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33
© Springer Nature Switzerland AG 2019
F. R. Pérez-López (ed.), Postmenopausal Diseases and Disorders,
https://doi.org/10.1007/978-3-030-13936-0_3
A. Podgurna · A. Szeliga · M. Maciejewska-Jeske · B. Meczekalski (*)
Department of Gynecological Endocrinology, Poznan University of Medical Sciences,
Poznan, Poland
e-mail: marzena@jeske.pl
M. Grymowicz · E. Rudnicka · R. Smolarczyk
Department of Gynecological Endocrinology, Warsaw Medical University, Warsaw, Poland
e-mail: monika.grymowicz@wp.pl; ewa.rudnicka@poczta.onet.pl; rsmolarczyk@poczta.onet.pl
3
Premature Ovarian Insufficiency
AgnieszkaPodfigurna, MonikaGrymowicz, AnnaSzeliga,
EwaRudnicka, MarzenaMaciejewska-Jeske,
RomanSmolarczyk, andBlazejMeczekalski
3.1 Definition
Premature ovarian insufciency (POI)—rst described in 1942 by Fuller Albright
[1] is dened as the loss of ovarian function before the age of 40years. It’s a state
of female hypogonadism associated with amenorrhoea, increased gonadotropin lev-
els, and hypoestrogenism [1, 2]. The ESHRE guideline criteria recommend the fol-
lowing diagnosis criteria for POI: oligo-/amenorrhoea for at least 4months and
elevated follicle-stimulating hormone (FSH) level >25 IU/L on two occa-
sion>4weeks apart [3, 4].
3.2 Etiopathogenesis
Spontaneous causes of POI include genetic abnormalities, autoimmune disorders,
infections, enzyme deciency, metabolic diseases, or very often idiopathic causes
[5, 6]. Induced or iatrogenic POI is often a result of oncological treatment: radio-
therapy, chemotherapy, and surgery (bilateral ovariectomy) [5, 7, 8].
Approximately 10–12% of women with POI have chromosomal abnormalities.
Among them 94% represent X chromosome abnormalities (X structural defects or
X aneuploidy), and the rest 6% are autosomal gene defects. In women with POI and
primary amenorrhoea, the incidence of karyotype abnormalities is higher (21%)
than in women with secondary amenorrhoea (11%) [9, 10].
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Turner syndrome is characterized by 45,X0 karyotype and occurrence of dysge-
netic gonads and has an incidence of 1in 2500 females [11]. 80% patients with
Turner syndrome lack paternal X chromosome; in the remaining cases, there is an
incorrect chromosome X (isochromosome X), the failure of short arm of chromo-
some X, or damage to chromosomal segment 2.6Mb Xp-Yp of pseudoautosomal
region [12]. Having two chromosomes X is necessary for full development of the
ovary and the correct course of folliculogenesis. In case of absence or abnormal
chromosome X, the oocytes cannot properly undergo meiosis and degrade [13]. In
some cases of Turner syndrome with mosaicism 45,X0/46,XX, we can observe
menarche and the occurrence of menstruations for many years [11]. In a study by
Gravholt, 12% of women with Turner syndrome (12 of 114 patients) had Y chromo-
some and elevated risk of developing gonadal neoplasia (10–30%) [14].
Trisomy X (karyotype 47,XXX), with the incidence of 1:800 born girls, is caused
by nondisjunction of the X chromosome during maternal meiosis. It’s also con-
nected with POI and development of mental disorders, but the prevalence of POI in
this group is unknown [15, 16].
One of the most common genetic contributors to POI is permutation of the frag-
ile X mental retardation 1 (FMR1) gene, which is responsible for up to 13% of
familial cases and 0.8–7.5% of sporadic cases of POI [17, 18]. FMR1 gene is located
on chromosome X and normally contains 5–44 CGG repeats in a region within the
5′ untranslated region of the gen [19]. Expansion of the triplet to 55–199 repeats is
considered a “permutation,” and 200 or more repeats provide basis for the diagnosis
of full mutation FMR1, which can result in mental retardation but primarily in men
[19]. 20% of women who carry this permutation will develop POI, which is a much
higher percentage than the 1% among women of the general population [20, 21].
3.2.1 Autosomal Gene Mutations
POI is a heterogeneous condition with no single underlying cause, but a number of
autosomal genes were indicated as the cause of premature ovarian function deple-
tion [22]. For some of these genes, the mutations are recognized, while the others
are listed as candidate genes with the necessity for future investigation. The genes
that could result in POI are genes involved in folliculogenesis (NRA51, NOBOX,
FIGLA, and FOXL2), folliculogenesis growth factors (BMP15, GDF9, inhibin A),
ovarian steroidogenesis (FSH, FSHR, LH, LHR), or genes identied in syndromes
often associated with POI (BLM, WRN, RTS) [23–25].
Galactosemia is a rare autosomal disorder due to a defect in galactose 1- phosphate
uridyltransferase (GALT) metabolism. Proper galactose metabolism is required for
ovarian function, and without that its metabolites accumulate to toxic levels and
accelerate follicular atresia or the glycosylation of gonadotropin subunits leading to
biological inactivity [26].
Autoimmune diseases, such as Addison’s disease, Hashimoto’s thyroiditis, sys-
temic lupus erythematosus, type 1 diabetes mellitus, Sjögren’s syndrome, and rheu-
matoid arthritis, often occur with POI
27
. POI can be a part of the autoimmune
polyglandular syndrome (APS) types 1 and 2. Type 1 is characterized by
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hypoparathyroidism, adrenal insufciency, chronic mucocutaneous candidiasis, and
the prevalence of POI in 15% cases [28]. Type 2 is associated with adrenal insuf-
ciency, autoimmune thyroid disease, type I diabetes mellitus, and POI with the fre-
quency of 3.6–10% [29]. It has been suggested that autoimmunity explains up to 30%
of POI cases [27] [30]. Although coexistence of autoimmune or immune- mediated
disorders is frequent in POI, histological examinations on ovarian tissue have docu-
mented that signs of oophoritis can be detected only in those women with circulating
adrenal or ovarian autoantibodies directed to steroidogenic enzymes (steroid cell
autoantibodies (SCA)) [31]. The prevalence of SCA in POI patients is 4–5% [27].
POI is also associated with thyroid autoimmunity; the prevalence of POI among
women with Hashimoto’s thyroiditis is about 14–27% [31, 32].
Chemotherapy and radiotherapy for treatment of malignant disease are also fre-
quent causes of premature ovarian insufciency. The risk that oncological treatment
will lead to POI increases with age after puberty, with high-dose chemotherapy regi-
mens and with combined chemo- and radiation therapy [33]. Age, radiation eld,
and dosage of radiation are the most important factors affecting the risk of POI
during radiotherapy [34]. Doses of 9 Grays or higher are of high risk of ovarian
insufciency [35]. Chemotherapy affects the structure and function of oocytes and
granulosa cells and decreases the number of oocytes in a dose- and drug-dependent
manner. The use of anthracycline and alkylating agents has been shown to be most
gonadotoxic in childhood and in adulthood [36, 37]. Induced POI could be tempo-
rary, but the recovery of ovarian function decreases with patient age [38].
Pelvic surgery has a potential role in early menopause. Laparoscopic excision of
bilateral endometriomas leads in 2,4% to premature ovarian insufciency [39] and
ovarian endometrioma surgery is associated with a decline in serum AMH and
diminishing the ovarian reserve [40].
Several case reports have indicated the association between various infections,
including mumps, HIV, herpes zoster, cytomegalovirus, tuberculosis, malaria, vari-
cella and shigella, and POI [41]. Mumps oophoritis may cause POI, and the inci-
dence of 3–7% has been reported among POI patients [
42]. However none of the
remaining infectious agents have been able to establish any cause and relationship
between the infection and the diagnosis of POI [42].
Smoking has been shown to be associated with earlier menopause, and the sug-
gested pathophysiology is that tobacco smoke contains polycyclic hydrocarbons
which are toxic to germ cells [43, 44].
In a signicant number of women with POI (up to 90% according the literature),
the cause is unknown, and these women are described as having unexplained or
idiopathic POI [42, 45].
3.3 Epidemiology
The prevalence of POI is about 1% [46, 47] and is variable depending on the age:
1% of women younger than 40years, 0.1% under 30years, and 0.01% under the age
of 20years [48]. There are also ethnic differences ranging from 1.4% in women of
African-American and Hispanic descent to 1,0% in Caucasian, 0,5% in Chinese,
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and 0,1% in Japanese women [47]. Among women with primary amenorrhoea, the
frequency of POI is 10–28% and in those with secondary amenorrhoea 4–18% [49].
3.4 Clinical Features ofPremature Ovarian
Insufficiency Patients
In particular, women suffering from POI experience abnormalities in menstrual
cycle. Secondary amenorrhea or prolonged oligomenorrhea and primary amenor-
rhea may be the rst symptoms and are the most common complains. About 75% of
patients suffering from POI may also manifest typical postmenopausal symptoms.
Hot ushes and night sweats are most common and appear, respectively, in 59.2%
and 41.5% of POI patients. Moreover patients suffer from vaginal dryness (23.8%),
vaginal mucus atrophy or dyspareunia, as well as mood disturbances, such as
depression, anxiety (20.3%), and low libido (14.8%) [50]. Iatrogenic POI and older
age at diagnosis are associated with exacerbation of symptoms [51].
3.5 Diagnostic Evaluation ofPOI
The diagnosis of POI should be based on the presence of menstrual disturbances
and biochemical parameters: 4-month period of oligo-/amenorrhoea and two mea-
surement of elevated FSH>25IU/L on two occasions>4weeks [3, 4].
The second part of the diagnostic process is to establish a cause of POI.It is
necessary to examine karyotype in every woman with POI, and in case of inci-
dence of Y chromosome, gonadectomy should be advised [52, 53]. FMR1 pre-
mutation testing is indicated in all women with POI to determine the cause of
hypergonadotropic hypogonadism and also because of the risk of developing
POI or cases of mental retardation associated with fragile X syndrome in family
members [52, 54]. Routine autosomal genetic testing in POI is not recom-
mended, unless the typical phenotype characteristics of type 1 blepharophimo-
sis, ptosis, and epicanthus inversus syndrome (BPES) (dysplasia of the eyelids)
are present [55].
According to data from the literature, autoimmunity explains up to 30% of POI
cases [27, 30]. The ESHRE Committee recommended screening for 21OH-Ab (or
alternatively adrenocortical antibodies (ACA)) in women with POI and to refer the
21OH-Ab/ACA patients to endocrinologist for testing of adrenal function and to
rule out Addison’s disease [3, 4]. The screening for thyroid peroxidase autoantibod-
ies (TPO-Ab) is also recommended in all women with POI, and in case of positive
test, thyroid-stimulating hormone (TSH) should be marked every year to exclude
hypo- and hyperthyroidism [3, 4]. There is no evidence to recommend routinely
screening for diabetes or for infectious disease in women with POI [3, 4]. Although
there is no causal relation between cigarette smoking and POI, women with POI
should be advised to stop smoking.
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3.6 Consequences ofPremature Ovarian Insufficiency
forWomen’s Health
3.6.1 Cardiovascular System
Cardiovascular disease (CVD) seems to be the main cause of death among women.
Though there has been an overall decline in CVD mortality over the past 40years,
the mortality in younger women has plateaued since around the year 2000. The
incidence of myocardial infarction (MI) in women, although lower than in men,
increases dramatically following menopause. The role of menopause itself is not so
clear [56].
CVD includes four major areas:
– Coronary heart disease (CHD) clinically manifested by myocardial infarction
(MI), angina pectoris, heart failure (HF), and coronary death
– Cerebrovascular disease clinically manifested by stroke and transient ischemic
attack
– Peripheral artery disease clinically manifested by intermittent claudication
– Aortic atherosclerosis and thoracic or abdominal aortic aneurysm
It has been postulated that women with POI may be at higher risk for CVD and
death due to loss of ovarian function and subsequent deciency of endogenous
estrogens. They present several risk factors for the development of cardiovascular
disease: endothelial dysfunction, autonomic dysfunction, abnormal lipid prole,
insulin action disturbances, and metabolic syndrome.
Women in the premenopausal period with premature coronary artery disease
have signicantly lower plasma estradiol levels in comparison to healthy women.
Estrogens have effects on ventricular myocyte contractile function and on intracel-
lular Ca
2+
kinetics in coronary endothelial cells, thus having antiarrhythmic effects
in cardiac myocytes. There is also evidence that estrogens decrease insulin resis-
tance and protect against lipid peroxidation. There may be different effects of HRT
in younger women (with early menopause starting treatment within 3years of their
last menstrual period in life), compared to older women (with age at menopause
higher than 50, starting treatment 10years after their last menstrual period in life).
The difference most probably results from the complexity of estrogen and progesto-
gen receptor systems. A higher expression of the estrogen receptors and higher level
of enzymes involved in estrogen metabolism have been found in the vascular smooth
muscle cells seen in aortas of women suffered from mild atherosclerosis than in the
cells seen in aortas of women with severe atherosclerosis. The abovementioned
observations are consistent with experimental data from animal models showing
that estrogen administration protects against atherosclerosis only if vessels are
healthy without established atherosclerosis. In more advanced stages of atheroscle-
rosis, oral estrogen administration can have negative effects on the cardiovascular
system via its prothrombotic effects possibly contributing to plaque instability.
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Despite lack of longitudinal outcome data, hormone replacement therapy (HRT)
when used early is strongly recommended in women with the diagnosis of POI to
control future risk of cardiovascular disease. HRT should be continued at least until
the average age of natural menopause [57].
Women with the diagnosis of POI should be advised that HRT may have a role
in primary prevention of diseases of the cardiovascular system [58].
Endothelial function, measured as the ow-mediated dilation of the brachial
artery, has been demonstrated to be signicantly reduced in women with
POI.Likewise, the amount of circulating endothelial progenitor cells is decreased
and correlated with reduced serum estradiol level [59].
Women with natural POI before the age of 40years have earlier onset of coro-
nary heart disease and increased CVD mortality [60]. There is an inverse relation-
ship between age at natural menopause and cardiovascular mortality [61].The POI
women present an increased carotid intima media thickness and left ventricular dia-
stolic function [62].
Moreover, patients diagnosed with POI present abnormalities in lipid prole, but
the results are conicting regarding particular lipoproteins. Even though there are
conicting data regarding lipid prole and insulin resistance indices, the overall
cardiovascular risk in POI women seems to be signicantly increased, as the mortal-
ity. Especially the risk of mortality from ischemic heart disease is increased approx-
imately 80% in the POI women group compared to women with menopause at
49–55 years [63].
The primary cardiovascular risk factors in women, along with the conditions con-
sidered CHD equivalents are: personal history of CHD or other atherosclerotic vas-
cular disease (peripheral arterial, cerebrovascular, and aortic disease), age over 55,
family history of premature CHD (rst-degree male relative under age 50 or a female
under age 60), hypertension, dyslipidemia—high low-density lipoprotein (LDL)
and/or low high-density lipoprotein (HDL), diabetes mellitus, metabolic syndrome,
chronic kidney disease (CKD), smoking, postmenopausal status, psychological
stress (e.g., depression, posttraumatic stress disorder), inammatory/rheumatic dis-
eases, pregnancy-related complications (e.g., eclampsia, preeclampsia, gestational
hypertension, gestational diabetes). All these risk factors and their assessment should
be an important component of periodic health examinations [
64, 65].
POI women should be advised of risk factors that they can modify through
behavioral change (e.g., stopping smoking, taking regular weight-bearing exercise,
and maintaining a healthy weight).
Cardiovascular risk should be assessed in women diagnosed with POI.At least
blood pressure, weight, and smoking status should be monitored annually with
other risk factors being assessed if indicated [66].
POI is an independent though modest risk factor of ischemic heart disease and
overall CVD [67].
Women undergoing prophylactic bilateral oophorectomy before the age of 40
consistently showed an increased risk for cardiovascular disease and cerebral infarc-
tion [68–70].
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Reduced life expectancy, due to cardiovascular disease, is observed among
women with untreated POI [71].
Observational data suggest that early menopause may be associated with small
increases in total mortality and mortality due to ischemic heart disease and also pos-
sibly ischemic stroke. However, at this time, evidence is insufcient to recommend
hormone replacement therapy for the sole purpose of preventing cardiovascular dis-
ease or stroke [72].
It is said that for each year’s delay in menopause, the cardiovascular mortality
risk decreased by 2% [73].
3.6.2 Metabolic Health
Data concerning metabolic health among women with POI are conicting. Women
with POI present similar levels of glucose, insulin, HOMA-IR, low-density lipopro-
tein cholesterol (LDL-C), and triglyceride as the controls, but the incidence of meta-
bolic syndrome is signicantly increased [74]. In contrast, other authors detected
increased serum glucose, insulin, and the homeostatic model assessment of insulin
resistance (HOMA-IR) in POI women (N=43) vs. controls (N=33) [75].
3.6.3 Bone Metabolism
It is well established that prolonged estrogen deciency exerts negative inuence on
bone mineral density (BMD) and is well-known risk factor of decrease in BMD.POI
patients have on average 2–3% lower BMD at L1–L4 spine, femoral neck, and total
hip than healthy age-matched controls [76, 77]. Despite the underlying pathomecha-
nism of POI, either Turner syndrome, other gonadal dysgenesis, chemotherapy, or
idiopathic POI, patients are particularly vulnerable to decreased BMD [4]. In the
study conducted by Maclaran etal. [51], at the moment of diagnosis, over one third
of patients had low BMD (29.7% osteopenia, 5% osteoporosis). Moreover it was
noticed that women suffering from idiopathic POI had signicantly lower BMD in
comparison to iatrogenic POI (respectively, 1.108g/cm
3
and 1.174g/cm
3
, p=0.0043).
In another study percentage of POI women with abnormal BMD reached even 67%
[78]. Risk factors, which particularly contribute to the degree of BMD loss, are dura-
tion of estrogen deciency, POI before the age of 20years, long period before the
beginning of the disease, and initiation of HRT, as well as low calcium intake, lack
of physical exercise, and low vitamin D3 concentration (<32ng/mL) [4, 77, 79].
3.6.4 Genitourinary Syndrome
Hypoestrogenism leads to diminished elastin, collagen, and hyaluronic acid content
and loss of vascularity in the urogenital region, leading to thinning of vaginal
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epithelium and impaired smooth muscle proliferation [80]. Symptoms of urogenital
estrogen deciency known as genitourinary syndrome (GS) include vaginal dry-
ness, dyspareunia, vaginal itching and discharge, lesions, vaginal vault prolapse or
vaginal stenosis, and shortening. Urological symptoms of GS are connected with
stress urinary incontinence and recurrent urinary tract infections. The patients expe-
rience loss of libido and dyspareunia.
Information about genitourinary syndrome in patients with POI is scant. The
incidence of genitourinary syndrome probably differs depending on the age of the
diagnosis and etiology of the ovarian function depletion (from 10 to 42%) [81]. The
West London POI database found lower incidence of vaginal dryness and loss of
libido in women younger than 30years than in the patients of age 30–35 years [81].
Moreover, women with POI as a consequence of malignant disease more frequently
experienced vaginal dryness and loss of libido than patients with the cessation of
ovarian function without malignant cause [81]. Sexual function of POI patients dur-
ing estrogen therapy stays within the normal range; however the scores are lower
than achieved by control women [82]. Interestingly worse sexual function seems to
be more related to the psychological than to physiological aspects such as pain or
lubrication [83]. No urodynamic changes before and after oral and vaginal estrogen
therapy were found in a small group of patients with POI [84]. The authors con-
cluded that estrogen deciency alone in the absence of aging and other risk factors
for stress incontinence is of minimal signicance.
Standard and the most efcacious treatment of genitourinary syndrome is estro-
gen therapy. It restores vaginal epithelium and vasculature and lowers vaginal pH
[85, 86]. Both systemic and vaginal estrogens are effective [87].
Non-hormonal treatment modalities, such as local treatment with lubricants and
moisturizers, intravaginal laser therapy, oral selective estrogen receptor modula-
tor– ospemifene, or pelvic oor physical therapy, have not been studied in patients
with POI.
3.6.5 Fertility
Fertility in women is determined by numerous factors; however normal function of
hypothalamic-pituitary-ovarian axis plays a key role. Dysfunction at each level of
this axis can lead to the infertility. Normal ovarian function is of crucial signicance
for proper ovulation process. Premature ovarian insufciency (POI) dened as the
loss of ovarian function before age 40 has important inuence on hypoestrogenism
and infertility [88]. This condition is regarded as pathological state in contrast to the
menopause which is physiological state. There are numerous factors related to etio-
pathogenesis of this disorder which were described at the beginning of this chapter
[89]. Depending on the causes, ovaries of some POI patients may present activity,
particularly at the early stage of this disorder. However chance for spontaneous
conception is very limited and ranges from 4.0 to 8.0% [90]. Therefore women
diagnosed with this disorder should be informed that there is a small chance of
spontaneous pregnancy.
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3.6.6 Central Nervous System
Cognitive functions of POI patients are particularly impaired in cases of genetic
disorders associated with POI.Fragile X syndrome is an X-linked mutation of the
FMR1 gene leading to mental retardation, especially in males. Women with premu-
tation of FMR1 are at high risk of developing POI, but they do not suffer from
mental retardation. Women with FMR1 full mutation had a signicantly lower IQ
when compared to healthy controls; moreover they suffered from weakness on
executive function, spatial ability, and visual memory [91]. Trisomy of X chromo-
some (47,XXX) is anomaly associated with increased prevalence of POI.Moreover
women suffering from trisomy X have higher rates of cognitive decits and learning
disabilities in the school-age years with an increased risk of speech and motor
delays [92].
It is suspected that early menopause may contribute to increased risk of cognitive
impairment and dementia; nevertheless data are not consistent [93]. Earlier age of
premature menopause, especially due to oophorectomy, is a risk factor of more
rapid cognitive decline [94].
Recently conducted studies indicated that untreated surgical menopause may
result in development of Parkinson’s disease, while oophorectomy due to nonmalig-
nant pathologies increased the risk of cognitive decline by 64% [95]. Moreover
patients after oophorectomy present worse word recall, decreased episodic memory,
and semantic memory, which are particularly associated with development of
dementia [96, 97]. Moreover earlier menopause contributed to AD neuropathology,
particularly to development of neurotic plaques and thus increased risk of
Alzheimer’s disease [97].
3.6.7 Emotional Health andSexual Life
It is well estimated that POI patients develop distressing symptoms associated with
disturbances in sexual health and quality of life. Taking into consideration Female
Sexual Function Index (FSFI), almost all domains of sexual life such as arousal,
lubrication, orgasm, satisfaction, and pain are affected [98, 99]. Results from previ-
ously conducted studies presented evidence that POI patients are less sexually
responsive, have lower libido, and suffer from dyspareunia more often than healthy
premenopausal controls [100]. Moreover estrogen deciency leads to vaginal dry-
ness and difculties in orgasm achieving and painful intercourse [101]. Lower con-
centration of androgens associated with POI may also contribute to impaired sexual
function; nevertheless data are inconsistent [102]. Problems in sexual life may con-
tribute to loss of self-condence and self-esteem, increased anxiety, and concerns
[101]. Other complications associated with emotional health of POI patients are
depression, somatization, sensitivity, hostility, blue mood, despair, depression, and
psychological distress [102, 103]. In World Health Organization Quality of Life
(WHOQOL-100) questionnaire, physical and psychological health are two main
affected domains [103].
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3.7 Management ofPremature Ovarian
Insufficiency Patients
3.7.1 The Role ofHormonal Replacement Therapy
The mainstay of treatment of POI is hormone replacement therapy (HRT) until at
least the age of natural menopause [3, 104, 105].
Estrogen replacement therapy has several important goals, such as puberty induc-
tion, maintaining the optimal bone mass density, protection against cardiovascular
risk, and alleviating the symptoms of hypoestrogenism. 17β-Estradiol, estradiol val-
erate, conjugated equine estrogens, and synthetic ethinylestradiol are available in
many different forms: oral pills, transdermal patches or gels, vaginal rings, or cream.
Progestagen therapy has to be added to systemic estrogen treatment (oral or
transdermal) to protect from endometrial cancer. Micronized progesterone is avail-
able as oral or vaginal pill, while synthetic progestins are administered in a form of
tablets, injections, rings, implants, or an intrauterine device.
Estrogens or progestins can be administered in a separate regimen or can be
combined in a form of hormonal replacement therapy intended for postmenopausal
women or contraceptive formulations in forms of pills, rings, or patches.
3.7.1.1 Puberty Induction
In prepubertal girls with hypogonadism, small doses of estrogen help to achieve
secondary sexual characteristics, induce growth spurt, build maximal bone mass
density, and increase the volume and vasculature of the uterus. Natural 17β-estradiol
is recommended at the age of 12 at initial doses of 6.25μg/day transdermally or
0.25mg/day orally [3]. Then during 2–3years, the doses are gradually increased
reaching at 15–16years of age doses of 50–100μg/day transdermally or 1–2mg/
day orally [3]. Cyclic progestagen (for 10–12days a month) is recommended after
2years of estrogen treatment or when the breakthrough bleeding occurs [3, 106].
Regular withdrawal bleeding in POI patients provides a sense of normalcy in com-
parison with their peers.
3.7.1.2 HRT Risk
There is no evidence that risk connected with HRT when used in postmenopausal
women can be applied to the younger population of women with POI.Breast cancer
is not increased in women treated with HRT before the age of natural menopause;
however, HRT is contraindicated in breast cancer survivors [3, 107, 108].
Increased risk of thromboembolism depends on estrogen concentration and type
of progestins [109]. Second-generation progestins (levonorgestrel) carry lower risk
than third-generation progestins or new progestins (gestodene, desogestrel, cyprot-
erone acetate, drospirenone). Transdermal estrogens have lower risk of venous
thromboembolism (VTE) than estrogens administered orally.
3.7.1.3 Androgens
Serum androgen levels are decreased in POI patients [110], and some clinicians
recommend testosterone supplementation in order to increase libido [111]. The
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