Premature Ovarian Insufficiency PDF - The Obstetrician & Gynaecologist 2024

DOI: 10.1111/tog.12943 2024;26:152–62 The Obstetrician & Gynaecologist Review http://onlinetog.org...

DOI: 10.1111/tog.12943 2024;26:152–62 The Obstetrician & Gynaecologist Review http://onlinetog.org Premature ovarian insufficiency a b,c Hazem Sayed MBBCh MRCOG,* Kanna Jayaprakasan MBBS MD DNB FRCOG PhD a Obstetrics and Gynaecology Registrar - ST7, Royal Derby Hospital, Uttoxeter Rd, Derby DE22 3NE, UK b Consultant Gynaecologist and Subspecialist in Reproductive Medicine & Surgery, Royal Derby Hospital, Uttoxeter Rd, Derby DE22 3NE, UK c Honorary Professor, University of Nottingham, Nottingham, UK *Correspondence: Hazem Sayed. Email: [email protected] Accepted on 8 May 2024. Key content: Learning objectives:  Premature ovarian insufficiency (POI) is a clinical syndrome  To raise awareness of early diagnosis of POI. involving ovarian follicle depletion and defined by loss of ovarian  To be able to discuss the implications of POI for the health of function before 40 years of age. women affected and their families, as well as for different  The diagnostic workup in women with suspected POI is in two hormonal and non-hormonal treatment options. steps: confirming the diagnosis and establishing its cause; it is  To understand various fertility treatment options for POI. important to understand the rationale for performing each Ethical issues: diagnostic test, how to interpret results and appropriate  It is important to consider the reproductive and diagnostic multidisciplinary team involvement.  Treatment options include various regimens and preparations of implications for women with chromosomal or genetic problems (e.g. Turner syndrome, Fragile X mutation carriers) and for their hormone replacement therapy (HRT), monitoring and family members. surveillance, induction of puberty in those with very early POI,  A diagnosis of POI may have differing implications based on social complimentary treatment and fertility treatment. and cultural factors, and healthcare providers should consider a  Management of POI requires a comprehensive and personalised patient’s values, beliefs, cultural background and preferences. strategy that addresses not only the physical symptoms and disease risks, but also the psychosocial and reproductive health Keywords: adolescent gynaecology / HRT regimens < menopause / aspects, and it is important that women receive infertility / ovarian function < reproductive science / Premature adequate counselling. Ovarian Insufficiency Please cite this paper as: Sayed H, Jayaprakasan K. Premature ovarian insufficiency. The Obstetrician & Gynaecologist 2024;26:152–62. https://doi.org/ 10.1111/tog.12943 assessment, health implications, effective management and Introduction future considerations. It aims to improve understanding Premature ovarian insufficiency (POI) is a clinical syndrome and awareness of this significant health issue affecting women defined by loss of ovarian function before 40 years of age. It of reproductive age, thereby promoting better clinical involves ovarian follicle depletion, leading to estrogen practices and research directions. deficiency and reproductive consequences,1 and it is characterised by menstrual disturbance (oligo-amenorrhoea), Terminology high gonadotrophins and low estradiol.2 Despite research advances in the field of reproductive ageing, POI remains POI is characterised by hypergonadotrophic hypogonadism underdiagnosed and undertreated.3 POI encompasses various in women aged 40 IU/l on two and education. tests 6 weeks apart for initial diagnosis, the National Institute for Health and Care Excellence (NICE) uses >30 IU/l on tests Pathophysiology of premature ovarian 4–6 weeks apart. ESHRE recommends using a lower insufficiency threshold of >25 IU/l on two occasions >4 weeks apart for POI diagnosis to ensure inclusion of women with POI involves disrupted ovarian physiology. Ovarian autoimmune POI, who have lower range of FSH levels.8 folliculogenesis involves the progression and development of ovarian follicles from primordial stage, and the process initiates prenatally. Approximately seven million primordial Epidemiology and prevalence of premature follicles form by the fourth fetal month, reducing to one ovarian insufficiency million at birth as the follicles continually undergo apoptosis POI demands early identification and management owing to or atresia.15 By puberty, this number drops to around its profound impacts, emphasising the need for enhanced 400 000.15 While women ovulate only about 400 oocytes in ª 2024 Royal College of Obstetricians and Gynaecologists. 153  17444667, 2024, 3, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/tog.12943 by NHS Education for Scotland NES, Edinburgh Central Office, Wiley Online Library on [22/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Premature ovarian insufficiency their reproductive life, the follicle number decreases by 25– POI are found to be positive for SCA. Adrenocortical 150 per day until the menopause.15 Ovarian ageing, antibodies (ACA), particularly 21-hydroxylase autoantibodies characterised by a decline in follicle number and quality, is (21OH-Ab), have been identified as the sensitive diagnostic pronounced by the mid-thirties, culminating in menopause indicator for autoimmune POI. Consequently, it is in the early fifties. Menopause timing depends on two key recommended to measure these antibodies in all POI patients factors: peak follicle count and rate of follicular atresia.16 to identify the presence of latent Addison’s disease in this Women or girls with a small follicle pool at birth or population.28 POI is often seen in cases of thyroid experiencing an accelerated depletion of follicles through autoimmunity ranging from 14% to 27%, in the absence of apoptosis develop POI.17 adrenal autoimmunity.26 Iatrogenic Aetiology of premature ovarian Iatrogenic POI can arise after cytotoxic treatments such as insufficiency chemotherapy and radiotherapy, which can cause While there are many known pathogenic pathways leading to considerable tissue damage and decreased ovarian reserve. POI, the cause remains unknown in most cases. The causes Alkylating substances have been shown to be highly that could lead to POI include genetic/chromosomal, gonadotoxic and poses a substantial risk of POI.29 Surgical autoimmune, iatrogenic, infective, environmental and interventions, such as oophorectomy for treating idiopathic factors.4 gynaecological disorders, are obvious causes of POI. Studies reported an association between hysterectomy and tubal Genetic factors sterilisation and early menopause.30,31 Surgical removal of Genetic factors account for 20–25% of all POI cases.2 Turner ovarian endometriomas is correlated with a decrease in syndrome, characterised by premature follicular atresia due serum anti-M€ ullerian hormone (AMH) levels and ovarian to the full or partial absence of one X chromosome, is the reserve.32 While surgery for bilateral ovarian endometriomas most common chromosomal abnormality associated with may result in POI, unilateral surgery does not exhibit the POI, accounting for about 10% of cases.19 XY gonadal same association. dysgenesis, another cause for POI, poses a 45% risk of gonadal neoplasia, warranting consideration of Infective gonadectomy.20 In addition, the FMR1 (Fragile-X-mental POI has been reported following various infections like retardation 1) gene’s CGG trinucleotide repeat amplification HIV, herpes, cytomegalovirus, tuberculosis, malaria, leads to Fragile X syndrome premutation (FXPOI). Women varicella and shigella, though a direct causal relationship with FMR1 gene mutation do not carry a risk of intellectual remains unestablished.1 disability but have a 13–26% risk of developing POI.21 Apart from chromosomal disorders, other gene mutations Idiopathic linked to POI include those affecting folliculogenesis POI can be idiopathic, and it may relate to environmental (FOXL2, NOBOX),22 as well as those involved in influences, lifestyle choices or unexplained genetic DNA repair, like ATM (ataxia tielangactasia mutated). variants.33,34 Such cases may involve a rapid decline in Galactosaemia, an autosomal recessive disorder, may also ovarian follicles or reduced gonadotrophin responsiveness.3 elevate POI risk due to secondary hypoglycosylation.23 Women with blepharophimosis, ptosis, epicanthus inversus Environmental syndrome (BPES) are at high risk for POI, necessitating Toxin exposure and smoking have been related to an elevated FOXL2 gene testing.24 Recent advances in genomic risk of POI.35 Life characteristics such as early menarche age technologies, such as whole-exome sequencing, are likely to and nulliparity have also been linked to POI.36 uncover more genetic causes in the near future.25 Diagnosis and assessment of premature Autoimmune ovarian insufficiency Up to 20% of cases of POI may be caused by ovarian autoimmunity, and up to 30% of women with POI may also The diagnostic workup in women with suspected POI is in have an autoimmune illness.26 POI can coexist with two steps: confirming the diagnosis and establishing its cause. autoimmune disorders such as Addison’s disease and ESHRE criteria for diagnosing POI in women under the age thyroid illness.27 of 40 are a combination of oligomenorrhea or amenorrhea Steroid cell antibodies (SCA) are specifically designed to for at least 4 months and two measurements of high FSH target autoantigens expressed by endocrine organs, such as the levels (>25 IU/l) taken at least 4 weeks apart.1 Elevated cortex, ovary, placenta and testes. About 4–5% of women with FSH levels are indicative of the reduced inhibitory feedback 154 ª 2024 Royal College of Obstetricians and Gynaecologists.  17444667, 2024, 3, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/tog.12943 by NHS Education for Scotland NES, Edinburgh Central Office, Wiley Online Library on [22/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Sayed and Jayaprakasan from low estrogen and inhibin B levels, secondary to Psychosocial assessment is critical, considering POI’s diminished ovarian follicular activity.37 impact on fertility and long-term health, often leading to A thorough medical history and physical examination is anxiety, depression and emotional distress.40 Affected women needed. A comprehensive family history is crucial to identify and their partners should receive psychosocial support and any genetic or familial patterns of POI or associated diseases. counselling to help them cope with the diagnosis and make In teenagers with suspected POI, assessing secondary sexual educated decisions about their reproductive future. development is critical, as delayed or halted puberty may Figure 2 presents a flowchart for diagnostic workup suggest POI.2 of POI. Levels of estradiol, LH and AMH, among other hormones, might provide additional indications of diminished Implications of premature ovarian functional ovarian reserve. Estradiol levels are often low or insufficiency in the lower limit of the normal range in POI, while LH levels may be elevated.2 AMH, a direct measure of residual ovarian POI has far-reaching consequences, affecting many aspects follicle pool, is often very low or undetectable. Given some of a woman’s health and quality of life. The primary women with POI may intermittently ovulate, pregnancy consequence is infertility, which can be upsetting and exclusion is essential.38 distressing for those who have not yet had children or are in Chromosomal analysis is recommended in all the process of starting a family.41 Hypo-estrogenemia can also non-iatrogenic POI, regardless of age, to evaluate for cause physical symptoms such as hot flushes, night sweats, chromosomal abnormalities as a cause for POI. Screening sleep problems and mood changes. Furthermore, it causes for causes, like Turner syndrome and presence of Y sexual dysfunction, such as decreased desire, dyspareunia chromosome material, is typically performed in confirmed and vaginal dryness.1 These symptoms are equivalent to POI cases.3 Testing for Fragile X syndrome premutation is those experienced by postmenopausal women.42 indicated after careful counselling, not just to establish as a Women with POI are at risk for developing osteoporosis in cause, but because presence of the mutation has further the long term, if not treated promptly with HRT. implications for the women and her family. Female family Hypo-estrogenemia causes an increase in bone turnover members including daughters or siblings may be carriers and and loss, resulting in a decrease in bone mineral density are at risk of developing POI. Male carriers are at risk of (BMD) and an increased risk of fracture.14 developing a late-onset neurological problem, Fragile X POI is linked to an elevated risk of cardiovascular disease. Ataxia syndrome (FXTAS), while severity and penetrance of Estrogen insufficiency may result in negative alterations to the this is less in female carriers.1,21 Autosomal genetic testing is lipid profile and vascular health and therefore an increased reserved for only for specific cases, like BPES.24 risk of cardiovascular disease5 and coronary heart disease. If Pelvic ultrasound can exclude uterine causes of secondary untreated, POI could shorten life expectancy by approximately amenorrhea (e.g. Asherman syndrome). Ultrasound 2 years, primarily due to cardiovascular disease.43 assessment of ovarian follicles may be helpful, although its Many women with POI experience feelings of loss, anxiety utility in diagnosing POI is limited owing to fluctuating and despair as a result of the rapid, unexpected change in ovarian function.1 their health condition and the impact on their fertility. Autoimmune profiling is also recommended to evaluate Mental health problems are much higher in women with POI as a potential cause for POI, despite lack of available than in the overall population. POI might also increase the specific treatment. The presence of adrenal or thyroid risks of cognitive decline and neurological disorders such as autoantibodies suggests autoimmune POI and indicates Parkinson’s disease, although further research is needed to potential risk of Addison’s disease or hypothyroidism in the explore this.44 future.27 ESHRE recommends testing for ACA, 21-OHAb POI can be linked to autoimmune illnesses. Autoimmune and thyroid peroxidase antibodies (TPO-Ab). Annual POI, as a component of autoimmune polyendocrine TSH level monitoring is recommended for TPO- syndromes, is frequently related to autoimmune thyroid Ab-positive patients.4 disease, adrenal insufficiency (Addison’s disease), type 1 Once POI is diagnosed, baseline general health assessment diabetes and other conditions.27 Women with POI should be is crucial. Bone health, assessed with dual-energy x-ray regularly assessed for the development of these disorders. absorptiometry (DEXA) at diagnosis and on a regular basis, is vital owing to increased osteoporosis risk. Cardiovascular Management of premature ovarian health assessments are needed, as hypo-estrogenemia elevates insufficiency cardiovascular risks.5 Regular monitoring of lipid profile and blood pressure, along with lifestyle modification, can help POI requires a comprehensive and personalised strategy that mitigate this risk.1 addresses not only the physical symptoms and disease risks, ª 2024 Royal College of Obstetricians and Gynaecologists. 155  17444667, 2024, 3, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/tog.12943 by NHS Education for Scotland NES, Edinburgh Central Office, Wiley Online Library on [22/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Premature ovarian insufficiency Oligo/ amenorrhoea for at least 4 months Diagnosis of POI FSH level > 25 IU/I on two occasions > 4 weeks apart Karyotyping/ Check antibodies in case POI of unknown cause or genetic testing if an immune disorder is suspected Essential work up Diagnosis of Presence of Y- Turner Positive Positive for Positive for after diagnosis of chromosomal syndrome for Fra-X ACA/210H TPO-Ab POI material Refer to Discuss endocrinologist, gonadectomy Refer to Refer to Test TSH cardiologist and with the geneticist endocrinologist every year geneticist patient Figure 2. Flowchart of diagnostic workup for premature ovarian insufficiency. but also the psychosocial and reproductive health aspects. associated with the usage of HRT.34 Studies in women with The care needs to be comprehensive, yet individualised, iatrogenic POI45 and women with chemotherapy-induced comprising hormonal therapy, lifestyle changes, fertility POI46 support the use of HRT for relief of vasomotor management and psychological support. It is critical that symptoms. Importantly, HRT has been shown to protect women with POI receive information about their diagnosis against bone loss and osteoporosis.14 Evidence shows estrogen and treatment options and that they participate in decision- therapy enhances BMD and reduces the likelihood of spine and making. General advice on health, including lifestyle hip fractures.47 Earlier studies have also suggested that modifications and maintaining bone health, should be estrogen replacement therapy can influence bone mineral given. Women should be informed about the potential density in women diagnosed with POI48 and Turner increased risk of cardiovascular disease and counselled to syndrome.49 It is essential for women who do not want to follow healthy lifestyle habits that can help decrease this risk. become pregnant to use reliable contraception, given the slight Relevant information on healthy balanced diet, adequate chance of unexpected conception. intake of vitamin D and calcium, regular exercise, smoking cessation, and avoidance of excessive alcohol intake needs to Type of preparations be provided. Regular blood pressure and lipid profile HRT typically consists of estrogen and progesterone and can be monitoring is also essential.35 taken orally, trans-dermally or through a mix of these modalities.1 The progesterone component of HRT can also Hormone replacement therapy be supplemented through an intrauterine device (e.g. HRT is the basis of treatment for women with POI, aiming to Mirena). The HRT regimen, dose and mode of achieve physiological levels of estradiol. Initiating HRT early administration should be tailored to the woman’s symptoms, may hold particular significance for young women diagnosed health state, personal preferences and risk of side effects. with POI, as it optimises the attainment of peak bone mass During HRT, women should be continually followed-up to and mitigates cardiovascular risk factors. To mitigate the check response, adjust treatment as needed and screen for any enduring health ramifications resulting from ovarian adverse effects. function loss, ESHRE recommends the continuation of HRT for women with POI aims to mimic natural estrogen HRT until the average age of natural menopause (50– levels. Available estrogen types are 17b-estradiol (more 51 years), unless there is any contraindication.1 natural as of ovarian origin), ethinylestradiol (synthetic) Improvements in vasomotor symptoms, sleep problems, and conjugated equine estrogen (CEE; derived from pregnant mood, sexual function and general quality of life have been mare urine). CEE is rarely used nowadays because of 156 ª 2024 Royal College of Obstetricians and Gynaecologists.  17444667, 2024, 3, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/tog.12943 by NHS Education for Scotland NES, Edinburgh Central Office, Wiley Online Library on [22/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Sayed and Jayaprakasan increased risk of hypertension and thrombosis compared higher dose than conventional because of being younger. It is with conventional HRT with 17b-estradiol. The combined appropriate to achieve physiological estradiol levels (180–370 oral contraceptive pill (COCP) with ethinylestradiol is an pmol/l) as found in blood from normally menstruating option for estrogen replacement for those requiring women.55 These levels are generally achieved with 50–100 contraception, considering a small risk of conception in mcg estradiol transdermal patches;56 the equivalent daily oral women with POI. COCP is preferred by some women dose of estradiol would be 2–4 mg. The dosage of progestogen because of its familiarity; however, it provides excessive depends on the estrogen dose and the type of regimen hormones than needed for physiological replacement, with (continuous or sequential). The continuous regimens involve less favourable effects on lipid profiles and thrombotic factors a minimum dose of 100 mg of micronised progesterone or 2.5– with increasing thromboembolic risk.50 If better compliance 5 mg medroxyprogesterone acetate (MPA) or 1 mg of with contraception can be assured with the preferred option norethisterone for continuous oral intake. In sequential of COCP, a low dose (20 mcg) pill is advised. It is best to run regimens, it is recommended to administer 200 mg through packets (with fewer breaks of one week every 3–6 micronised oral progesterone or 10 mg MPA or for a months, or no breaks at all) to avoid frequent estrogen-free minimum of 12 days per month.51 intervals of the conventional regimes with a pill-free week every month. Route of administration HRT regimens with 17b-estradiol are more beneficial for Systemic administration of estrogen can be achieved via the bone mineralisation and cardiovascular health than COCP. oral route or through transdermal patches and gels. Such treatments have been shown to increase lumbar spine Recent developments include nasal sprays and injectable BMD and positively affect bone formation markers and estrogen preparations. Local estrogen treatment includes cardiovascular health.51 vaginal rings, creams and pessaries primarily for For women with a uterus, progestogen supplementation is genitourinary symptoms. important to prevent endometrial hyperplasia and reduce the One significant benefit of transdermal estrogen is the risk of cancer.51 Progesterone serves a protective role ability to bypass the initial metabolism in the liver,57 by mitigating the mitogenic impact of estrogen on the achieving higher plasma estradiol concentrations with lower endometrium. Synthetic progestogens provide effective cycle dosages, resembling premenopausal conditions more control and endometrial protection. However, closely.58 Postmenopausal women using transdermal ‘body-identical’ (micronised natural) progesterone may have oestrogen have a reduced risk of myocardial infarction,59 a more favourable cardiovascular safety profile than synthetic deep vein thrombosis60 and stroke61 compared with those progestogens.52 Further, there may be a preference for using oral administration. The transdermal route of micronised natural progesterone over synthetic progestogens administration is preferable for specific high-risk women with regard to breast cancer risk.53 such as smokers or those with migraine or venous thromboembolism risk factors.62 Regimens and dosage Progestogens may be administered through various routes, Continuous estrogen replacement is needed to minimise including oral, transdermal application (such as patches) or symptoms and long-term health implications of estrogen intra-uterine delivery. Table 1 demonstrates doses, routes, deficiency. Progesterone can be given continuously or and suggested combinations of HRT options.63 cyclically. While continuous combined HRT may prevent endometrial hyperplasia and cancer, cyclical progesterone of Fertility management 12–14 days lowers the risk.51 Most women with POI need help conceiving. The most Both COCP and HRT have been shown to reduce prevalent approach for these women is IVF with donor long-term health risks and are safe in women with POI. oocytes.17 Women should be educated about the risk of Women seeking to achieve pregnancy and planning oocyte treatment failure, potential problems, obstetric complications, donation treatment may experience more favourable and the psychological, ethical and legal aspects of using donor outcomes with a sequential (cyclical) regimen compared oocytes.1 Pregnancy after oocyte donation is considered with a continuous regimen. A cyclical regimen promotes the high risk and women should therefore receive active functioning of the endometrium, characterised by hospital-based antenatal care. regular episodes of proliferation and withdrawal bleedings.54 Fertility preservation procedures, such as Women with POI but without a uterus can be treated with cryopreservation of oocytes, embryos or ovarian tissue, estrogen-only therapy. have been developed in recent years; however, these options The lowest effective dose of estrogen should be used to treat have no place in already established POI. These procedures the symptoms of hypo-estrogenemia and to prevent associated could mainly be used for women who are undergoing long-term health consequences. Women with POI may need a iatrogenic POI.64 In women with impending POI, fertility ª 2024 Royal College of Obstetricians and Gynaecologists. 157  17444667, 2024, 3, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/tog.12943 by NHS Education for Scotland NES, Edinburgh Central Office, Wiley Online Library on [22/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Premature ovarian insufficiency Table 1. Bioequivalent hormonal dosages for hormone therapy for primary ovarian insufficiency.* Table adapted from Committee Opinion No. 698: Hormone Therapy in Primary Ovarian Insufficiency63 Progesterone Estrogen Continuous Sequential 2 mg micronised 17b-estradiol (oral) 2.5–5 mg medroxyprogesterone acetate (oral) 10 mg medroxyprogesterone acetate (oral) for 12 days each month 50–100 mcg 17b-estradiol (transdermal) 100 mg micronised progesterone 200 mg micronised progesterone 0.625–1.25 mg conjugated equine oestrogen (oral) daily (oral) daily (oral) for 12 days each month *Select one of the estrogen options to combine with one of the progesterone option; progesterone dose needs to be increased if using higher dose of estrogen. preservation options may be considered although the testosterone levels, and subsequently reassess these levels at potential success rates are very low. regular intervals with initial follow-up levels checked at 3– 6 months.1 Psychological support Given the significant psychological burden associated with a Management of premature ovarian diagnosis of POI, referral to a psychologist or psychiatrist for insufficiency in special situations ongoing support and cognitive behavioural therapy may be beneficial.65 Peer support and information can also The evidence is limited on the use of HRT in women with be obtained through support groups and online resources POI and its relationship with the development of breast such as The Daisy Network and the Turner Syndrome cancer, risks of migraine, recurrence of VTE and obesity. Support Society. Several studies have shown a connection between HRT and the occurrence of breast cancer in postmenopausal women.67 Other preventive and supportive care HRT is not recommended for breast cancer survivors The administration of GnRH agonists during standard to manage vasomotor symptoms,68 while gabapentin, chemotherapy protocols has been shown to reduce the venlafaxine and fluoxetine are alternative strategies.69 incidence of ovarian dysfunction and POI.66 ESHRE suggests HRT can be used for people who have the It is important to assess and monitor compliance, BRCA1/2 gene mutations and have had bilateral salpingo satisfaction, potential side effects and the need for oophorectomy but do not have a previous record of breast adjustments in the treatment dose or administration method. cancer.1 While transdermal HRT is considered safe to use in In cases where osteoporosis is diagnosed and treatments such as women with a history of migraines with aura, COCP is not estrogen replacement or alternative therapies are started, it is recommended. Transdermal oestrogen in postmenopausal advisable to conduct a follow-up BMD assessment every 3– women does not increase the risk of thrombosis, unlike 5 years. However, if BMD falls within the normal range and an oral oestrogen.70 adequate systemic estrogen replacement therapy is initiated, For women with POI and hypertension, it is recommended women may not need follow up DEXA scans. to use transdermal estradiol as the preferred method of Testosterone can be useful for low libido despite adequate administration. Women who have been diagnosed with POI oestrogen replacement. Testosterone can be administered via and are at an increased risk of venous thromboembolism may gels. Decisions regarding androgen replacement should potentially benefit from transdermal HRT after consulting a consider women’s preferences. While there isn’t a licensed haematologist for evaluation before starting the treatment.1 preparation available for women, Testogel 40.5 mg sachet can Canonico et al.71 reported that the use of transdermal estrogen be used over 8 days such that women get a 5 mg dose daily. did not increase the risk of venous thromboembolism in Androfeme 1% cream in 50 ml tubes (0.5 ml per day = 5 mg overweight and obese women compared with non-users. per day), licensed in Australia for female use, is imported to However, the risk was higher in women who used oral estrogen. the UK for private use under a special MHRA license and is In cases of endometriosis necessitating oophorectomy, well tolerated, with less side effects. Prior to commencing the combined estrogen/progestogen therapy addresses vasomotor androgen treatment, it is advisable to establish baseline symptoms and reduces disease reactivation risk.1 158 ª 2024 Royal College of Obstetricians and Gynaecologists.  17444667, 2024, 3, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/tog.12943 by NHS Education for Scotland NES, Edinburgh Central Office, Wiley Online Library on [22/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Sayed and Jayaprakasan Table 2. Estrogen substitution therapy in adolescence. Table adapted from Bondy and Turner Syndrome Study Group77 Age Age-specific suggestions Preparation/dose/comments 12–13 years If no spontaneous development and follicle-stimulating 17b-oestradiol (E2) transdermal: 6.25 lg/day E2 via patch hormone (FSH) elevated, start low-dose estrogens Oral micronised E2: 5 lg/kg/day or 0.25 mg/day 12.5–15 years Gradually increase E2 dose at 6–12 month interval over 2– Transdermal E2: 12.5, 25, 37.5, 50, 75, 100 lg/day. (Adult dose: 3 years to adult dose 100 lg/day) Oral E2: 5, 7.5, 10, 15 lg/kg/day. (Adult dose: 2–4 mg/day) 14–16 years Begin cyclic progestogen after 2 years of estrogen or when Oral micronized progesterone 100–200 mg/day or dydrogesterone breakthrough bleeding occurs 5–10 mg/day during 12–14 days of the month Puberty induction initiate estrogen therapy at higher doses and increase the Management of young women presenting with primary dosage more rapidly. One potential therapeutic approach amenorrhoea would need input from paediatric/reproductive involves initiating treatment with a daily oral micronised endocrinologists experienced in induction of puberty to estradiol (E2) dose of 0.5 mg, or alternatively, a transdermal optimise general growth, breast and uterine development. A estrogen dose of 12.5 lg per day. The initial dosage of E2 small proportion, 5–10%, of girls diagnosed with Turner should be progressively escalated at intervals of 3–6 months syndrome could maintain adequate ovarian function, over a span of 2 years until reaching the recommended adult resulting in the spontaneous onset of puberty. However, dosage. The treatment regimen should be tailored to the most of those girls experience a gradual decline in ovarian individual, with careful monitoring of breast development.78 function leading to significantly reduced ovarian reserve, Bondy and Turner Syndrome Study Group77 suggested age- resulting in the need for estrogen therapy to achieve full specific estrogen substitution therapy regimes in adolescence, breast development and induce withdrawal bleeding.72 The as shown in Table 2. initiation of estrogen therapy is recommended for those aged ≥12 years who have not experienced spontaneous onset of Ethical considerations and psychological impact puberty or progression of breast development. Achieving an In managing POI, informed consent for testing, sensitive optimal adult height by growth hormone therapy is decision-making and clear communication of diagnoses and an additional factor to consider. While Ross et al. (1983; implications are crucial. This includes ethical considerations 1986)73,74 observed lower doses of estrogen have the potential in genetic testing, such as for Fragile-X, necessitating detailed to promote growth, higher estrogen doses have been found to counselling about potential impacts for both the individual accelerate bone maturation and consequently lead to a and their family; therefore, genetic counselling should decrease in adult height. be offered.79 The process of puberty is characterised by a relatively Ethical considerations arise in ensuring patients have gradual progression, and it is recommended that access to accurate and unbiased information about their replacement therapy during the induction process should different management options. Healthcare providers should aim to replicate this natural tempo.75 While the optimal consider the patient’s values, beliefs, cultural background and initial dosage for estrogen replacement remains preferences, emphasising shared decision-making.80 undetermined, it is typically initiated at a fraction ranging Additionally, addressing the psychological and social from one-tenth to one-eighth of the recommended adult impacts of POI, such as feelings of grief, inadequacy or dosage. Subsequently, the dosage is incrementally augmented stigma is crucial, warranting empathetic support and over 2–4 years.76 To facilitate the appropriate development psychological counselling.81 of the breasts and uterus, it is recommended to postpone the introduction of progesterone for a minimum of 2 years after Future considerations and conclusion initiation of estrogen therapy, or until the occurrence of breakthrough bleeding.77 POI represents not just a reproductive concern but a When pubertal failure is diagnosed at a later stage and broader health challenge for women affected. The potential growth is not a primary concern, it may be appropriate to for early screening, guided by ESHRE diagnosis criteria, is ª 2024 Royal College of Obstetricians and Gynaecologists. 159  17444667, 2024, 3, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/tog.12943 by NHS Education for Scotland NES, Edinburgh Central Office, Wiley Online Library on [22/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Premature ovarian insufficiency vital for timely intervention and fertility preservation 8 La Marca A, Brozzetti A, Sighinolfi G, Marzotti S, Volpe A, Falorni A. Primary ovarian insufficiency: autoimmune causes. Curr Opin Obstet Gynecol options like egg freezing, enhancing women’s 2010;22(4):277-82. reproductive autonomy. 9 Leone T, Brown L, Gemmill A. Secular trends in premature and early Genetics is a prominent area of interest in POI research. menopause in low-income and middle-income countries. BMJ Glob Health 2023;8(6):e012312. Most cases remain unexplained, indicating that other genetic 10 van Noord PA, Dubas JS, Dorland M, Boersma H, te Velde E. Age at natural variables remain unknown.18 Novel genomic technologies, menopause in a population-based screening cohort: the role of menarche, such as next-generation sequencing, are likely to aid in fecundity, and lifestyle factors. Fertil Steril 1997;68(1):95-102. 11 Jiao X, Zhang H, Ke H, Zhang J, Cheng L, et al. Premature Ovarian finding these unknown genetic causes and in the early Insufficiency: Phenotypic Characterization Within Different Etiologies. J Clin detection of disease.82 Furthermore, understanding the Endocrinol Metab 2017;102(7):2281-90. genetic basis of POI can pave the way for personalised 12 Murray A, Schoemaker MJ, Bennett CE, Ennis S, Macpherson JN, et al. Population-based estimates of the prevalence of FMR1 expansion mutations therapy, in which treatment is matched to the individual’s in women with early menopause and primary ovarian insufficiency. Genet genetic make-up.18 Med 2014;16(1):19-24. By stratifying patients based on the aetiology of POI, 13 Ventura JL, Fitzgerald OR, Koziol DE, Covington SN, Vanderhoof VH, et al. Functional well-being is positively correlated with spiritual well-being in treatment modalities can be fine-tuned. A deeper women who have spontaneous premature ovarian failure. Fertility Steril understanding of the underlying causes will enable 2007;87(3):584-90. clinicians to tailor the dose and regime of HRT more 14 Popat VB, Calis KA, Kalantaridou SN, Vanderhoof VH, Koziol D, et al. Bone mineral density in young women with primary ovarian insufficiency: results effectively, ensuring optimal outcomes for every individual. of a three-year randomized controlled trial of physiological transdermal Future research should focus on standardised mental estradiol and testosterone replacement. J Clin Endocrinol Metab 2014 health screenings, long-term health risks such as Sep;99(9):3418-26. 15 Wallace WH, Kelsey TW. Human ovarian reserve from conception to the cardiovascular disease and osteoporosis and the impact on menopause. PLoS One 2010;5(1):e8772. cognitive function and neurodegenerative illnesses.83 16 Broekmans FJ, Knauff EA, te Velde ER, Macklon NS, Fauser BC. Female Advancing our approach to POI through screening, reproductive ageing: current knowledge and future trends. Trends Endocrinol Metab 2007;18(2):58-65. fertility preservation options and tailored treatment 17 Maclaran K, Nikolaou D. Early ovarian ageing. The Obstetrician & strategies is the future. It promises a paradigm where Gynaecologist 2019;21(2):107-16. women with POI not only manage their condition but 18 Rossetti R, Ferrari I, Bonomi M, Persani L. Genetics of primary ovarian insufficiency. Clin Genet 2017;91(2):183-98. thrive without compromising their quality of life. 19 Gravholt CH, Andersen NH, Conway GS, Dekkers OM, Geffner ME, et al. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Contribution to authorship Turner Syndrome Meeting. Eur J Endocrinol 2017;177(3):G1-g70. HS researched and wrote the article. KJ instigated and edited 20 Michala L, Goswami D, Creighton SM, Conway GS. Swyer syndrome: the article. Both authors approved the final version. presentation and outcomes. BJOG 2008;115(6):737-41. 21 Wittenberger MD, Hagerman RJ, Sherman SL, McConkie-Rosell A, Welt CK, et al. The FMR1 premutation and reproduction. Fertil Steril 2007;87 Disclosure of interests (3):456-65. HS has no conflicts of interest. KJ is an Associate Editor for 22 Laissue P. Aetiological coding sequence variants in non-syndromic premature ovarian failure: From genetic linkage analysis to next generation The Obstetrician & Gynaecologist; he was excluded from sequencing. 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