The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 107, No.

3, 825–835
https://doi.org/10.1210/clinem/dgab766
Approach to the Patient

Approach to the Patient

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Approach to the Patient With New-Onset
Secondary Amenorrhea: Is This Primary Ovarian
Insufficiency?
Cynthia A. Stuenkel,1 Anne Gompel,2 Susan R. Davis,3 JoAnn V. Pinkerton,4
Mary Ann Lumsden,5 and Richard J. Santen6
1
Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093,
USA; 2Unite de Gynecologie Medicale, l’Universite de Paris Descartes, 75015 Paris, France 3Women’s
Health Research Program, School of Public Health and Preventive Medicine, Monash University,
3004 Melbourne, Australia; 4Division Director of Midlife Health, University of Virginia Health System,
Charlottesville, VA 22908, USA; 5University of Glasgow School of Medicine, CEO, International Federation
of Obstetrics and Gynecology, Glasgow G31 2ER, UK; and 6Department of Medicine, University of Virginia
Health System, Charlottesville, VA 22908, USA
ORCiD numbers: 0000-0003-0943-9450 (C. A. Stuenkel).

No reprints available.

Abbreviations: CVD, cardiovascular disease; FSH, follicle-stimulating hormone; HRT, hormone replacement therapy; IUD,
intrauterine device; POI, primary ovarian insufficiency; TSH, thyrotropin (thyroid stimulating hormone).
Received: 4 August 2021; Editorial Decision: 20 October 2021; First Published Online: 25 October 2021; Corrected and Typeset:
12 November 2021.

Abstract 
Menstrual cyclicity is a marker of health for reproductively mature women. Absent menses, or
amenorrhea, is often the initial sign of pregnancy—an indication that the system is functioning
appropriately and capable of generating the intended evolutionary outcome. Perturbations
of menstrual regularity in the absence of pregnancy provide a marker for physiological or
pathological disruption of this well-orchestrated process. New-onset amenorrhea with dur-
ation of 3 to 6  months should be promptly evaluated. Secondary amenorrhea can reflect
structural or functional disturbances occurring from higher centers in the hypothalamus to
the pituitary, the ovary, and finally, the uterus. Amenorrhea can also be a manifestation of
systemic disorders resulting in compensatory inhibition of reproduction. Identifying the point
of the breakdown is essential to restoring reproductive homeostasis to maintain future fer-
tility and reestablish reproductive hormonal integrity. Among the most challenging disorders
contributing to secondary amenorrhea is primary ovarian insufficiency (POI). This diagnosis
stems from a number of possible etiologies, including autoimmune, genetic, metabolic, toxic,
iatrogenic, and idiopathic, each with associated conditions and attendant medical concerns.
The dual assaults of unanticipated compromised fertility concurrently with depletion of the

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826  The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 107, No. 3

normal reproductive hormonal milieu yield multiple management challenges. Fertility res-
toration is an area of active research, while optimal management of estrogen deficiency
symptoms and the anticipated preventive benefits of hormone replacement for bone, car-
diovascular, and neurocognitive health remain understudied. The state of the evidence for an
optimal, individualized, clinical management approach to women with POI is discussed along
with priorities for additional research in this population.

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Key Words: secondary amenorrhea, primary ovarian insufficiency, estrogen therapy

Case Presentation development. The etiology of amenorrhea will usually be

A 36-year-old gravida 2, para 2 woman, with a history
of regular menstrual cycles up to 1  year before, presents
with the chief complaint of missing her last few menstrual
cycles. She is quite certain that the date of her last men-
strual period (LMP) was 4 months ago as she uses a phone
app to track menses. She has already purchased 2 at-home
pregnancy tests which were negative. She denies symptoms
of pregnancy, including morning sickness, which she had
experienced in 2 prior pregnancies.
Secondary Amenorrhea
Secondary amenorrhea is generally defined as absence of menses
for 3 months in a woman with previously regular monthly cycles
or absence of menses for 6 months in a woman with previously
irregular cycles. The exact duration varies between countries,
with the USA investigating after 3  months (1-4) and the UK
after 6 months (5). Perturbation of the menstrual cycle may be
the first sign of an underlying endocrine or metabolic disorder
such as primary ovarian insufficiency (POI). Therefore, secondary
amenorrhea requires a diagnostic evaluation if occurring prior
to the anticipated lower age range of natural menopause (ie, <
45 years) (1-5). The first step is to exclude pregnancy with a la-
boratory pregnancy test (serum beta-subunit of human chorionic
gonadotropin) regardless of the history, including reports of nega-
tive home pregnancy tests. If this is negative, a complete personal
medical and family history, physical examination, and based on
the findings, laboratory evaluation should follow.
The laboratory pregnancy test was negative. The patient
described having menarche at age 12. After the first year,
her menstrual cycles became regular, occurring every 28 to
30  days. She used oral contraceptives from her late teens
until the age of 29. Her menses resumed within 3 months of
discontinuing the pill and she conceived 3 months later. Her
pregnancies (ages 30 and 32) were uncomplicated, without
hemorrhage or uterine instrumentation. Since her second
pregnancy, she has used barrier contraception.
Etiology of Secondary Amenorrhea
The history of regular menstrual cycles and ease of con-
ceiving suggests that recent amenorrhea reflects a new
suggested by clinical signs and symptoms (1-5), but preg-
nancy must always be considered. A  prior history of ir-
regular menses is suggestive of polycystic ovary syndrome
(6). Eating disorders (anorexia or bulimia), or excessive ex-
ercise or stress, may not be apparent on initial evaluation,
yet may contribute to functional amenorrhea (7). Therefore,
these specific aspects of the patient’s history should be care-
fully sought (7). Visual disturbances and headache might
indicate a pituitary/hypothalamic tumor. Galactorrhea
suggests a prolactinoma (8), other pituitary adenoma,
or iatrogenic hyperprolactinemia (administration of cer-
tain antidepressants, neuroleptics, or metoclopramide).
More rarely, symptoms suggest other etiologies: weight
loss with systemic disorders such as celiac disease, clin-
ical hyperandrogenic features (hirsutism (9), nonclassic
congenital adrenal hyperplasia (10), or virilizing ovarian
or adrenal tumors (11, 12)). Finally, consideration should
be given to history of iatrogenic factors: chemotherapy or
radiation therapy (13, 14); toxic and environmental expos-
ures (15); and obstetric complications resulting in endo-
metrial scarring (Asherman syndrome) (16).
The patient reported that in the last year, prior to
becoming amenorrheic, her menstrual cycles became ir-
regular. Menstrual bleeding had shortened from 5 to
3  days and the flow had been lighter. She also reported
that her family had noted that she had a “shorter fuse”
and seemed more irritable than previously. She has had
no weight change, headaches, visual disturbance, alopecia,
acne, excess hair growth, or galactorrhea. Functional con-
tributors to amenorrhea were not suggested; she denied
any past or present food restriction, extreme exercise, or
excessive stress. She had no other medical illnesses, sur-
geries, or allergies. She was taking no medication or nutri-
tional supplements.
She did report, however, occasional hot flushes and
increased sweating, especially at night with sleep dis-
ruption. She noted decreased libido for several months
and wondered if she could be depressed. The patient
reported no known personal or family history of early
menopause.
On examination, her body mass index was 24 kg/m2, and
she had no clinical evidence of androgen excess, galactorrhea,
The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 107, No. 3
or hypo- or hyperthyroidism. The remainder, including geni-
talia, was unremarkable. Blood samples were drawn.
Clues to Cause of Secondary Amenorrhea
As our patient displayed symptoms consistent with POI
(17), the next step in assessment was measuring follicle
stimulating hormone (FSH) and estradiol concentration.
Due to the frequency of hyperprolactinemia as a cause
of secondary amenorrhea, a prolactin (fasting) level was
measured. As abnormal thyroid function can affect men-
strual cycles and commonly occurs with POI, thyroid
stimulating hormone (TSH) was also measured. Had
hyperandrogenic symptoms or signs been present, inves-
tigations to identify a hyperandrogenic condition would
have included serum androgen measurements (testosterone,
androstenedione, dehydroepiandrosterone sulfate, and
17-hydroxyprogesterone) and pelvic ultrasonography for
ovarian morphology, if indicated.
The FSH level directs subsequent diagnostic evaluation.
Normal or low FSH reflects a hypothalamic or pituitary
cause of amenorrhea (neoplastic, infiltrative, or functional)
and will usually indicate magnetic resonance imaging of
this region, additional laboratory testing, and referral to
an endocrinologist to exclude pituitary failure. As FSH is
regulated by feedback from ovarian estradiol and inhibin,
an elevated FSH indicates an ovarian origin of the amen-
orrhea. This requires confirmation with at least a second
sample, concurrently with a serum estradiol determination,
after an interval of 4 to 6 weeks.
On laboratory evaluation the FSH level was elevated at
65 IU/mL. Both serum prolactin and TSH were normal.
Diagnosis of Primary Ovarian Insufficiency
Elevated FSH in a woman younger than 40 years of age sug-
gests POI, with compromised ovarian function and reduced
fecundity due to a decrease in ovarian follicle number, ac-
celerated follicle destruction, or poor follicle response to
gonadotropins (18, 19). Approximately 1% of US women
experience POI, with a global prevalence of 3.7% (20).
With FSH in the postmenopausal range, several months of
amenorrhea, irregular periods preceding the onset of amen-
orrhea, and climacteric symptoms (hot flashes, sleep dis-
turbance, mood disorders), the diagnosis of POI must be
considered (Table 1).
The patient was advised that her ovaries were not pro-
ducing the usual premenopausal levels of estrogen, and this
explained her amenorrhea and other climacteric symptoms.
Repeat measures of FSH and serum estradiol (a month after
initial testing) were performed. The results showed per-
sistent elevation of FSH at 57 IU/mL and low estradiol of
827
37 pg/mL, confirming the diagnosis of POI. The patient
wanted to know what caused POI and whether this could
affect her family members.
Etiology of POI
Although there are a number of known causes of POI,
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until recently, more than 70% of cases were considered to
be idiopathic (21, 22). A  focus of contemporary research
has been to identify genetic causes with next-generation
sequencing and especially whole exome sequencing in large
pedigrees. The present genetic findings must be considered
the tip of the iceberg as more intensive genetic analyses will
likely uncover de novo mutations as etiologies of this dis-
order in more than 30% of affected women (21-23).
Several points argue for the role of heritability: maternal
age of menopause helps to predict POI in daughters (24),
the prevalence of POI is higher for monozygotic twins (25),
and approximately 10% of women with “idiopathic” POI
have an affected family member (26). Having a first-degree
relative with POI confers a 6- to 12-fold likelihood of a
genetic disorder (27). This high likelihood of genetic fac-
tors illustrates the importance of meticulously detailing
the family history during consultation for menstrual ir-
regularity or amenorrhea. Identification of a genetic cause
provides the basis for counseling other first-degree family
members.
Other causes of POI include iatrogenic causes (pelvic
or ovarian surgery, chemotherapy, and pelvic irradiation)
which may affect 10% of cases (28), autoimmune disorders,
accounting for approximately 10%, and galactosemia, a
rare metabolic disease (21, 22).
Genetic Etiologies
Genetic disorders are increasingly recognized as contrib-
uting to the development of POI. In order of prevalence,
Fragile X premutation, Turner syndrome, and less common
genetic mutations are most relevant to consider.
Fragile X Premutation
The Fragile X premutation, occurring in approximately 1
in 150 women, is the most commonly identified single-gene
cause for POI (29). Loss-of-function mutation in the FMR1
gene of the X chromosome (Fragile X premutation) yields
expansion of an unstable CGG repeat in the 5′ untrans-
lated region (FMR1, Xq27) (29). The full mutation (> 200
repeats), Fragile X syndrome, is the most common cause
of inherited intellectual disability in males (X-linked) and
the leading single-gene defect associated with autism (29-
31). One in 5 women with Fragile X premutation (55-200
828  The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 107, No. 3

Table 1.  Confirming the diagnosis of primary ovarian insufficiency and investigating the etiology in patients presenting with
secondary amenorrhea and elevated follicle stimulating hormone

1.Clinical suspicion based upon menstrual history and initial elevated FSH
  • Presence of climacteric symptoms?
o Vasomotor symptoms (hot flashes)
o Mood disorders (depressive and anxiety symptoms)
o Sleep disruption (insomnia and early awakening)

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o Vaginal dryness and dyspareunia
  • History of autoimmune disorder?
o Type 1 diabetes
o Adrenal insufficiency
o Thyroid disorders
  • History of possible iatrogenic contribution?
o Pelvic or ovarian surgery
o Cancer treatment (chemotherapy/pelvic radiation)
o Cyclophosphamide for autoimmune disorders
  • History of toxic/metabolic/infectious disorder?
o Environmental exposures
o Galactosemia
o Mumps or tuberculosis
  • Family history of menopause?
o Early (< age 45)
o Premature (< age 40)
  • Family history of Fragile X?
o Affected member with Fragile X Syndrome
o Fragile X premutation carrier identified
2.Physical examination
  • Absence of hirsutism, galactorrhea, signs of substantial weight loss, or underlying illness
  • Anticipate normal sexual development and secondary sexual characteristics
  • Depending upon duration of amenorrhea at evaluation, might find signs of vaginal dry-
ness
3.Additional laboratory evaluation
  • Confirm elevated FSH
o Repeat FSH with concurrent estradiol determination 4 weeks after initial testing
  • Evaluate possible etiologies of POI (not identified ~70% of cases)
o Genetic etiologies
▪ Fragile X (FMR1) premutation carrier status
▪ Karyotype
▪ Additional genetic testing may be indicated
o Autoimmune disorders
▪ Adrenal antibodies
  ▫  21-hydroxylase antibodies
  ▫  If unavailable, measure adrenocortical antibodies or early morning cortisol
▪ Thyroid peroxidase antibodies
▪ Fasting blood glucose or glycosylated hemoglobin
  • Evaluation of ovarian reserve (if indicated)
o Anti-Müllerian hormone
o Antral follicle count (transvaginal ultrasound)

Abbreviations: FSH, follicle stimulating hormone; POI, primary ovarian insufficiency.

repeats) experiences POI; risk increases for those with 70
to 100 CGG repeats, with the highest likelihood for those
with paternal inheritance and 85 to 89 repeats (of note, in
a recent analysis, women with < 65 repeats or > 120 repeats
did not demonstrate increased POI risk) (32). The additive
effects of common gene variants associated with natural
age at menopause and rare modifying variants may play a
role in determining POI risk (33).
For women diagnosed with Fragile X premutation, family
screening should be offered (31). Sibling referral is recom-
mended for genetic counseling, and if tested and identified
as a premutation carrier, referral for fertility preservation
The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 107, No. 3
(31). Beyond POI, women with Fragile X premutation can
be affected by Fragile X-associated subfertility (30), tremor/
ataxia syndrome (34), neuropsychiatric disorders and con-
ditions (anxiety, depression, and learning disabilities) (31,
35), and possibly, increased cardiovascular problems (36).
Turner Syndrome
A karyotype to evaluate chromosomal abnormalities is re-
commended for all women presenting with POI, even after
a pregnancy (17, 18, 22, 37). Turner syndrome, with an in-
cidence of 25/100 000 to 50/100 000 (or approximately 1
in 2000 to 1 in 2500 live births), is diagnosed with a 45, X
karyotype (38, 39). Characteristic phenotypic features in-
clude short stature, webbed neck, shield chest, and cubitus
valgus. Although most girls with classic Turner syndrome
present with primary amenorrhea, those with a mosaic
karyotype (eg. 45X, 46XX or 45X, 47XXX) can experi-
ence menarche, and for 4.8% to 7.6%, pregnancy prior
to premature ovarian failure (38). The lack of stigmata of
Turner syndrome, the patient’s age, the history of regular
menses, and the fact that she has had 2 children made this
diagnosis unlikely.
Rare Genetic Abnormalities
In 1 recent study, 38% of patients with POI screened
for variants of 18 known POI genes were subsequently
identified as having at least 1 genetic abnormality (40).
A  candidate gene panel for targeted sequencing in POI
patients—already utilized as a tool in some settings—has
been refined (41). The majority of genes are involved in
double-strand break repair, mismatch repair, and base ex-
cision repair; others involve cell energy metabolism and
immune response (42). Additional genetic defects either in
the context of isolated or syndromic POI include transloca-
tions of the long arm of the X chromosome (43), or genes
involved in follicular growth (the most frequent being
NOBOX, associated with about 6% of the POI in women
with Caucasian and African origin), FOXL2, and other mu-
tations (40).
The genetic test for the Fragile X premutation was
obtained and found to be negative.
The patient’s karyotype and a panel of genetic tests as-
sociated with POI were negative.
Autoimmune Etiologies
POI can be a manifestation of autoimmune polyendocrine
syndromes (44); Addison’s disease (45), autoimmune
829
thyroid disorders, and type 1 diabetes can co-occur (44).
Diagnosis is made by measurement of 21-hydroxylase
antibodies (if unavailable, then adrenocortical antibodies
or early morning cortisol) (46), thyroid peroxidase anti-
bodies, and fasting blood glucose or glycosylated hemo-
globin (44). Ovarian antibody tests lack sensitivity and
specificity.
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The 21-hydroxylase antibodies and thyroid peroxidase
antibodies were negative, and fasting glucose was normal.
The patient was informed of the need to monitor periodic-
ally for the development of autoimmune thyroid disorders.
Symptom Presentation with POI
The loss of hormone production by the ovaries in women
with POI results in symptoms that can severely impair
quality of life. These include hot flushes, night sweats,
mood changes, vaginal dryness, and sexual dysfunction
(17, 21, 22, 47, 48). The anticipated loss of fertility and
sudden loss of menses due to POI may trigger grief, di-
minished self-esteem, sadness, anxiety, and depression.
Clinicians need to be aware of these symptoms and convey
empathy when revealing the diagnosis (21). Evaluation for
mood disorders is essential, with a low threshold for re-
ferral to a mental health professional.
Substantial time was spent with the patient to explain
the ramifications of the diagnosis, express empathy for her
feelings, and share that her symptoms were consistent with
the diagnosis. Her concern was the likelihood of return of
menses and her fertility. An additional appointment was
scheduled to talk again and fully discuss contraceptive op-
tions and possible pathways to pregnancy, depending upon
her wishes.
Fertility Considerations
One of the most devastating aspects of receiving a diag-
nosis of POI is the specter of unanticipated, premature in-
fertility (21). Spontaneous pregnancy occurs in 5% to 10%
of women with secondary amenorrhea due to POI, while
intermittent ovulation occurs in 50% to 75% (49). The re-
turn of menses, usually transient, occurs in 25% to 50%
of women with POI (49, 50). A clinical test that accurately
identifies which women with POI will go on to possible
fertility does not currently exist. Markers of ovarian re-
serve (anti-Müllerian hormone and antral follicle count)
should be documented initially for those interested in con-
ceiving but may not predict future pregnancy potential
(51). Prompt referral to a reproductive specialist is recom-
mended for women desirous of pregnancy.
830  The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 107, No. 3
Options for Fertility Preservation
Traditionally, women with POI have been counseled that
because of the low (approximately 1 in 20)  likelihood of
spontaneous ovulation and pregnancy, the best means to
achieve pregnancy is through donor oocytes, available
through oocyte banks. Given that the degree of residual
ovarian function in women with documented POI is vari-
able, autologous oocyte cryopreservation (egg banking)
is a possibility if there is sufficient ovarian reserve. For
those women fortuitously identified as a carrier of the
Fragile X premutation before developing POI, oocyte re-
trieval and cryopreservation is an option that allows for
preimplantation blastocyst screening for Fragile X should
that be desired. For women already diagnosed with POI,
autologous oocytes derived from repeated oocyte retrievals
may be an option based on findings of a recent retrospective
cohort study (52). In POI patients using viable embryos de-
rived from this process, cumulative clinical pregnancy rates
following frozen embryo transfer were comparable between
women with POI and the control group (52). However,
women with POI had only one-sixth of the clinical preg-
nancy rate per oocyte retrieval cycle, a lower implantation
rate, and a 2-fold higher early miscarriage rate per frozen
embryo transfer (52). Selection of an optimal management
strategy depends on individual clinical issues, degree of ex-
isting ovarian reserve, and more evidence of efficacy (53).
Oncofertility
For those who anticipate chemotherapy, ovarian tissue
cryopreservation and transplantation is available. Various
methods designed to reduce the risk of reseeding cancer
cells after thawing ovarian tissue are being evaluated (53).
Oophoropexy, surgical transposition of the ovaries within
the pelvis, may preserve ovarian function prior to radiation
therapy. Depending upon uterine effects of cancer treat-
ment, in vitro fertilization with an autologous or donor
embryo transfer to a gestational carrier is an option (53).
Investigational “ferto-protective” agents as adjuvant ther-
apies may protect against ovarian damage and follicle de-
pletion during chemotherapy (53).
New Investigative Approaches
In recent years, case reports and small patient series have
highlighted the spectrum of novel approaches under inves-
tigation to restore fertility for women with poor ovarian
reserve or POI (54-56). For example, transplantation of
mesenchymal stem cells to the ovary from a number of
sources (amniotic membrane, umbilical cord, placenta,
human menstrual blood, adipose tissue, and bone marrow)
has yielded improved ovarian function and resulted in a
few pregnancies and live births (55, 56). A second approach
involves intra-ovarian injection of autologous platelet-rich
plasma with a few case reports of pregnancies and live
births (55, 56). In vitro activation of dormant primordial
follicles constitutes a third approach to fertility (55, 56).
Most investigators concur that more research with con-
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trolled trials is needed before these exciting but limited in-
vestigational findings can be applied in the clinical setting.
Contraception
Conversely, for women who do not wish to become preg-
nant, contraceptive options (combined oral contraceptives,
barrier methods, or intrauterine devices [IUDs]) should
be instituted promptly, as intermittent ovulation precedes
menses, and women may be unaware of their transient fer-
tility. Hormone replacement therapy (HRT) (which does not
suppress spontaneous ovulation or provide contraception)
is proposed if the woman is willing to become pregnant
(19). The levonorgestrel IUD provides both contraception
and endometrial protection when used with systemic es-
trogen therapy.
As the patient had reported symptoms consistent with
estrogen insufficiency and did not desire another preg-
nancy, she elected to use replacement transdermal estradiol
patches with the levonorgestrel IUD. She was informed
that the IUD could be removed at any time to allow for the
unlikely possibility of spontaneous pregnancy should she so
desire; available options for assisted reproduction (donor
eggs) were reviewed. A  metabolic evaluation including
25-OH vitamin D and a baseline dual-energy x-ray absorp-
tiometry (DXA) scan to assess bone mineral density were
ordered.
Approach to Hormone Replacement Therapy
Given the young age of onset of POI, at least a decade
prior to the anticipated age of natural menopause, the term
hormone “replacement” therapy, is accurate. For HRT, a
transdermal 100 mcg estradiol patch, or equivalent dose
of transdermal gel, has lower risks of thrombosis than oral
estrogen (57), and is recommended by published guidelines
(17, 19, 22, 58, 59) and expert opinion (60-62) to achieve
an estradiol level roughly comparable to endogenous es-
trogen levels in younger women. It is often judicious to
start with a lower dose and gradually increase to the 100-
mcg patch or equivalent to avoid unwanted side effects due
to a sudden increase in estradiol. If preferred, a vaginal es-
tradiol ring delivering systemic doses, or oral estrogen can
be prescribed (19).
The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 107, No. 3
For women desirous of possible pregnancy, HRT should
be used rather than an oral contraceptive pill. For women
with a uterus, cyclical micronized progesterone 200 mg/d
may be preferred to synthetic progestins that could pos-
sibly be associated with teratotoxicity and fetotoxicity.
This would be administered for at least 12 days/month to
provide endometrial protection. A pregnancy test is recom-
mended if anticipated monthly withdrawal bleeding does
not occur. Women with POI without a uterus do not re-
quire progesterone, and the ideal pharmacotherapy in these
patients is physiologic transdermal estradiol. Justification
for combined therapy with progesterone beyond endomet-
rial protection in young women with POI has not been
established.
Combined oral contraceptives can be used for HRT, but
nonoral estradiol is preferred because of the more favorable
metabolic effects (58). Oral contraceptives contain pharma-
cological rather than physiological replacement preparations
which can have unfavorable effects on the lipid profile,
hemostatic factors, blood pressure, and an increased risk of
venous thromboembolism. Transdermal estradiol therapies,
often combined with micronized progesterone, do not pro-
vide contraception, but appear beneficial with regard to bone
health (increased bone formation and decreased resorption),
cardiovascular health, and decreased thrombotic risk (22).
In contrast with recommendations for treatment duration
in women with natural menopause occurring at the antici-
pated average age, the duration of HRT in women with POI
should be targeted to the average age of natural menopause
(age 51), and then reassessed (17, 19, 22, 58, 59).
Sexual Considerations and Clinical Approach
Women with POI frequently suffer sexual dysfunction, yet
this remains a poorly managed issue adversely affecting
quality of life (17, 63, 64). It is important to ask patients
about dyspareunia and libido. Supplemental vaginal es-
trogen (cream, tablet, insert, silastic ring) could be pre-
scribed if vaginal dryness persists despite systemic estrogen
therapy. Sexual counseling, if indicated, is recommended.
Testosterone blood levels are about 50% lower in women
with POI than those matched for age and body mass index
with normal ovarian function (65). For women who con-
tinue to experience persistent low sexual desire that causes
distress after treatment with vaginal estrogen and sexual
counseling, a trial of physiologic transdermal testosterone
therapy could be considered but is not recommended by all
guidelines (17). Given that a specific approved formulation
for women is not available in most countries, and concerns
raised about compounded preparations due to inconsist-
encies regarding dosing and purity (66), a fractionated
dose of a transdermal testosterone formulation approved
831
for men can be used with regular clinical and biochemical
monitoring (67, 68). While studies do not demonstrate that
physiologic testosterone replacement is associated with ser-
ious adverse events, some women may experience increased
acne or hair growth (69). If a trial of transdermal testos-
terone therapy of up to 6  months duration is of no per-
ceived benefit by the patient, it should be discontinued (67).
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Health Consequences of POI
The presentation and diagnosis of POI in our patient was
relatively straightforward. Unfortunately, this is not al-
ways the case. In one survey, 25% of women reported
that it took more than 5 years to establish the diagnosis
of POI; half reported seeing 3 or more clinicians prior
to securing a diagnosis (70). Perhaps clinicians do not
think of the menstrual cycle as a vital sign (1) or of the
possibility of POI when presented with a patient with sec-
ondary amenorrhea. While delayed diagnosis contributes
to delays in symptom relief, the opportunity to address
potential long-term health consequences of premature
estrogen deficiency—osteoporosis, increased cardiovas-
cular disease, and possible neurocognitive decline—is
also delayed. In spite of guideline recommendations to
initiate HRT early and continue until the anticipated age
of natural menopause, some studies have found that more
than 50% of women with POI were either untreated or
not treated sufficiently (60).
Bone Loss and Osteoporosis
Women with POI suffer progressive bone loss leading to
osteoporosis and the potential for fragility fractures (22,
71). Early initiation of HRT and administration until the
average age of natural menopause is recommended and an-
ticipated (but not proven) to reduce fracture risk. Clinical
trials suggest that transdermal estradiol therapy at a dosage
of > 100 mcg is effective at restoring bone mineral density in
women with POI (72) and may be superior to oral contra-
ceptives for bone preservation (73). Oral estradiol 2 mg/d
therapy has also been shown to be more effective than oral
contraceptives at restoring bone density (74). Results of an
observational study, however, suggest that oral contracep-
tives administered continuously, rather than with a 7-day
pill-free interval as in prior trials, can provide comparable
bone benefit to oral estradiol 2  mg or conjugated equine
estrogens 1.25 mg daily (transdermal therapy not included
in this study) (75). More clinical trial evidence is required
to establish the relative efficacy and safety of available
estrogen therapies for bone benefit in women with POI.
Current considerations for choice of therapy include in-
dividual health concerns, personal preference, availability,
832  The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 107, No. 3
and cost. Usual lifestyle measures—adequate calcium and
vitamin D, weight bearing exercise, smoking cessation, and
moderation of alcohol consumption—should be adopted.
Cardiovascular Considerations
Weight gain and dyslipidemia predispose women with POI
to type 2 diabetes, early cardiovascular disease (CVD), and
premature death (76). Premature menopause has been ac-
knowledged as a CVD risk enhancer by the American Heart
Association (77, 78). These findings underscore the import-
ance of the reproductive life span—usually ~ 40 years but
truncated in women with POI—for cardiovascular health
(76, 79). Hormone therapy, when initiated promptly after
diagnosis of POI and taken until the anticipated age of nat-
ural menopause, could possibly delay CVD and premature
death, although adequate trials are lacking. A pooled ana-
lysis of individual patient data supports this hypothesis:
women who initiated menopausal hormone therapy 1 year
after menopause and used it for longer than 10 years had
the lowest risk of CVD when compared with women with
premature menopause who did not use menopausal hor-
mone therapy or who initiated hormone therapy more than
1 year postmenopausal (80). Aggressive lifestyle modifica-
tion is also recommended (77).
Oophorectomy as a Possible Model
In the absence of randomized trials of HRT with clinical
outcomes in women with POI, one practical approach is
to extrapolate the findings from observational studies of
women < age 45 who have undergone bilateral oophor-
ectomy. After 20-plus years of longitudinal follow-up,
those treated with estrogen had markedly fewer osteopor-
otic fractures and CVD events than those untreated (81).
Women with POI, however, can intermittently experience
ovarian ovulatory activity and steroid hormone production
and therefore might be less estrogen deficient than women
who have undergone oophorectomy. When compared be-
tween women with natural vs surgical menopause at an
even younger age—before age 40—the risk of CVD was
greater for those with surgical menopause; in fully adjusted
models, however, these differences did not persist (79).
Summary and Charge Moving Forward
In conclusion, the diagnosis of POI should be considered
in women younger than age 40 with secondary amenor-
rhea, after excluding pregnancy and other identifiable
causes. Depending upon the etiology of POI, if identi-
fied, additional medical concerns should be addressed.
Administration of estrogen provides effective treatment of
symptoms of vasomotor instability and dyspareunia, and
very likely, prevention of osteoporosis. Progestogen therapy
is required for endometrial protection for women with a
uterus. More evidence to support the early and prolonged
administration of HRT in women with POI for prevention
of fractures, CVD, diabetes, and neurocognitive decline
is needed (82). Examination of the efficacy and safety of
Downloaded from https://academic.oup.com/jcem/article/107/3/825/6409726 by Endocrine Society Member Access 3 user on 04 December 2022
complementary and alternative therapies will likely provide
additional clinical guidance (83). Finally, the evolution of
novel reproductive technologies may offer renewed hope
for fertility.
Financial Support
No grants or fellowships supported writing of this paper.
Disclosures
C.A.S.  serves on the Data and Safety Monitoring Board for
Mithra Pharmaceuticals. A.G.  serves on the advisory board on
Dydrogesterone, Viatris in April 2021; has received personal honor-
arium. S.R.D. has received honoraria from Besins Healthcare, Pfizer
Australia, BioFemme, BioSyent, Lawley Pharmaceuticals, South-
ern Star Research, and Que Oncology; she has served on Advisory
Boards for Mayne Pharmaceuticals, Astellas Pharmaceuticals, Roche
Diagnostics, Theramex, and Abbott Pharmaceuticals, and is an insti-
tutional investigator for Que Oncology and Ovoca. J.V.P. has noth-
ing to declare. M.A.L. reports no conflicts of interest. R.J.S. has no
conflicts of interest.
Additional Information
Correspondence: Cynthia A.  Stuenkel, MD, NCMP, University
of California, San Diego, 9500 Gilman Drive, La Jolla, California
92093, USA. Email: castuenkel@health.ucsd.edu.
Data Availability: Data sharing is not applicable to this article
as no datasets were generated or analyzed during the current study.
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