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A current perspective into young female sex hormone replacement: a review
ABSTRACT
Introduction: Hormone replacement in females with hypogonadism is advocated to address the various clinical aspects of estrogen deficiency.
Areas covered: This article focuses on hormone replacement in young females with hypogonadism, including a rationale as to why hormone replacement in such patients differs from treatment in postmenopausal females, a summary of symptoms encountered by females with hypogonadism, and a comprehensive discussion of the various treatment options available, specifically focusing on the latest advances in the subject. A Medline search was conducted using different combinations of relevant keywords, giving preference to recent publications.
Expert opinion: Whilst traditionally oral contraceptive pills (containing ethynyl estradiol) were commonly used as a form of hormone replacement, it is now increasingly recognized that this is not the optimal treatment option. Physiological hormone replacement with transdermal estradiol is found to be superior. Evidence suggests that micronized progesterone may be associated with fewer side effects, although its effect on endometrial protection is not yet proven. Synthetic progestins confer varying degrees of androgenic and thromboembolic properties which should be kept in mind when prescribing individualized treatment. Further studies in different sub-cohorts of female patients with hypogonadism might help address the specific needs of individual patients.
Article highlights
● The etiology of female hypogonadism is varied and may be classified as premature ovarian insufficiency (failure arising from the ovaries themselves) or secondary gonadal failure, also known as hypogonadotropic hypogonadism; the result of inadequate gonadotropin stimulation.
● Women exhibiting features of gonadal failure prior to 50 years of age, especially prior to the age of 40, should be considered for sex hormone replacement therapy in order to avoid the complications of early menopause (menopausal symptoms, increased mortality mainly related to cardiovascular disease, bone health, and neurological sequelae).
● By prescribing sex hormone replacement, one aims to restore normal physiological states, therefore in such a context the term ‘replacement’ is indeed pertinent as opposed to the concept of ‘extension’ of hormone therapy in the post-menopausal age group.
● The hormonal replacement consists of an estrogen component as well as a progestogen component, in females possessing a uterus.
● Oestradiol is superior to ethinyloestradiol in terms of cardiovascular parameters, thromboembolic risk, and bone health. Furthermore, the use of transdermal or transvaginal estrogen therapy has been associated with a decreased risk of thromboembolism and possibly stroke, when compared to the classical oral formulation.
● Different progestogens have a varying affinity to the progesterone receptor and other steroid receptors: mineralocorticoid, glucocorticoid, and androgen receptors. These differing actions, together with other factors including route of administration, pharmacokinetics, and protein-binding strength, explains the differing androgenic and thromboembolic profiles.
● Treatment with testosterone was found to have positive effects on cardiometabolic risk factors, quality of life, and neurocognitive functions but long-term studies confirming safety and efficacy are lacking.
● With regards to follow up, a multidisciplinary setting is advisable and aims to address specific patients’ needs according to the varied etiology of female hypogonadism.
4. Symptoms of estrogen deficiency in young females
Early menopause is associated with increased mortality [17– 22] mainly related to cardiovascular disease. They also have increased morbidity related to bone health and neurological sequelae [2,16].
4.1. Cardiovascular consequences
4.2. Bone related consequences
4.3. Cognitive function
4.4. Other symptoms
5. Hormone replacement therapy (HRT)
The hormonal replacement consists of an estrogen component as well as a progestogen component, in females possessing a uterus. Replacement aims to promote and maintain secondary sexual characteristics and, as already alluded to, to reduce the risk of developing long-term complications such as cardiovascular disease and osteoporosis [4]. Both estrogen and progestogen can be administered via multiple different formulations. Recently, the management of female patients with hypogonadism is moving away from the conventional oral contraceptive pill and post-menopausal hormone replacement therapy, toward a more physiological hormonal mode of replacement [2,6,45,55,56].
5.1. Estrogen replacement
5.2. Progestogen replacement
5.3. Testosterone treatment
Around 50% of endogenous testosterone in females is produced by the ovaries [110]. Therefore conceptually, there is an element of androgen deficiency in patients with premature ovarian insufficiency which may play a role in some of the symptoms experienced by these patients [15]. In postmenopausal females, testosterone treatment may be effective in improving sexual function [111]; however, long-term effects may not be clear [112]. In a randomized placebo-controlled trial in patients with bilateral salpingo-oophorectomy and hysterectomy, patients treated with 300ug of testosterone were found to have an improvement in the sexual activity score and treatment was well tolerated over a 24 week period [113]. Androgen replacement, in patients with Turner’s syndrome having POI, was found to be safe and provided beneficial effects on body composition, neurocognition, and quality of life [114]. Treatment with androgens in patients with POI should be considered only after obtaining comprehensive-informed consent, which includes information about the emerging evidence regarding androgen treatment and its beneficial outcomes, but also information about the paucity of data regarding long-term health effects [6].
7. Conclusion
In premenopausal females, hormonal replacement of ovarian sex steroids is truly replacing hormones that would normally be present in this age group. It is in fact paramount to prevent the morbidity and mortality associated without treatment. Recent advances and studies have shown that some of the more recently available drugs can better mimic normal ovarian physiology, in such a way to reduce menopausal symptoms, whilst maintaining bone health and cardiovascular protectivity. In this review, we have highlighted the latest approaches to replacement whilst discussing the various options available.
ABSTRACT
Introduction: Hormone replacement in females with hypogonadism is advocated to address the various clinical aspects of estrogen deficiency.
Areas covered: This article focuses on hormone replacement in young females with hypogonadism, including a rationale as to why hormone replacement in such patients differs from treatment in postmenopausal females, a summary of symptoms encountered by females with hypogonadism, and a comprehensive discussion of the various treatment options available, specifically focusing on the latest advances in the subject. A Medline search was conducted using different combinations of relevant keywords, giving preference to recent publications.
Expert opinion: Whilst traditionally oral contraceptive pills (containing ethynyl estradiol) were commonly used as a form of hormone replacement, it is now increasingly recognized that this is not the optimal treatment option. Physiological hormone replacement with transdermal estradiol is found to be superior. Evidence suggests that micronized progesterone may be associated with fewer side effects, although its effect on endometrial protection is not yet proven. Synthetic progestins confer varying degrees of androgenic and thromboembolic properties which should be kept in mind when prescribing individualized treatment. Further studies in different sub-cohorts of female patients with hypogonadism might help address the specific needs of individual patients.
Article highlights
● The etiology of female hypogonadism is varied and may be classified as premature ovarian insufficiency (failure arising from the ovaries themselves) or secondary gonadal failure, also known as hypogonadotropic hypogonadism; the result of inadequate gonadotropin stimulation.
● Women exhibiting features of gonadal failure prior to 50 years of age, especially prior to the age of 40, should be considered for sex hormone replacement therapy in order to avoid the complications of early menopause (menopausal symptoms, increased mortality mainly related to cardiovascular disease, bone health, and neurological sequelae).
● By prescribing sex hormone replacement, one aims to restore normal physiological states, therefore in such a context the term ‘replacement’ is indeed pertinent as opposed to the concept of ‘extension’ of hormone therapy in the post-menopausal age group.
● The hormonal replacement consists of an estrogen component as well as a progestogen component, in females possessing a uterus.
● Oestradiol is superior to ethinyloestradiol in terms of cardiovascular parameters, thromboembolic risk, and bone health. Furthermore, the use of transdermal or transvaginal estrogen therapy has been associated with a decreased risk of thromboembolism and possibly stroke, when compared to the classical oral formulation.
● Different progestogens have a varying affinity to the progesterone receptor and other steroid receptors: mineralocorticoid, glucocorticoid, and androgen receptors. These differing actions, together with other factors including route of administration, pharmacokinetics, and protein-binding strength, explains the differing androgenic and thromboembolic profiles.
● Treatment with testosterone was found to have positive effects on cardiometabolic risk factors, quality of life, and neurocognitive functions but long-term studies confirming safety and efficacy are lacking.
● With regards to follow up, a multidisciplinary setting is advisable and aims to address specific patients’ needs according to the varied etiology of female hypogonadism.
4. Symptoms of estrogen deficiency in young females
Early menopause is associated with increased mortality [17– 22] mainly related to cardiovascular disease. They also have increased morbidity related to bone health and neurological sequelae [2,16].
4.1. Cardiovascular consequences
4.2. Bone related consequences
4.3. Cognitive function
4.4. Other symptoms
5. Hormone replacement therapy (HRT)
The hormonal replacement consists of an estrogen component as well as a progestogen component, in females possessing a uterus. Replacement aims to promote and maintain secondary sexual characteristics and, as already alluded to, to reduce the risk of developing long-term complications such as cardiovascular disease and osteoporosis [4]. Both estrogen and progestogen can be administered via multiple different formulations. Recently, the management of female patients with hypogonadism is moving away from the conventional oral contraceptive pill and post-menopausal hormone replacement therapy, toward a more physiological hormonal mode of replacement [2,6,45,55,56].
5.1. Estrogen replacement
5.2. Progestogen replacement
5.3. Testosterone treatment
Around 50% of endogenous testosterone in females is produced by the ovaries [110]. Therefore conceptually, there is an element of androgen deficiency in patients with premature ovarian insufficiency which may play a role in some of the symptoms experienced by these patients [15]. In postmenopausal females, testosterone treatment may be effective in improving sexual function [111]; however, long-term effects may not be clear [112]. In a randomized placebo-controlled trial in patients with bilateral salpingo-oophorectomy and hysterectomy, patients treated with 300ug of testosterone were found to have an improvement in the sexual activity score and treatment was well tolerated over a 24 week period [113]. Androgen replacement, in patients with Turner’s syndrome having POI, was found to be safe and provided beneficial effects on body composition, neurocognition, and quality of life [114]. Treatment with androgens in patients with POI should be considered only after obtaining comprehensive-informed consent, which includes information about the emerging evidence regarding androgen treatment and its beneficial outcomes, but also information about the paucity of data regarding long-term health effects [6].
7. Conclusion
In premenopausal females, hormonal replacement of ovarian sex steroids is truly replacing hormones that would normally be present in this age group. It is in fact paramount to prevent the morbidity and mortality associated without treatment. Recent advances and studies have shown that some of the more recently available drugs can better mimic normal ovarian physiology, in such a way to reduce menopausal symptoms, whilst maintaining bone health and cardiovascular protectivity. In this review, we have highlighted the latest approaches to replacement whilst discussing the various options available.
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