes which is designated as 45, X
• Gonadotropins are the hormones responsible for detecting ovarian failure in girls with Turner syndrome, especially the FSH hormone
• Growth hormone therapy is the principal treatment for Turner syndrome as it maintains body stature
• Girls with Turner syndrome are at high risk for developing premature ovarian failure, thus, oestrogen replacement therapy is essential in the initiation of puberty and maintaining the secondary sexual features
• Another steroid sex hormone which is considered for replacement therapy in Turner syndrome individuals is known as progestin
• Recent studies propose that systemically administered oestrogen is the most optimal route and biological approach to puberty induction
• To avoid the risk of development of endometrial cancer and endometrial hyperplasia due to the prolonged use of oestrogen therapy, patients should be guided about the benefits of adding on progestin therapy
• Lower doses of estradiol are recommended for puberty induction to preserve growth potential