madman
Super Moderator
Abstract
Female hypogonadism (FH) is a relatively common endocrine disorder in women of premenopausal age, but there are significant uncertainties and wide variation in its management. Most current guidelines are mono specialty and only address premature ovarian insufficiency (POI); some allude to management in very brief and general terms, and most rely upon the extrapolation of evidence from the studies relating to physiological estrogen deficiency in postmenopausal women. The Society for Endocrinology commissioned new guidance to provide all care providers with a multidisciplinary perspective on managing patients with all forms of FH. It has been compiled using expertise from Endocrinology, Primary Care, Gynaecology and Reproductive Health practices, with contributions from expert patients and a patient support group, to help clinicians best manage FH resulting from both POI and hypothalamo‐pituitary disorders, whether organic or functional.
3 | THE BIOLOGICAL EFFECTS OF THE FEMALE SEX HORMONES
Estradiol is the major hormone of deficiency in hypogonadism in women, but it is also essential to consider the importance of progesterone. The role of androgens, notably testosterone but also weak adrenal androgens, is more controversial although they have contributory actions in normal female physiology. Adrenal androgen secretion is impaired in women with hypopituitarism and ACTH deficiency, but not with other forms of FH, although ovarian androgen secretion is impaired in all forms. This section very briefly reviews the main physiological effects of the sex steroids of relevance to replacement therapy, though it is important to consider how closely pharmacological replacement mimics physiology.
Estradiol is essential for the key secondary sex characteristics, emerging normally at puberty. These effects develop over several years with the larche being the initial sign, initiated with still low levels of circulating estradiol.14 This highlights the need for an appropriate pace of incremental estrogen administration to mimic normal puberty, with the avoidance of early progesterone exposure which can affect full development of the breast by limiting the branching morphogenesis necessary for complete development of the ductal tree,15 and may also limit uterine development.11 Estradiol is also essential for uterine growth and maturation, and ongoing health of the urogenital tract. The vaginal epithelium requires estrogen for proliferation and keratin production and there is also evidence of a role in immune regulation.16 This is increasingly topical with increasing interest in the vaginal microbiome and its role in sexual and reproductive health, including in states of estrogen deficiency.17
In addition to its role in uterine growth, estradiol is essential for cyclic endometrial repair and proliferation after menstruation. Estrogen exposure is also necessary for the expression of endometrial progesterone receptors, underlying the necessary changes to a secretory pattern which are required for embryo implantation and the establishment of pregnancy.18
Centrally acting estrogen negatively regulates hypothalamic kisspeptin (Kp) and gonadotrophin‐releasing hormone (GnRH), which is the principal regulator of reproduction, controlling pituitary gonadotrophin secretion and, thereby, ovarian function. Distinct hypothalamic kisspeptin neuronal populations mediate estrogenic positive feedback to generate the mid‐cycle GnRH/LH surge necessary for ovulation. Estradiol also acts on the gonadotrophs of the anterior pituitary to regulate FSH and LH secretion, physiologically in concert with other ovarian hormones, notably the inhibins, in the regulation of FSH secretion.19 This locus of action is also very important in generating the mid cycle LH surge. It is now recognised that kisspeptin neurons also project from the infundibular nucleus to the medial preoptic nucleus, where they innovate the warm sensing neurons (signalling primarily through neurokinin B‐mediated synaptic activity), whose excess activity in states of hypergonadotrophic estrogen deficiency results in the characteristic vasomotor symptoms of the menopause,20 which are notably absent when the cause is hypogonadotrophic or with very early onset POI.
Estrogen receptors are also very widely expressed across the body, with notable effects on regulating bone, brain, cardiovascular and metabolic function. Within bone, estradiol controls both osteoblast and osteoclast number and function, through which i tregulates both cortical and trabecular bone turnover.21 Effects on other physiological systems have been less comprehensively studied and controversy remains, but there is increasing evidence that estrogen is required for continuing cardio‐metabolic and, potentially, neurocognitive health.22–24 Evidence of relevance to hypogonadism in young women is, however, largely indirect. Surgical oophorectomyin premenopausal women is associated with several adverse effects across these physiological systems,25 including an increased risk of cardiovascular disease and—at least in the short‐medium term—neurocognitive impairment.26 However, some of these effects mightre late to the sudden withdrawal of ovarian hormones, and may thus not be so applicable to the waxing and waning of these same hormones experienced during the onset of most spontaneous hypoestrogenic states, or to the complete absence of puberty, where the body has never been exposed to normal adult levels of estradiol and vasomotor symptoms are unusual
Estrogen regulates cerebral blood flow, flow‐mediated blood vessel dilatation and regulates hepatic lipid metabolism.14,27–29 It increases cleavage of small dense low‐density lipoprotein (LDL) particles and increases endothelial nitric oxide synthase, thus increasing production of nitric oxide, with additional effects on other pathways such as renin‐angiotensin (especially with EE) and salt sensitivity that regulate blood pressure.30 Other aspects of endothelial function may also be enhanced. Through effects on mitochondrial bioenergetics, estrogen is an important regulator of insulin sensitivity with actions on adipose tissue, liver, muscle and pancreatic beta cells.31
The key role of progesterone is in preparing the endometrium for implantation. It limits the proliferative action of estrogen and thus counteracts the pathological effects of unopposed estrogen exposure. Progesterone also acts on bone, albeit with limited effect compared to estradiol.32 It may also have neuroprotective effects, but the evidence on whether this is of clinical relevance is difficult to disentangle from controversies over the effects of estrogen replacement and the varied pharmacology of synthetic progestogens.33–35
The ovary is a significant source of testosterone and other androgens, with reduced production in women with both POI,36 and hypogonadotrophic (or central) hypogonadism (CH). The clinical implications of this are unclear, although it may impact on sexual health,37 and it is important to recognise the substantial interconversion of sex steroids that occurs in peripheral tissues and organs. Thus half of circulating testosterone in women derives from peripheral conversion of androstenedione, and testosterone itself is a direct precursor to estradiol.
14 | CONCLUSIONS
FH comprises a disparate group of conditions affecting younger women, many of whom have other significant medical issues and/or may need to continue taking HRT for several decades. Despite this, no HRT products have been specifically tailored for women with FH. FH is often confused with menopause; women with FH frequently describe obstacles in accessing HRT, including overstated warnings about breast cancer and cardiovascular risks, which can lead to prolonged gaps in treatment or premature discontinuation. Instead, the benefits of physiological estradiol replacement should be emphasised, which confer no risks above the baseline for eugonadal females. Biological parenthood has long been achievable for women with CH through ovulation induction or IVF, but many patients assume that they are irrevocably infertile and thus may not seek help unless prompted to do so. Management of FH may be modified by the underlying aetiology and so specialist advice is usually necessary to establish a treatment plan. Future research is needed to establish the monitoring and management requirements to optimise health outcomes for women with FH.
Female hypogonadism (FH) is a relatively common endocrine disorder in women of premenopausal age, but there are significant uncertainties and wide variation in its management. Most current guidelines are mono specialty and only address premature ovarian insufficiency (POI); some allude to management in very brief and general terms, and most rely upon the extrapolation of evidence from the studies relating to physiological estrogen deficiency in postmenopausal women. The Society for Endocrinology commissioned new guidance to provide all care providers with a multidisciplinary perspective on managing patients with all forms of FH. It has been compiled using expertise from Endocrinology, Primary Care, Gynaecology and Reproductive Health practices, with contributions from expert patients and a patient support group, to help clinicians best manage FH resulting from both POI and hypothalamo‐pituitary disorders, whether organic or functional.
3 | THE BIOLOGICAL EFFECTS OF THE FEMALE SEX HORMONES
Estradiol is the major hormone of deficiency in hypogonadism in women, but it is also essential to consider the importance of progesterone. The role of androgens, notably testosterone but also weak adrenal androgens, is more controversial although they have contributory actions in normal female physiology. Adrenal androgen secretion is impaired in women with hypopituitarism and ACTH deficiency, but not with other forms of FH, although ovarian androgen secretion is impaired in all forms. This section very briefly reviews the main physiological effects of the sex steroids of relevance to replacement therapy, though it is important to consider how closely pharmacological replacement mimics physiology.
Estradiol is essential for the key secondary sex characteristics, emerging normally at puberty. These effects develop over several years with the larche being the initial sign, initiated with still low levels of circulating estradiol.14 This highlights the need for an appropriate pace of incremental estrogen administration to mimic normal puberty, with the avoidance of early progesterone exposure which can affect full development of the breast by limiting the branching morphogenesis necessary for complete development of the ductal tree,15 and may also limit uterine development.11 Estradiol is also essential for uterine growth and maturation, and ongoing health of the urogenital tract. The vaginal epithelium requires estrogen for proliferation and keratin production and there is also evidence of a role in immune regulation.16 This is increasingly topical with increasing interest in the vaginal microbiome and its role in sexual and reproductive health, including in states of estrogen deficiency.17
In addition to its role in uterine growth, estradiol is essential for cyclic endometrial repair and proliferation after menstruation. Estrogen exposure is also necessary for the expression of endometrial progesterone receptors, underlying the necessary changes to a secretory pattern which are required for embryo implantation and the establishment of pregnancy.18
Centrally acting estrogen negatively regulates hypothalamic kisspeptin (Kp) and gonadotrophin‐releasing hormone (GnRH), which is the principal regulator of reproduction, controlling pituitary gonadotrophin secretion and, thereby, ovarian function. Distinct hypothalamic kisspeptin neuronal populations mediate estrogenic positive feedback to generate the mid‐cycle GnRH/LH surge necessary for ovulation. Estradiol also acts on the gonadotrophs of the anterior pituitary to regulate FSH and LH secretion, physiologically in concert with other ovarian hormones, notably the inhibins, in the regulation of FSH secretion.19 This locus of action is also very important in generating the mid cycle LH surge. It is now recognised that kisspeptin neurons also project from the infundibular nucleus to the medial preoptic nucleus, where they innovate the warm sensing neurons (signalling primarily through neurokinin B‐mediated synaptic activity), whose excess activity in states of hypergonadotrophic estrogen deficiency results in the characteristic vasomotor symptoms of the menopause,20 which are notably absent when the cause is hypogonadotrophic or with very early onset POI.
Estrogen receptors are also very widely expressed across the body, with notable effects on regulating bone, brain, cardiovascular and metabolic function. Within bone, estradiol controls both osteoblast and osteoclast number and function, through which i tregulates both cortical and trabecular bone turnover.21 Effects on other physiological systems have been less comprehensively studied and controversy remains, but there is increasing evidence that estrogen is required for continuing cardio‐metabolic and, potentially, neurocognitive health.22–24 Evidence of relevance to hypogonadism in young women is, however, largely indirect. Surgical oophorectomyin premenopausal women is associated with several adverse effects across these physiological systems,25 including an increased risk of cardiovascular disease and—at least in the short‐medium term—neurocognitive impairment.26 However, some of these effects mightre late to the sudden withdrawal of ovarian hormones, and may thus not be so applicable to the waxing and waning of these same hormones experienced during the onset of most spontaneous hypoestrogenic states, or to the complete absence of puberty, where the body has never been exposed to normal adult levels of estradiol and vasomotor symptoms are unusual
Estrogen regulates cerebral blood flow, flow‐mediated blood vessel dilatation and regulates hepatic lipid metabolism.14,27–29 It increases cleavage of small dense low‐density lipoprotein (LDL) particles and increases endothelial nitric oxide synthase, thus increasing production of nitric oxide, with additional effects on other pathways such as renin‐angiotensin (especially with EE) and salt sensitivity that regulate blood pressure.30 Other aspects of endothelial function may also be enhanced. Through effects on mitochondrial bioenergetics, estrogen is an important regulator of insulin sensitivity with actions on adipose tissue, liver, muscle and pancreatic beta cells.31
The key role of progesterone is in preparing the endometrium for implantation. It limits the proliferative action of estrogen and thus counteracts the pathological effects of unopposed estrogen exposure. Progesterone also acts on bone, albeit with limited effect compared to estradiol.32 It may also have neuroprotective effects, but the evidence on whether this is of clinical relevance is difficult to disentangle from controversies over the effects of estrogen replacement and the varied pharmacology of synthetic progestogens.33–35
The ovary is a significant source of testosterone and other androgens, with reduced production in women with both POI,36 and hypogonadotrophic (or central) hypogonadism (CH). The clinical implications of this are unclear, although it may impact on sexual health,37 and it is important to recognise the substantial interconversion of sex steroids that occurs in peripheral tissues and organs. Thus half of circulating testosterone in women derives from peripheral conversion of androstenedione, and testosterone itself is a direct precursor to estradiol.
14 | CONCLUSIONS
FH comprises a disparate group of conditions affecting younger women, many of whom have other significant medical issues and/or may need to continue taking HRT for several decades. Despite this, no HRT products have been specifically tailored for women with FH. FH is often confused with menopause; women with FH frequently describe obstacles in accessing HRT, including overstated warnings about breast cancer and cardiovascular risks, which can lead to prolonged gaps in treatment or premature discontinuation. Instead, the benefits of physiological estradiol replacement should be emphasised, which confer no risks above the baseline for eugonadal females. Biological parenthood has long been achievable for women with CH through ovulation induction or IVF, but many patients assume that they are irrevocably infertile and thus may not seek help unless prompted to do so. Management of FH may be modified by the underlying aetiology and so specialist advice is usually necessary to establish a treatment plan. Future research is needed to establish the monitoring and management requirements to optimise health outcomes for women with FH.
