Best Practice & Research Clinical Endocrinology & Metabolism 35 (2021) 101600

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Best Practice & Research Clinical

Diagnosis and management of premature

a r t i c l e i n f o
Premature ovarian insufficiency (POI) is a complex clinical syn-
Article history: drome with life-changing physiological and psychological conse-
Available online 16 November 2021 quence in young women of reproductive age. However, the
understanding of the etiology, diagnosis and optimal intervention
Keywords: strategies for this condition remains poorly understood. In recent
premature ovarian insufficiency years advances in epidemiologic and genetic research has
hormone replacement therapy improved our knowledge and awareness of POI. Further prospec-
estrogen-deficiency tive randomised trials are required to improve the psychological
cardiovascular disease and sexual health, fertility treatment options and long-term
cognitive health
management of the impact on bone, cardiovascular and cognitive
reproductive health
impact in women with POI. In this paper we aim to provide an
overview on the diagnosis and management of POI, discuss the
current understanding of the condition and future directions.
Crown Copyright © 2021 Published by Elsevier Ltd. All rights
reserved.

Introduction

Premature ovarian insufficiency (POI) is a clinical syndrome defined by the premature loss of ovarian
activity leading to a chronic hypo-estrogenic state in women under the age of 40 years. It was first
described as ‘primary’ ovarian insufficiency in 1942 by Fuller Albright [1]. The terminology to describe

* Corresponding author. The Fertility Centre, Chelsea and Westminster Hospital, 369 Fulham Road, London, SW10 9NH, UK.
E-mail address: [email protected] (R. Rahman).

https://doi.org/10.1016/j.beem.2021.101600
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R. Rahman, N. Panay Best Practice & Research Clinical Endocrinology & Metabolism 35 (2021) 101600

this disorder has long been debated with the use of a variety of terms such as, premature ovarian failure,
premature menopause and hypergonadotropic hypogonadism. However, the most commonly used term
in Europe is premature ovarian insufficiency which encompasses both spontaneous POI as well as
secondary POI resulting from iatrogenic interventions including chemotherapy, radiotherapy and sur-
gery [2]. POI is characterised by menstrual disturbances such as amenorrhoea or oligomenorrhoea,
raised gonadotropin levels and sex-steroid deficiency resulting in long term physical and psychological
consequences in women diagnosed with this syndrome. POI is associated with reduction in fertility that
can be devastating for women who have not completed their family. Unfortunately, despite the
potentially life-changing effects of POI, many gaps remain in our knowledge of the underlying etiology
and optimum management strategies for this complex condition. It is therefore pertinent to be up to date
with the current advances that can lead to improved diagnosis and effective treatment of POI.
In this paper we aim to review the latest literature on the pathophysiology, diagnosis and man-
agement of POI and discuss the current advances in our knowledge and future directions in this field.

Epidemiology

Studies investigating the prevalence of POI are lacking but it has been estimated that spontaneous
POI occurs in approximately 1% of women below the age of 40 and 0.1% below the age of 30 [3]. A recent
meta-analysis on the global prevalence of POI and early menopause showed that the pooled prevalence
of POI was as high as 3.7% and was found to be higher in countries with medium and low Human
Development Index [4]. Although the incidence of spontaneous POI has remained unchanged over the
years, there is a rising trend in the incidence of POI due to iatrogenic causes, such as chemotherapy,
radiation or surgery. The increasing success of cancer treatment and survival following childhood
malignancies has led to an increasing number of women experiencing long-term effects of chemo- or
radiotherapy. The Childhood Cancer Survival Study in 2006 showed that the incidence of acute ovarian
failure among this cohort was 6.3% [5]. In childhood cancer survivors who retained their ovarian
function following cancer treatment, the incidence of developing non-surgical POI was 13-fold higher
(8%) when compared with their siblings, used as controls (0.8%). Those treated with both alkylating
agents and abdominopelvic radiotherapy had higher cumulative incidence of nonsurgical POI, up to
30% [6]. Various factors, including ethnicity and lifestyle, can influence the risk of developing spon-
taneous POI. Smoking is a well-established risk factor for POI [7e9]. A cross-sectional study of 11652
women of multi-ethnic origin in the USA found that the difference in the prevalence of POI was sta-
tistically significant in the different ethnic groups. The prevalence was higher in Caucasian (p ¼ 0.02),
African American (p ¼ 0.004) and Hispanic (p ¼ 0.004) women compared to Chinese (p ¼ 0.2) and
Japanese women (p ¼ 0.2) [10]. Although the etiology of POI remains unknown in up to 90% [11] of
diagnosed cases, the most common causes include, genetic, autoimmune, metabolic, infectious and
iatrogenic.

Pathophysiology

The initial pool of primordial follicles at birth is typically between 700,000 and 1 million, which
gradually declines through the process of atresia and folliculogenesis during the reproductive lifespan,
with a few thousand oocytes remaining at the age of 40 years [2,12]. POI can occur through several
mechanisms including reduced peak follicle quantity, accelerated depletion of follicles through
apoptosis or dysfunctional folliculogenesis [2]. These processes can be triggered by a multitude of
exogenous factors like recreational drugs, chemicals, surgery and environmental factors, and also
endogenous factors including genetic predisposition, chromosomal defects, autoimmune diseases,
congenital enzyme deficiencies and stress [13]. It is thought that some women can undergo a pre-
mature ageing process, which is associated with spontaneous POI. A recent paper describes the process
of inflammatory ageing and suggests that inflammatory ageing plays a crucial role in the pathogenesis
of POI [13]. Premature ovarian insufficiency is a complex, multifactorial condition and its aetiology
remains poorly understood. POI can be classified as primary or secondary and although some under-
lying causes for POI have been established, the aetiology remains unknown in majority of the cases
despite exhaustive investigations.

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R. Rahman, N. Panay Best Practice & Research Clinical Endocrinology & Metabolism 35 (2021) 101600

 Genetic

Around 10.8% of cases of POI can be attributed to genetic abnormalities [14]. Karyotypic abnor-
malities are more commonly found in women presenting with primary amenorrhoea compared to
those with secondary amenorrhoea. One of the common genetic dysfunctions that leads to an
increased risk of POI is the FMR1 gene premutation located on the X chromosome. This mutation
involves expansion of CGG triplets in the regulatory region of the FMR1 gene. The premutation stage
with CGG repeats between 55 and 199 is associated with syndromic POI in approximately 20% of
carriers of this genetic mutation. Full mutation is found in affected women and is characterised by
more than 200 CGG repeats in FMR1 leading to methylation and silencing of this gene and causing
Fragile X syndrome [15]. Genome-wide analysis has enabled identification of several novel pathogenic
variants of genes that have been associated with non-syndromic POI. These mutations are primarily in
genes involved in ovarian development and function such as those associated with follicle atresia
(NR5A1, NOBOX, FIGLA and FOXL2), growth factors involved in folliculogenesis (BMP15 and GDF9) and
ovarian steroidogenesis (CYP17A1, CYP19, follicle stimulating hormone/luteinizing hormone receptors,
NR5A1 and Inhibin A) [2,15,16]. There are numerous other candidate genes that remain under inves-
tigation and it is likely that more “idiopathic” cases of POI will actually have a genetic etiology.

 Chromosomal

X chromosome abnormalities are commonly found in women with POI presenting with primary
amenorrhoea and those with a family history of POI. X chromosome related abnormalities are esti-
mated to occur in 12e14% of the POI population. Diagnosing a chromosomal origin may be helpful for
family planning decisions and genetic counselling [2]. The most common X chromosome abnormality
in POI patients is Turner's syndrome, 45XO, which occurs in 1:2500 live births [12]. It arises from partial
or complete deletion of one X chromosome through deletion, translocation, inversion, isochromosome
or mosaicism [12]. Clinical features characteristic of Turner's syndrome includes amenorrhoea, short
stature, lymphedema, webbed neck, visual disturbance, strabismus, high arched palate, otitis media,
shield chest, wide-spaced nipples, cubitus valgus, multiple nevi, short fourth metacarpal, and cardiac
and renal abnormalities [14,12]. Women with this syndrome have accelerated follicular atresia
resulting in diminished ovarian reserve. This causes POI prior to menarche, thus exhibiting as primary
amenorrhoea. In mosaic Turner syndrome (45X/46XX) women show milder phenotypic characteristics
and present with secondary amenorrhoea or hypogonadotropic hypogonadism [2]. The potential long-
term health problems in patients with Turner syndrome includes hearing and learning difficulties,
possible pregnancy risks, coeliac disease, diabetes, hypothyroidism, liver dysfunction, dyslipidaemia,
coronary artery disease and cerebrovascular disease. It is, therefore, important to have a multidisci-
plinary approach in managing these patients [12]. Other rarer chromosomal causes of POI include Xq
isochromosome in which an unbalanced chromosomal constitution leads to streak gonads and Turner-
like features. In addition, multiple deletions and translocations within the Xq13-27 loci in the long arm
on the X chromosome and also on the short arm have also been associated with POI [2].

 Autoimmune

An autoimmune etiology can be found in up to 5% of POI cases and is often associated with ovarian,
adrenal or steroidogenic cell autoantibodies [2]. Up to 30% of autoimmune POI coexist with additional
autoimmune diseases including both endocrine disorders such as, autoimmune thyroid disease, type 1
diabetes mellitus, adrenal insufficiency and non-endocrine disorders like, rheumatoid arthritis, Sjog-
ren's syndrome, systemic lupus erythematosus, inflammatory bowel disease, pernicious anaemia,
multiple sclerosis, celiac disease and alopecia. Ovarian dysfunction and POI may occur in women with
inherited autoimmune conditions like autoimmune poly-glandular syndromes (APS), both Types 1 and
2, in up to 15% of cases [14]. Type 1 APS usually presents with hypoparathyroidism, chronic muco-
cutaneous candidiasis and adrenal insufficiency. It results from mutations in the autoimmune regulator
gene AIRE on chromosome 21 [12]. Type 2 APS is characterised by hypothyroidism, adrenal

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R. Rahman, N. Panay Best Practice & Research Clinical Endocrinology & Metabolism 35 (2021) 101600

insufficiency and Type 1 diabetes. Involvement of an autoimmune process in the pathogenesis of POI
can be determined by the presence of lymphocytic oophoritis, evidence of autoimmune antibodies and
coexistence of autoimmune conditions [17]. Although ovarian autoantibodies are present in almost half
of the POI cases, its clinical significance remain debatable as they can be found commonly, in up to 31%,
of non- POI cases [14]. Adrenal autoantibodies are thought to be accountable for 60e80% of autoim-
mune POI cases and is strongly associated with a diagnosis of autoimmune lymphocytic oophoritis [2].
The mechanism involved in autoantibody related POI includes the initiation of an immune response to
ovarian tissue through cytokines, B cells and T cells that leads to the infiltration of lymphocytes,
oophoritis resulting from the destruction of ovarian follicles and cystic ovaries are often noted early in
the disease process. Women with adrenal antibodies may develop adrenal insufficiency following POI
and hence, it is advisable to have a multidisciplinary approach in managing these patients jointly with
the endocrinologist [12].

 Infectious

Some POI cases have an infectious etiology and there are two main viruses suspected to be involved
in the pathogenesis of this condition. The parotitis virus that causes mumps and results in mumps
oophoritis can lead to ovarian failure in 2e8% of cases. However, this tends to be transient in most
affected women and normal ovarian function resumes after recovery [14]. The true incidence of POI
following mumps oophoritis remains unknown. Secondly, both the human immunodeficiency virus
and its treatment can impair ovarian function, leading to POI. In addition, POI has been thought to be
associated with other infections such as, tuberculosis, varicella, cytomegalovirus or malaria. However,
the degree of association has not been confirmed yet [14].

 Iatrogenic

Iatrogenic POI can occur in oncology patients following chemotherapy, pelvic irradiation therapy or
surgery for malignant disease. Diagnosis of iatrogenic POI has increased as the recent advances in the
diagnosis and treatment of cancer has led to improved survival rates and higher POI rates in women of
reproductive age [17]. The effects of chemotherapy vary depending on type, dosage, age at start of
treatment and baseline ovarian reserve. Certain chemotherapy agents including cisplatinum, cyclo-
phosphamide and doxorubicin put patients at a higher risk of developing POI than other agents. The
use of gonadotrophin releasing hormone analogues to protect the ovaries during chemotherapy has
been studied showing varying results. Treatment with anthracyclines and alkylating agents can be
gonadotoxic and women undergoing autologous stem cell transplantation are at significantly higher
risk of developing POI (>90%) [12]. Radiotherapy to the abdomen, pelvis or spine can be gonadotoxic in
women with doses as low as 1 Gray. Doses greater than 20 Gray can result in ovarian insufficiency in
almost 70% of the cases [2]. Other common iatrogenic causes that lead to POI in the process of treating
non-malignant gynaecological diseases include, uterine artery embolization and pelvic surgery for
ovarian cysts, endometriomas and ovarian torsion [12]. It has been shown that excision of bilateral
endometriomas can lead to POI in 2.4% of cases [14].

 Environmental

Smoking has been associated with impaired ovarian function in many studies and generally
smokers have been found to go through earlier menopause than non-smoking women, hence sug-
gesting a detrimental effect of cigarette smoking on ovarian function [17]. An increased risk of POI has
also been found in women exposed to toxins like phthalates and bisphenol-A found in plastics and
other environmental pollutants. These toxins have been shown to increase follicular depletion and
accelerated atresia of preantral follicles resulting in an earlier onset of menopause [18].

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R. Rahman, N. Panay Best Practice & Research Clinical Endocrinology & Metabolism 35 (2021) 101600

 Metabolic

POI can result from metabolic disorders including 17- OH deficiency and classic galactosemia.
Galactosemia is an autosomal genetic defect caused by mutation of the GALT gene. This leads to
impaired galactose metabolism through a deficiency of galactose-1-phosphate uridylotransferase
enzyme [12]. POI has been found to be a common long-term complication in patients with this con-
dition as the galactose accumulates at toxic levels in various organs including the ovaries, thus having a
detrimental effect on the oocytes. 17-OH deficiency is characterised by enzymatic defect associated
with CYP17A1, which is active in adrenal glands and the gonads and shares the activity of steroid 17a-
hydroxylase and 17-20-lyase. 17-OH deficiency prevents synthesis of all 19 carbon steroids including
estrogen, hence leading to ovarian insufficiency and POI-like features [14].

Clinical evaluation and diagnosis

A recent position statement provided evidence on the predictors of POI. These include family his-
tory of POI, specific genetic abnormalities, being a child of a multiple pregnancy, early menarche,
nulliparity or low parity, cigarette smoking (doseeresponse dependent) and being underweight [19]. It
is therefore crucial to take a thorough personal and family history to establish these risk factors and aid
in the correct and timely diagnosis of POI.

 Symptoms

Women with POI may present with symptoms typical of menopause, that includes secondary
amenorrhoea or menstrual disturbance and subfertility with or without symptoms characteristic of
estrogen deficiency [12]. The clinical presentation of estrogen deficiency includes hot flushes and night
sweats as classic symptoms, vaginal symptoms, sleep disturbance, mood disturbance, lack of con-
centration, dry eyes, urinary frequency and low libido [16,20]. These symptoms may present inter-
mittently and vary in severity due to the fluctuations in ovarian activity and intermittent production of
ovarian hormones that occur during the onset of spontaneous POI. In contrast, the iatrogenic POI
phenotype tends to be more severe and persistent. Although symptoms may be variable, women with
POI are consistently found to have low ovarian reserve.

 Ovarian reserve assessment

Anti-Mullerian hormone (AMH) produced by developing antral follicles is considered to be the most
reliable biomarker for detecting impaired ovarian reserve [12]. However, it is not recognised as a
diagnostic test for POI due to its lack of availability in primary care and the costs involved. AMH is often
performed in secondary care to support the diagnosis of POI, especially in cases of diagnostic uncer-
tainty. AMH levels tend to start declining even before the onset of menstrual disturbance or rise in FSH
levels and can reach undetectable levels up to 5 years prior to the occurrence of menopause. Future
development multi-modal models using AMH and other biomarkers can be used to predict a women's
reproductive lifespan with a high degree of accuracy [2].

 Diagnostic criteria

The diagnosis of POI is confirmed in women <40 years of age with a history of oligo/amenor-
rhoea for at least 4 months and two serial measurements of raised follicle stimulating hormone
(FSH) levels taken >4 weeks apart [20]. There is a lack of high-quality evidence on the adequate cut
off levels for FSH. Although the most widely recognised threshold of FSH for diagnosis of POI is >40
IU/l, The European Society of Human Reproduction and Embryology has proposed a lower cut-ff
level of >25 IU/l. The rationale is that women with autoimmune POI have significantly lower
FSH levels when compared to the idiopathic POI group, hence a lower threshold of FSH enables to
include women with autoimmune POI in the diagnosis. The National Institute for Health and Care

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R. Rahman, N. Panay Best Practice & Research Clinical Endocrinology & Metabolism 35 (2021) 101600

Excellence (NICE) guidelines recommend an FSH cut off of >30IU/l [12]. The diagnostic accuracy of
FSH needs to be assessed robustly before a consensus can be reached on the most accurate cut-off
value.

 Investigations of underlying aetiology

Once investigations have been completed to confirm the diagnosis of POI, the second part of
diagnostic work-up to establish the underlying etiology should be considered.

Chromosomal and genetic testing

Evidence suggests that 10e12% of women diagnosed with POI have chromosomal abnormalities
[16]. Patients with suspected spontaneous POI should have karyotyping for Turner syndrome and
further chromosomal analysis including FMR1 gene premutation for Fragile X syndrome. Genetic
screening should be considered in all POI patients but is especially important in younger women and
those with a positive family history of POI or learning difficulties. A genetic etiology has implications on
future pregnancies and risk of passing on the gene mutation to their offspring. In addition, Fragile X
syndrome is associated with tremor/ataxia syndrome (FXTAS), which is a late onset neurological
complication common in male carriers of the genetic mutation and presents clinically with progressive
cerebellar gait ataxia and intention tremor. Due to these implications it is recommended that women
should be appropriately counselled before genetic testing is performed [16]. Women with detectable Y
chromosome on karyotyping should be counselled regarding risk of developing gonadal tumour and
should therefore be offered gonadectomy [16]. Autosomal genetic testing is not offered to women with
POI at present unless there is evidence of phenotypic characteristics specific to a certain genetic
mutation, such as type 1 Blepharophimosis Epicanthus Ptosis Syndrome [16]. Autoantibody screening
is recommended in women with POI due to the close association between autoimmune disorders and
POI. This includes screening for adrenal autoimmunity by testing for 21- hydroxylase antibodies and
thyroid peroxidase antibodies for detecting autoimmune thyroid disorders. The most prevalent
autoimmune pathology associated with POI is adrenal insufficiency with 2.5e20% of POI patients
showing presence of anti-adrenal antibody and histological evidence of oophoritis. POI is also common
among patients with Addison's disease with 10e20% patients being affected. Patients with adrenal
antibodies should be referred to endocrinologists as they are at high risk of developing adrenal
insufficiency and therefore should have close monitoring of their adrenal function. Anti-ovarian an-
tibodies are not routinely tested due to lack of correlation with clinical symptoms and incidence of high
positive result [12].

 Baseline investigations of general health

Investigations should include tests to assess general health of the individual, mainly car-
diometabolic and bone health, since POI is known to have long term effects and consequences on
general health. These should include screening tests for diabetes, hypertension and dyslipidemia. It is
important to carry out baseline work-up and follow-up measurements of body weight, body mass
index, fasting glucose, glycated haemoglobin (HbA1c), insulin resistance, lipid profile, blood pressure
and a dual energy X ray absorptiometry (DXA) scan [20]. The frequency of monitoring these levels
depend on local resources, patient's risk factors and personal characteristics, baseline results and
family history [12].

Management

 HRT

Most of the symptoms and long-term health morbidities experienced by women with POI are a
result of hypoestrogenism. The goal of hormone replacement therapy (HRT) in POI is therefore, to

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R. Rahman, N. Panay Best Practice & Research Clinical Endocrinology & Metabolism 35 (2021) 101600

alleviate these symptoms and improve long-term health by restoring normal serum estrogen levels
according to age of the patient. In adolescent girls with pre-pubertal POI, estrogen replacement is
crucial for the development of secondary sexual characteristics and to achieve maximal bone mineral
density (BMD). Women should receive HRT from the time of diagnosis at least until they reach the
average age of natural menopause [21]. Currently, there is limited research on the optimum regimen
for hormone replacement and options include both HRT and combined contraceptive pill (COCP) [2].
There is wide variation in practice in terms of the route of administration, dosing and the type of
estrogen and progestogen preparation used for treating women with POI. Ideally hormone replace-
ment should mimic normal ovarian function and aim to maintain physiological concentrations of es-
trogen and progesterone.

 Estradiol and progestin replacement

Patients with POI typically need higher doses of estrogen replacement compared to women going
through natural menopause at expected age. Although data on optimum estradiol levels to be main-
tained in POI is lacking, it is believed that dosing should aim at achieving average serum estradiol levels
of 367 pmol/L in order to mimic the daily ovarian production rate of the hormone expected in a
premenopausal state [22]. The three commonly used estrogen preparation for hormone replacement
include 17b-estradiol, ethinylestradiol and conjugated equine estrogens. COCP contains the potent
synthetic estrogen, ethinylestradiol, which provides a supraphysiological replacement dose and has
unfavourable effects on lipid profile and coagulation factors thus increasing risk of venous thrombo-
embolism (VTE) [21]. Alternatively, HRT preparations provide a more physiological replacement of
hormones and contain 17b-estradiol (where the main physiological estrogen is the active component)
and may therefore be the more preferrable option for optimising bone and cardiovascular health in
women with POI [23]. A randomised, controlled, cross-over trial including 34 women with POI showed
that physiological replacement with oral estradiol and vaginal progesterone therapy was superior in
improving cardiovascular health when compared with COCP use in POI patients [24]. However, the
COCP provides effective contraception to avoid the 5% risk of spontaneous pregnancy in POI and is the
more practical option for younger patients not desiring pregnancy. More recent evidence suggests that
the transdermal or transvaginal route of administration is the more favourable first line of HRT for
women with POI [22]. These routes of administration help to deliver the hormones directly into the
circulation, thus having the advantage of avoiding first pass effect on the liver and its associated
complications with coagulopathy and risk of thromboembolism [22]. A randomised, double-blind,
placebo-controlled clinical trial by Popat et al., in 2014 supported the transdermal route of adminis-
tration of HRT in POI women by demonstrating that the use of transdermal estradiol (100 mg/day) and
oral medroxyprogesterone (10 mg/day) 12 days/month in women with POI restored the mean femoral
neck bone density to normal and comparable to controls over a 3 year period [25]. Transdermal
replacement of 17b-estradiol at a dose of 100 mg/day seems to be adequate in maintaining a physio-
logical serum estradiol level and may be the preferred option of treatment in POI [21]. A new study
(POISE) where women will be randomised to COCP versus HRT will provide better quality evidence
regarding the best option for hormone replacement in women with POI [26].
Estrogen should be combined with cyclical progesterone therapy in women with POI, in order to
prevent endometrial hyperplasia and risk of developing endometrial cancer [2]. Progestogens for HRT
use in POI patients can be given orally, vaginally and in the form of an intrauterine system. There is
limited evidence on the effectiveness of various forms of progestogens used in POI women as most of
the data available concentrates on HRT use in older postmenopausal women. This data suggests that, in
naturally menopausal women, micronized progesterone has advantages over medroxyprogesterone
acetate in combined HRT as there appears to be a reduced breast cancer risk, lower prothrombotic risks
and the metabolic benefits of estrogen are maintained. However, POI women using higher doses of
estrogen replacement need higher doses of progesterone, greater than 200 mg, to provide sufficient
long-term endometrial protection [12]. The only long term controlled published data on HRT for young
women with POI was provided by the NIH Intramural Research Program study. In this study oral
medroxyprogesterone acetate at a dose of 10 mg/day for 12 days per month was used as the preferred

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progestogen therapy. There is a lack of data comparing sequential and continuous combined HRT,
although patients using the continuous combined regimen may experience spontaneous breakthrough
bleeding when ovarian function resumes intermittently [2]. Young women with POI might prefer
sequential therapy as it gives monthly withdrawal bleeding and hence, a similarity with their peers
[21].
Clinicians should discuss patient preferences of the route and method of administration of the
hormones and also take into consideration their contraceptive needs prior to prescribing the most
suitable hormone replacement therapy. It is crucial to continue HRT at least until the natural age of
menopause both for symptomatic relief and improve quality of life and also to reduce risk of long-term
health complications. However, studies show that up to 40% of POI women do not adhere to HRT after
first year of therapy. Hence, it is important to consider patient preference and have a thorough dis-
cussion regarding risks and benefits when prescribing HRT in order to improve compliance [23]. The
table below shows the options for hormone replacement therapy and compares the recommended
doses for women with POI with the standard doses used in women going through natural menopause
at expected age (see Table 1).

 Risks of HRT

Women with POI should be carefully counselled regarding risks and benefits of HRT. HRT has not
been found to increase risk of breast cancer in young women with POI [16]. Estrogen only HRT can

Table 1
Options of hormone therapy (HT): comparing standard and POI regimens.

HT preparation Sequential combined HT Continuous combined HT

Estradiol type
Patch (transdermal) (mg) 75-100 (standard dose 25e50) 75-100 (standard dose 25e50)
Gel sachet (transdermal) (mg) 1.5e2 (standard dose 0.5-1.0) 1.5e2 (standard dose 0.5-1.0)
Gel pump (1 metered dose ¼ 0.75 mg) 3-4 (standard dose 1e2) 3-4 (standard dose 1e2)
Oral (mg) 3.0e4.0 (standard dose 1.0-2.0) 3.0e4.0 (standard dose 1.0-2.0)
Progesterone/progestogen type
Micronized progesterone (oral/pV) (mg) 200 (standard dose 100e200) 200 (standard dose 100)
Dydrogesterone (oral) (mg) 20 (standard dose 10) 10 (standard dose 5.0)
Medroxyprogesterone acetate (oral) 10 (standard dose 5.0) 5.0 (standard dose 2.5)
(mg)
Norethisterone acetate (oral) (mg) 2.5e10 (standard dose 2.5-5.0) 5.0 (standard dose 1.25-2.5)
E2/progesterone combined regimens
E2/micronized progesterone (oral) (mg) >2.0/>200 (standard dose 1.0-2.0/100 3.0e4.0/300e400 (standard dose 1.0-2.0/
e200) 100e200)
E2/norethisterone acetate (transdermal) 75-100/255e340 (standard dose 25 75-100/255e340 (standard dose 25e50/
(mg/24 h) e50/85-170) 85-170)
E2/dydrogesterone (oral) (mg) 3.0e4.0/20 (standard dose 1.0-2.0/10) 3.0e4.0/7.5e10 (standard dose 0.5-1.0/
2.5-5.0)
E2/norethisterone acetate (oral) (mg) 3.0e4.0/2.0e4.0 (standard dose 1.0-2.0/ 3.0e4.0/1.5e2.0 (standard dose 0.5-2.0/
1.0) 0.1-1.0)
Levonorgestrel intrauterine system. n/a 20 mg/day sufficient for higher POI doses

Table does not show all available options globally. HT, hormone therapy; E2, estradiol; n/a, not available; pV, per vagina.
Notes
1. Estrogen replacement should be offered to all women diagnosed with POI unless contraindicated.
2. Both HT and COC are appropriate to use but COC provides less favourable effects on bone density. It is preferrable to use 17b
estradiol for estrogen replacement.
3. Women with intact uterus should be prescribed combined treatment with progesterone/progestogen.
4. Patient preference should be considered for route and method of administration and contraceptive needs.
5. HRT should be continued at least until the time of anticipated natural menopause.
6. Women with POI usually need higher doses of estradiol, but in case of intolerance or adverse effects, lower doses can be
considered initially.
7. Sequential HT regimens require 12 days of progesterone/progestogen monthly for endometrial protection.
8. Endometrial safety is less assured with micronized progesterone when used for more than 5 years.
9. There is a lack of data on endometrial safety for the minimum effective dose of progesterone/progestogen with higher es-
trogen doses used for POI.

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R. Rahman, N. Panay Best Practice & Research Clinical Endocrinology & Metabolism 35 (2021) 101600

increase the risk of endometrial hyperplasia, therefore it is well established that women with POI with
an intact uterus should be prescribed only combined estrogen and progesterone therapy to reduce the
risk of endometrial cancer. Although no studies have assessed the effect of HRT on risk of stroke, the
overall absolute risk of stroke in young POI patients is known to be extremely low [23]. Risk of venous
thromboembolism (VTE) of POI patients on HRT is dependent on the formulation of estrogen and
progesterone used for hormone replacement. Therefore, transdermal and transvaginal estradiol that
avoids first pass effect on the liver and oral or vaginal micronized progesterone and progestogens have
a lower risk of VTE when compared with other types of HRT and the COCP [21].

 Treatment with androgens

Young women with POI often suffer from sexual dysfunction, including loss of libido. Studies have
shown that POI patients have lower androgen levels when compared with controls [2]. However, there
is currently a lack of studies investigating the role of androgen replacement in POI patients and its
effects on sexual function and the long-term health [16]. A randomised controlled trial (RCT) by Popat
et al. showed no additional benefit of transdermal testosterone replacement on BMD in POI patients
[25]. A further RCT investigating the benefit of physiological testosterone replacement in women with
POI showed no positive effect on quality of life, self-esteem or mood when compared with controls
[27]. Although more positive data are required in this group, androgen replacement should be dis-
cussed as an option for women with POI with distressing low sexual desire.

 Psychosocial and psychosexual support

Women with POI are at increased risk of psychological distress including anxiety, depression and
somatisation along with a lack of self-esteem and overall life satisfaction, which is largely associated
with the diagnosis of infertility and lack of support [22]. A cross sectional study investigated women's
experiences of diagnosis of POI, main concerns and impact on psychosexual health. The results
revealed that majority patients found the diagnosis traumatic and felt there was significant lack of
information and support. Psychological health along with fertility and bone health were among the
main areas of concern. 49% women reported that POI had negative impact on self-esteem and confi-
dence, thus requesting emotional support [28]. Therefore, psychosocial and psychosexual support is a
crucial aspect of POI management and patients should be offered referral to a psychologist or coun-
sellor and be given advice regarding support groups such as The Daisy Network (https://www.
daisynetwork.org) early on in the diagnosis [2]. Cognitive behavioural therapy and psychosexual in-
terventions should be tailor made according to the individual needs of women with POI [12].

 Contraception

Spontaneous ovarian activity may resume in women with POI, especially early on in their diagnosis,
thus leading to a possibility of spontaneous conception in up to 5% cases [16]. It is important to
remember that HRT does not prevent spontaneous ovulation, hence women on HRT who are wishing
to avoid a spontaneous conception should either switch to COCP or receive advice regarding additional
forms of contraception [23]. The levonorgestrel intrauterine system can be used for endometrial
protection with estrogen therapy as well as for contraception.

 Complementary therapy and non-hormonal treatments

HRT may be contraindicated in certain groups of patients such as those with estrogen sensitive
breast or endometrial cancer or those with high thromboembolic risks. In these patient groups if the
risks of using HRT outweighs the benefits then it is necessary to consider alternative options such as
complementary therapies, selective re-uptake inhibitors (SSRIs), venlafaxine or gabapentin. Although
the evidence on the efficacy of such non-hormonal options are limited, they may provide relief of

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vasomotor symptoms to some extent. However, they do not reduce the long-term complications
secondary to estrogen deficiency [12].

Long term consequences and management

The mean life expectancy in women with POI has been shown to be 2 years less than those reaching
menopause over 55 years of age. The increased mortality is thought to be due to the long-term health
complications related to cardiometabolic, bone and cognitive health [2].

 Cardiometabolic

Patients with POI are at increased risk of early mortality due to cardiovascular and cerebrovascular
disease compared to women reaching menopause at the expected age 49e55 years [12]. In a large
study using data pooled from 15 observational studies, women with POI had greater risk of coronary
heart disease and stroke when compared to women who had menopause at 50e51 years of age and
there was a 3% increase risk of cardiovascular disease (CVD) with each year of decrease in age at onset
of menopause [29].
POI has been associated with several cardiovascular risk factors including vascular endothelial
dysfunction, abnormal lipid profile, increased insulin resistance and metabolic syndrome [2]. There-
fore, it is important to assess cardiovascular risk in these patients and recommend annual monitoring
of blood pressure, weight and smoking status along with other modifiable risks if indicated [16]. A cross
sectional study involving 385 women with POI showed that lack of estrogen over a prolonged period of
time increases cardiovascular risks, whereas estrogen replacement over time reduces this estimated
risk. This and various other studies support early initiation of hormone replacement therapy in women
with POI and continuation till the average age of natural menopause to reduce future cardiovascular
risk and associated higher mortality rate [30,31,29]. One of the strong risk factors for CVD is Type 2
diabetes mellitus (T2DM). It is already known that menopause is associated with abnormal glucose
metabolism. A recent systematic review and meta-analysis including 13 studies have shown that both
early menopause (age of <45 years at menopause) and POI (age <40 at menopause) are directly
associated with an increased risk of T2DM thus putting these women at greater risk of developing CVD.
Therefore, it is imperative to perform appropriate screening for early detection of T2DM and to
commence lifestyle modifications and pharmacological therapy at an early stage [32].

 Bone health

One of the well-established long-term consequences of POI is the significant reduction in bone
mineral density (BMD) and the associated increased overall fracture risk due to the lack of protective
effect of estrogen on the bone [2]. The prevalence of osteoporosis in women with POI ranges between
8% and 27% and is significantly higher when compared to those reaching natural menopause at the
usual age [12]. The underlying mechanisms for bone remodelling associated with estrogen deficiency
includes, increased osteoclast activity resulting in increased bone resorption, which stimulates an
increase in osteoblast activity and bone formation, although bone resorption outweighs bone forma-
tion thus leading to an overall loss of bone density [16]. Common modifiable risk factors for low BMD
that are also relevant for women with POI include age <20 years at onset of perimenopausal state,
smoking, lack of exercise, low body mass index, low serum levels of calcium and vitamin D concen-
trations, non-compliance with hormone therapy or >1 years delay in diagnosis of POI and therefor
delay in initiating estrogen replacement [16,12]. It is therefore important to advise women with POI
regarding these risk factors. There is evidence to support the use of HRT to improve BMD to levels
similar to that of control groups and its use for more than 3 years has been shown to reduce subsequent
fracture risks [2]. Assessment of bone health in POI involves evaluation of clinical risk factors,
biochemistry to check serum levels of vitamin D and calcium, and Dual-Energy X-ray Absorptiometry
(DEXA). There are some reservations in using the DEXA-derived BMD T-score to diagnose POI related
osteoporosis in young women who have not yet achieved the peak bone mass. An International

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R. Rahman, N. Panay Best Practice & Research Clinical Endocrinology & Metabolism 35 (2021) 101600

Osteoporosis Foundation review suggests that a Z-score of <-2 and T score of <-2.5 in a young woman
with POI is diagnostic of osteoporosis, which is in line with the diagnostic criteria for osteoporosis set
by the World Health Organisation [12]. Management to improve bone health in POI includes prompt
initiation of HRT and continuation till natural age of menopause. Hormone replacement with ‘physi-
ological’ doses of 100e150 mg transdermal estrogen and vaginal progesterone appears more favourable
in improving bone mass in the lumbar spine in women with POI when compared to oral ethinyles-
tradiol and progestogens in the COCP [33].
There is currently no good evidence to support the use of other pharmacological agents such as
bisphosphonates or strontium in preventing loss of BMD in POI. These agents could pose harmful ef-
fects on a developing fetus in case of a spontaneous pregnancy [16]. In addition to HRT, 1200 mg of
calcium supplement and 800e1000IU of vitamin D daily is considered to be beneficial in women with
POI [12,21].
A lack of awareness and knowledge among patients with POI often leads to a delay in diagnosis, sub-
optimal screening, a delay in starting HRT and non-compliance to therapy. All of these factors result in a
negative impact on the management of bone health in POI patients [12]. It is therefore crucial to
educate women with POI and provide advice on appropriate lifestyle changes to optimise general
health, and weight bearing exercise to reduce risk of long-term complications. Although there is lack of
knowledge on the best modality and frequency of monitoring, it is advised that bone health should be
assessed when starting HRT and repeated according to findings and all risk factors [12]. A multi-
disciplinary team of clinicians including primary care physicians, endocrinologists and gynaecolo-
gists involved in the care of women with POI will have the required skills to optimise bone health.

 Cognitive health

POI has been shown to be associated with increased risk of neurological dysfunction, dementia,
Parkinson's disease and reduced cognitive function [16,21]. A population-based cohort study involving
4868 participants showed that both iatrogenic and spontaneous POI were associated with an increased
risk of cognitive impairment and there was a 30% increase in the risk of deterioration of psychomotor
speed and overall cognitive function over a 7-year period [34]. European Society of Human Repro-
duction and Embryology (ESHRE) suggests considering the use of HRT, mainly the estrogen component,
to reduce the risk of decline in cognitive function [16]. Estrogen replacement has also been found to
reduce depressive symptoms and other mood disturbances. The data on the beneficial effects of
testosterone supplement on quality of life, self-esteem and mood in POI patients remain inconclusive
[21].

 Reproductive health

One of the life-changing and frequently most devastating aspects of POI is infertility. In most cases it
does not entail a complete “failure’ of the ovaries but rather intermittent and unpredictable ovarian
activity that leads to involuntary childlessness. This can have significant impact on the psychological
well-being patients, especially those who have not completed their family. About 25% of women
diagnosed with POI may spontaneously ovulate, which gives the possibility for spontaneous concep-
tions in up to 5e10% of patients. The chances of pregnancy are highest in the first 1 year after diagnosis
[20]. However, spontaneous pregnancies in POI women still remain unlikely and rare [35,12]. Although
various treatment options to improve pregnancy rates have been investigated in women trying to
conceive using autologous oocytes, whether through natural conception or assisted reproductive
techniques, evidence on the most effective treatment strategy still remains inconclusive. This was
confirmed in a recent systematic review studying the occurrence of pregnancies in women with POI,
naturally or with different treatments. In this review the pregnancy rates across studies were found to
be between 2.2% and 14.2% and the mean age of patients achieving a pregnancy was 30 years, thus

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R. Rahman, N. Panay Best Practice & Research Clinical Endocrinology & Metabolism 35 (2021) 101600

suggesting that oocyte quality is preserved in younger POI patients [36]. There are currently many
novel treatments, such as stem cell therapy, platelet-rich plasma and primordial follicle activation, that
are being investigated but further research is required before their effectiveness and safety can be
confirmed [12]. To date, oocyte donation remains the most effective treatment option for POI related
infertility with success rates of up to 40e50% per cycle [2]. Other options include embryo donation,
surrogacy and adoption. Women with POI should be thoroughly counselled regarding treatment op-
tions, success rates and efficacy of different treatment so patients can make an informed decision. In
some cases, patients may choose to make a positive life decision to not have children at all [2].

 Fertility treatments using own oocytes

The depletion of primordial follicles and lack of ovarian feedback in POI leads to elevated gonad-
otrophin levels. It has been postulated that exogenous administration of estrogen may reinstate the
negative feedback on pituitary. This may result in suppression of the chronically raised endogenous
FSH levels and in turn upregulate FSH receptors in the granulosa cells of the remaining follicles, thus
allowing synchronisation of follicular growth and inducing ovulation [2]. Another proposed theory by
which estradiol may improve fertility rates is based on the ability of HRT to suppress elevated LH levels,
thereby avoiding premature luteinization. HRT is thought to improve the sensitivity of ovarian follicles
to gonadotrophin induced ovarian stimulation and undergo follicular maturation, thus improving
ovulation rates [37].
A double-blind, randomized, placebo-controlled study showed that estrogen replacement with
ethinylestradiol administered for 2 weeks prior to starting ovarian stimulation lowered FSH levels
significantly and resulted in improved success rate of ovulation induction in patients with POI and
suggested aiming for FSH level < or ¼ 15mIU/ml before starting ovarian stimulation [38]. In contrast, a
study investigating the role of COCP in reducing gonadotrophin levels and improving ovulation. Even
though administration of ethinylestradiol 30 mg and levonorgestrel 150 mg for 12 weeks resulted in a
decline in both FSH and LH to the normal follicular phase range, follicular growth could not be detected
on ultrasound scanning [39].
In recent years there has been increasing interest in the role of androgen (DHEA or testosterone)
replacement to improve fertility outcome in patients with POI. Androgen therapy is thought to increase
IGF-1 levels, which helps to improve follicular development. It upregulates FSH receptors and increases
production of estrogen and progesterone, thus resulting in recruitment of higher number of pre-antral
and small antral follicles [36]. A randomized, double-blinded, placebo-controlled study to assess the
effect of DHEA on ovarian response in POI patients showed that DHEA use for 16 weeks led to increase
in antral follicle count, ovarian volume and estradiol levels but no difference in AMH or FSH. However,
the authors did not include clinical pregnancy rate as one of the outcome measures [40]. Most studies
investigating the effect of androgens on pregnancy rates has been carried out on patients with
diminished ovarian reserve or poor response to ovarian stimulation. Studies involving POI patients are
limited and either underpowered or the sample size is too small to show any statistically significant
results [41,42]. Further large RCTs are required to obtain any robust evidence regarding the effect of
testosterone or DHEA on pregnancy rates in women with POI.
More recently promising new technologies are emerging, which include stem cell therapies, IVA
and treatment with platelet-rich plasma. Further conclusive evidence is required before these tech-
niques can be incorporated into clinical practice for the management of infertility in POI patients [36].

 Oocyte donation

At present oocyte donation offers the highest chance of achieving a pregnancy in POI patients.
However, patients diagnosed with POI are young and often not ready to accept egg donation as the first
option of treatment. There may be other issues including lack of suitable donors due to limited
availability, financial implications or religious or cultural restrictions. More recently there has been
growing interest in the possibility of egg sharing to meet the increasing demand for donor oocytes and
also to make the treatment more affordable [43].

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R. Rahman, N. Panay Best Practice & Research Clinical Endocrinology & Metabolism 35 (2021) 101600

 Cryopreservation-mainly for iatrogenic

The opportunity of fertility preservation is missed once patients develop symptoms of POI and the
diagnosis is established. Therefore, it is important to identify patients at risk of iatrogenic POI, such as
those following gonadotoxic cancer treatments or surgery, or patients with early decline in ovarian
reserve and impending POI so that they can be offered the option of oocyte or embryo cryopreser-
vation. In patients with a partner or those keen to use donor sperm, embryo freezing provides higher
success rates with IVF over oocyte freezing, despite the recent technical advances in oocyte cryo-
preservation such as vitrification to improve live birth rates [44].

 Counselling

The diagnosis of POI may be life-changing and often devastating for women due to its association
with long term health consequences, infertility and the stigma of being menopausal. This may
therefore have significant negative impact on the psychological well-being of patients. Thus, it is
equally important to manage both the physical as well as the psychological implications of this con-
dition. There is a very limited number of studies evaluating the impact of psychological interventions
on the mental wellbeing of patients with POI. The role of psychological interventions such as coun-
selling, focused education, group intervention and cognitive behavioural therapy should be researched
specifically in the POI group so that this can potentially be implemented as part of the overall man-
agement of patients with POI [16].

POI registry

There are various aspects in the diagnosis and management of POI that are still poorly understood.
Further directed research on crucial areas of this complex condition is required to improve our
knowledge and optimise management strategies. Therefore, an international POI registry can help to
create a global biobank for genetic data and characterise the different aetiologies of POI. POI is a rare
condition and hence, it is difficult to design large prospective RCTs to obtain statistically significant
results. A global multi-centre collaboration through the POI registry (https://poiregistry.net) will
provide researches with access to large data sets for analysis and studies that will help to develop
evidence-based guidelines and improve clinical management of POI patients [12].

Practice points

 POI is associated with significantly higher risk of long-term deterioration of the cardiovas-
cular, bone, cognitive and reproductive health.
 Investigations should include tests to assess general health of the individual, mainly car-
diometabolic and bone health.
 Estrogen replacement should be offered to all women diagnosed with POI unless
contraindicated
 Both HT and COC are appropriate to use but COC provides less favourable effects on bone
density
 Women with intact uterus should be prescribed estrogen combined with cyclical proges-
terone to prevent endometrial hyperplasia and risk of endometrial cancer.
 Patient preference should be considered for route and method of administration and con-
traceptive needs.
 HRT should be continued at least until the time of anticipated natural menopause
 Early diagnosis and prompt initiation of HRT improves quality of life and prevents osteo-
porosis and cardiovascular disease in the long-term.
 POI is a complex condition and is best managed with a multi-disciplinary approach.

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R. Rahman, N. Panay Best Practice & Research Clinical Endocrinology & Metabolism 35 (2021) 101600

Research agenda

 International databases such as the POI registry would play a crucial role in conducting
research that would help develop evidence-based treatment regimens
 Future research should concentrate on the discovery of reliable biomarkers for predicting POI
and understanding the pathophysiology of POI.
 Further evidence is required on the impact of different combinations of HRT on general,
psychological and sexual health in the long-term.
 Optimal dosage of hormone replacement should be documented.
 The role of androgen replacement on general quality of life and reproductive health need to
be investigated.
 Trials are needed on the management and long-term outcomes in women with hormone-
sensitive cancers.
 Studies are required on fertility enhancing treatments and techniques including the use of
oogonial stem cells.

Conclusion and future directions

POI is characterised by a premature loss of ovarian activity leading to a chronic hypoestrogenic state
in women under the age of 40. This can either be spontaneous or iatrogenic. Recent advances in cancer
treatments leading to improvements in long-term survival following malignancies in children means
that there is an increasing cohort of young women experiencing the complex physical and psycho-
logical consequences of POI. Women with POI are at a significantly higher risk of long-erm deterio-
ration of the cardiovascular, bone, cognitive and reproductive health compared to those going through
natural menopause at the average age of 51 years. It is, therefore, crucial to improve awareness of this
condition among clinicians and the general population so that these women can be diagnosed and
treated at an earlier stage to allow better treatment outcome. Preventive measures such as lifestyle
modifications and advice regarding long-term hormone replacement therapy should be implemented
at the earliest stage possible. This complex condition is best managed with a multi-disciplinary
approach to tackle the different problems that may manifest at different stages in a woman's life.
This condition requires further research with prospective randomised controlled trials. It is difficult
to conduct single centre large scale studies in this population due to the rarity of the condition and
hence international databases such as the POI registry would play a crucial role in conducting research
that would help develop evidence based treatment regimens to optimise women's health and reduce
long-term complications of POI.
Future research should concentrate on areas that remain poorly understood or has questions
unanswered. Key research priorities include discovery of reliable biomarkers for predicting and
diagnosing POI, understanding the pathophysiology and genetic etiology of POI, impact of different
combinations of HRT on general, psychological and sexual health in the long-term, determining the
optimal dosage of hormone replacement, role of androgen replacement on general quality of life and
reproductive health, management and long-term outcomes in women with hormone-sensitive cancers
and fertility treatment options and fertility enhancing treatments and techniques including the use of
oogonial stem cells for proliferation and production of mature oocytes both in vitro and in vivo. The
national and international collaboration of POI data would enable us to conduct large scale studies and
hence contribute to meaningful research.

Funding

No funding was used for this review.

Conflict of interest

The authors have no conflict of interest to declare.

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R. Rahman, N. Panay Best Practice & Research Clinical Endocrinology & Metabolism 35 (2021) 101600

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