Background: The human ovary
functions as both a reproductive organ and an endocrine organ. These functions
are tightly coupled.
Predictable cyclicity is the hallmark of healthy ovarian function during the
reproductive years. Each month, highly coordinated hormonal and ovarian
morphological changes develop and release a mature oocyte that is ready for
fertilization. A disruption of this process results in reproductive failure (anovulation)
or endocrine failure (low serum levels of ovarian steroid hormones and inhibins).
Ovarian failure due to inappropriate regulatory signals (hypothalamic or
pituitary pathology) is known as secondary ovarian failure. Ovarian failure due
to a pathological process directly affecting the ovaries (eg, chemotherapy,
irradiation, autoimmunity, chromosomal abnormalities) is known as primary
ovarian failure (POF). A simple means of distinguishing between the 2 conditions
is to measure serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH)
levels (elevated in POF and low or normal in secondary ovarian failure).
Aging is associated with a decline in the number of ovarian follicles,
menstrual irregularities, ovarian hormonal deficiency, anovulation, decreased
fertility, and, finally, a complete and irreversible cessation of menses known
as menopause, usually occurring at a mean age of 51 years.
POF, also known as premature ovarian failure, premature menopause, or early
menopause, is a condition characterized by amenorrhea, hypoestrogenism, and
elevated serum gonadotropin levels in women younger than 40 years. Although
often used as synonyms, POF is not equivalent to menopause. Most women with POF
retain intermittent ovarian function for many years, and, unlike women who are
menopausal, pregnancies may occur.
The focus of this article is premature ovarian failure, a term that will be
used as an equivalent to ovarian failure.
Pathophysiology: Premature ovarian
failure can be subdivided into 2 major pathogenetic categories—induced
(iatrogenic) POF and spontaneous POF.
Induced (iatrogenic) ovarian failure
Women exposed to various forms of cancer therapy (high-dose chemotherapy
and/or gonadal irradiation) have increased risk of developing ovarian failure.
The risk is higher if the treatment occurs after the onset of puberty (relative
risk [RR] 2.32), in survivors of Hodgkin lymphoma (RR 3.25), and in patients
treated with combined chemotherapy and radiation therapy below the diaphragm (RR
8.56-9.6). After bone marrow transplant and therapy with busulfan, almost 100%
of women develop ovarian failure.
The mechanism of iatrogenic ovarian failure includes damage to the
proliferating ovarian granulosa cells and/or to the oocytes. Subsequently,
follicular depletion and premature ovarian failure develop. It can be temporary
in some cases, and ovarian function may return spontaneously. Some women
continue to have regular menstrual cycles despite elevated serum FSH levels and
reduced fertility (ovarian insufficiency).
Professional exposure to solvents (2-bromopropane) also can result in oocyte
destruction, low follicular number, and premature ovarian failure.
Finally, bilateral oophorectomy can be regarded as a form of induced POF.
Spontaneous premature ovarian failure
The pathogenesis of spontaneous premature ovarian failure in most cases is
unknown. Two mechanisms are presumed to play a role—follicle depletion and
Pathogenetic classification of premature ovarian
- Ovarian follicle depletion
- Low initial follicle number
- Pure gonadal dysgenesis
- Thymic aplasia/hypoplasia
- Autosomal recessive disorders (ataxia-telangiectasia mental
- Accelerated follicle atresia
- X chromosome related (Turner syndrome, X chromosome deletions and
- Viral oophoritis (theoretical possibility that has not been proven)
- Autoimmunity (theoretical possibility that has not been proven)
- Environmental toxins
- Ovarian follicle dysfunction
- Steroidogenic enzyme defects
- 17-alpha-hydroxylase deficiency
- 17-20-desmolase deficiency
- Aromatase enzyme deficiency
- Lymphocytic oophoritis with positive adrenal antibodies/Addison
disease (steroid hormone–producing cell autoimmunity)
- Gonadotropin receptor antibodies
- Signal defects
- Abnormal gonadotropin receptor
- Abnormality in the G-protein signaling pathway
- Specific genetic defects (blepharophimosis-epicanthus-ptosis syndrome)
- Idiopathic (resistant ovary syndrome)
Follicle depletion is a major pathogenetic mechanism for development of POF.
The presence of normal numbers of follicles in the ovaries (approximately
300,000-400,000 at the beginning of puberty) is crucial for normal periodic
ovulation. Full maturation of one dominant follicle is dependent on the
simultaneous development of a support cohort of nondominant follicles. These,
although destined to undergo atresia, play an important role in the fine-tuning
of the hypothalamic-pituitary-ovarian axis by secreting regulatory hormones such
as estradiol, inhibins, activins, and androgens.
Pathological conditions that cause depletion or a reduction of the follicle
number may lead to a disruption of the highly coordinated process of follicular
growth and ovulation. The lack of developing follicles leads to reduced
circulating estradiol and inhibin levels and elevated serum FSH and LH.
Occasionally, a "lonely" follicle may develop, stimulated by the high levels of
FSH; however, instead of progressing to a normal ovulation, it is
inappropriately luteinized (by the high LH levels) and may persist as a cystic
structure visible on ultrasound.
The ovarian follicle reserve can be depleted prematurely because of a low
initial number or an accelerated rate of follicle atresia.
Low initial number
- A disruption in any step of germ cell formation, migration, oogonia
proliferation, and meiosis will result in a deficient initial follicle number.
The final outcome could be a formation of streak gonads and primary
amenorrhea, as in familial 46,XX gonadal dysgenesis, an autosomal-dominant
disease with sex-linked inheritance.
- In milder cases, the initial follicle number is sufficient to support
pubertal development, initiation of menstrual cycles, and even fertility, but
ovarian failure due to follicle depletion develops early in the reproductive
- In primates, the fetal thymus plays an important role in establishing the
normal endowment of primordial follicles. Not surprisingly, human conditions
with thymic hypoplasia/aplasia have been associated with POF.
Accelerated follicle atresia: Accelerated follicle atresia or destruction
can result from one of the following:
Genes and chromosome regions implicated in the development of POF
- X chromosome monosomy/aneuploidy or mosaicism (as observed in Turner
syndrome or some cases with 47,XXX karyotype)
- X chromosome abnormalities (X chromosome rearrangement, X isochromosome
and ring chromosome, translocations of X chromosome material to an autosome [t(X;A)],
fragile X premutation)
- Cytotoxic therapy
- X chromosome genes: Multiple X chromosome genes are involved in regulating
female fertility and reproductive lifespan and may be involved in the
pathogenesis of ovarian failure.
- Xp (short arm) genes: Deletions or disruptions of critical regions of
the short arm of the X chromosome (Xp11, Xp22.1-21.3) have been described in
association with gonadal dysgenesis and primary or secondary amenorrhea. The
importance of the genes located on the short arm of the X chromosome for
normal ovarian development and survival is evident from the fact that half
of the patients with partial deletions of the short arm of the X chromosome
- Zfx (X-linked zinc finger protein): Located on Xp22.1-21.3, this gene
encodes a widely expressed protein of unknown function. Zfx "knockout"
mice are small, less fertile, and have a diminished germ cell number in
the ovaries and testes.
- USP9X gene (ubiquitin-specific protease 9 gene): It is
located on Xp11.4, and its product is widely expressed in many tissues. In
Drosophila, USP9X is required for eye development and oogenesis,
but its role in human gonadal development is unclear.
- Xq (long arm) genes: Analysis of terminal deletions and autosomal
translocations yielded information on the importance of several areas
located on the long arm of the X chromosome. These include Xq13-21, Xq22-25,
- XIST locus (X inactivation site): Located on Xq13, this locus is
required for the reactivation of the silenced X chromosome during oocyte
maturation. Two X chromosomes with 2 intact XIST loci are necessary for
normal meiosis to occur in oocytes. Thus, impairment of the XIST locus
results in meiotic arrest and oocyte depletion due to apoptosis.
- DIA gene (diaphanous gene): This gene, located on Xq21, is
homologous to the diaphanous gene in Drosophila. DIA protein is
abundantly expressed in the ovaries and other tissues and is important for
establishing cell polarity and morphogenesis. DIA mutations in
Drosophila lead to sterility in both sexes. The Xq21 region
contains at least 7 other genes involved in ovarian development. This
region is pseudoautosomal (present on both X and Y chromosomes).
- FMR1 gene (fragile mental retardation gene): It is located on
Xq27.3. The product is a protein of unknown function. Mutations in that
gene represent extreme expansions of CGG repeat in the first exon of the
FMR1 gene and are associated with mental retardation. Women who
carry a modest expansion of these repeats (60-200, designated as a
premutation) demonstrate an increased incidence of POF and are not
affected by mental retardation. Why women with the full mutation have no
ovarian failure and only those with premutation do is unclear.
- Autosomal abnormalities
- Trisomies 13 and 18, but not trisomy 21, are associated with ovarian
dysgenesis and failure. Therefore, a possibility exists that ovarian genes
are located on chromosomes 13 and 18.
- Balanced autosomal translocations have been found in otherwise healthy
women with POF.
- 46,XX gonadal dysgenesis
- Approximately two thirds of cases with gonadal dysgenesis in
individuals who are 46,XX are genetic. The inheritance is autosomal
recessive, and the penetrance is variable. Therefore, a possibility exists
that some of the sporadic cases of karyotypically normal POF could be due
to a mutant somatic gene for XX gonadal dysgenesis.
- 46,XX gonadal dysgenesis sometimes is a part of a genetic syndrome,
such as gonadal dysgenesis and neurosensory deafness (Perrault syndrome);
gonadal dysgenesis and cerebellar ataxia; gonadal dysgenesis,
arachnodactyly, and microcephaly; and gonadal dysgenesis, short stature,
and metabolic acidosis.
- Autosomal recessive disorders associated with POF include the following:
- Cockayne syndrome
- Nijmegen breakage syndrome
- Werner syndrome
- Bloom syndrome
- ATM gene (ataxia-telangiectasia mental retardation gene)
- ATM is a protein kinase involved in DNA metabolism and cell cycle
- Mutations in this gene, located on chromosome 11q22-23, are associated
with ovarian atrophy and amenorrhea despite normal female sexual
Some patients with spontaneous POF have numerous ovarian follicles with
seemingly normal oocytes that fail to grow and ovulate in the presence of
elevated gonadotropins. Most of these patients have idiopathic disease, but, in
some cases, a specific cause can be found.
- Specific gene defects
- FOXL2 gene (forkhead transcription factor gene): It is located
on chromosome 3q22-23. Abnormalities of this gene cause
blepharophimosis-epicanthus-ptosis syndrome, a rare congenital dysplasia of
the eyelids, which usually is inherited as autosomal dominant. In addition,
POF develops. The ovaries initially contain many follicles that do not grow
(resistant ovaries), and, later, ovarian depletion develops.
- FSH receptor gene abnormalities: Point mutations of this gene, located
on chromosome arm 2p, have been described in Finnish women with POF.
- LH receptor gene defects: Inactivation mutations of the LH receptor gene
(on chromosome arm 2p) have been described in women with primary amenorrhea,
normal breast development, high LH and FSH levels, and low estradiol levels.
- Enzyme deficiencies: The following enzyme deficiencies have been
associated with ovarian failure:
- Cholesterol desmolase deficiency: Patients with this enzyme deficiency
can barely produce any steroid hormone. They have enlarged lipid-filled
adrenals, lack of ovarian function, and rarely survive to adulthood.
- 17-alpha-hydroxylase deficiency: This is a form of congenital adrenal
hyperplasia. Patients have impaired adrenal and ovarian steroid hormone
synthesis. They develop hypertension, hypokalemia, and ovarian failure.
- 17-20-desmolase deficiency: Although this enzyme is a part of the
17-alpha-hydroxylase cytochrome P450 complex, an isolated deficiency is
possible. In this case, only ovarian failure develops. Patients with
17-alpha-hydroxylase/17-20-desmolase deficiency have low serum estrogens,
high gonadotropins, enlarged ovaries with multiple cysts, and amenorrhea.
- Aromatase enzyme deficiency: Several families with this defect have been
described. The female siblings in these kindreds demonstrated lack of
pubertal development, high serum gonadotropin levels, and multiple ovarian
cysts. Molecular analysis of the aromatase gene reveals a point mutation.
- Signal defects
- This is related to FSH and LH receptor abnormalities as described above.
- Pseudohypoparathyroidism: Ovarian resistance has been demonstrated in
patients with pseudohypoparathyroidism due to a defect in the Gsa subunit of
the G protein, which prevents normal cyclic adenosine monophosphate (cAMP)
- Autoimmunity: The immune system may play a role in some of the cases of
premature ovarian failure. The real prevalence of autoimmune premature ovarian
failure is unknown. According to one estimate, the rate is approximately 30%.
- POF associated with adrenal autoimmunity
- Numerous case reports exist of histological findings consistent with
autoimmune oophoritis. The ovaries are of normal size or are enlarged.
Many follicles at different stages of development are present. Most or all
follicles beyond antral stage are affected by lymphomonocytic infiltration
of the theca interna that rarely involves the granulosa. Primordial
follicles and follicles below the secondary stage of development are not
- The patients with histologic findings of autoimmune oophoritis have
circulating antiadrenal and/or steroid cell antibodies with unclear
functional significance. They may be regarded as markers of autoimmune
attack against steroid hormone–producing cells (both in the ovaries and the
- Such patients have high prevalence of Addison disease, which may be
evident at the time of diagnosis of POF or may develop later.
- Whether an isolated form of autoimmune oophoritis (without adrenal
involvement) exists is unclear. The authors have observed one woman with
spontaneous POF, histologically proven oophoritis, and positive adrenal
antibodies. The findings of her adrenal function tests have remained
completely normal over 3 years, and she has no clinical or laboratory
manifestation of other autoimmune diseases.
- Autoimmune oophoritis is a relatively rare condition, and it affects
less than 5% of women who present with POF.
- Spontaneous POF has been described as part of polyglandular autoimmune
syndromes type 1 and 2. In type 1 syndrome, POF is associated with
mucocutaneous candidiasis, ectodermal dystrophy, hypoparathyroidism,
celiac disease, chronic hepatitis, and Addison disease. This is a very
rare autosomal recessive disorder that presents in childhood, mainly in
people of Finnish, Sardinian, and Iranian Jewish descent. This disorder is
caused by mutations in a gene located on chromosome arm 21q22. The product
of that gene is a protein with unknown function, termed AIRE (autoimmune
regulator). Autoimmune polyglandular syndrome type 2 consists of
autoimmune thyroid diseases, type 1 diabetes, Addison disease, and, in
some cases, POF. This syndrome is less well defined than type 1 and is
associated with specific human leukocyte antigen (HLA) subtypes.
- Spontaneous POF can be associated with autoimmune endocrine and
nonendocrine diseases outside of the polyglandular autoimmune syndromes.
By far the most common is Hashimoto thyroiditis with or without
hypothyroidism. It is found in 15-25% of women with spontaneous POF. Other
associated diseases are type 1 diabetes, vitiligo, lupus, Sjögren syndrome,
and rheumatoid arthritis. Whether POF in these cases is autoimmune in
nature is unclear.
- The mere presence of other autoimmune disease should not lead by
default to the conclusion that POF is of autoimmune origin. Ovarian
biopsies of women with POF and other autoimmune diseases but without
adrenal/steroid cell antibodies or Addison diseases repeatedly have failed
to show any features of autoimmune inflammation.
- Autoimmune POF without adrenal autoimmunity
- Other forms of autoimmune POF that do not have the typical histologic
picture of autoimmune oophoritis and markers of adrenal/steroid-producing
cell autoimmunity are possible.
- Controversy exists regarding the presence of FSH receptor–blocking
antibodies. Chiauzzi et al reported FSH receptor–blocking antibodies in 2
patients with myasthenia and POF. Others have failed to find such
antibodies. Several researchers have reported the presence of a
nonimmunoglobulin serum inhibitor that effectively blocks the interaction
of FSH with its receptor.
- Recently, an antibody targeting a protein that is expressed
exclusively in the oocyte has been described in a mouse model of
autoimmune ovarian failure. In some cases, human ovarian failure possibly
is due to specific antibodies targeting a similar oocyte antigen.
- The presence of ovarian antibodies often is regarded as proof of the
autoimmune nature of POF. Several assays have been developed. These
include indirect immunofluorescence on monkey ovary slides or enzyme
immunoassays using different ovarian extracts containing numerous
unspecified antigens. These ovarian antibody assays have shown very little
specificity. As many as one third of women who cycle normally have
positive tests. On the other hand, a negative result with one assay does
not rule out the possibility of a positive result with a different assay.
Until assays with specific ovarian antigens are developed, ovarian
antibody tests have little value in determining the etiology of POF.
- In a retrospective study, Rebar and Connolly reported that 3.5% of
patients with POF had a previous infection (eg, varicella, shigellosis,
- Others have observed a 3-7% incidence of oophoritis in patients who
contracted mumps during an epidemic.
- Cytomegalovirus oophoritis has been described in various women who are
- Nevertheless, a true cause-and-effect relationship between POF and
infection has not been established.
- In the US: Premature ovarian failure occurs in
approximately 1% of women. The estimated incidence in the United States is 10
cases per 100,000 person-years at ages 15-29 years and 76 cases per 100,000
person-years at ages 30-39 years. Approximately 10-28% of women with primary
amenorrhea and 4-18% with secondary amenorrhea have premature ovarian failure.
Mortality/Morbidity: Long-term follow-up studies to evaluate
the impact of POF on the mortality rate at older age have not been conducted. In
a survey of 19,000 women aged 25-100 years, Snowdon et al have shown increased
all-cause mortality in women who had ovarian failure before age 40 years
(age-adjusted odds ratio of death 2.14 [95% confidence interval, 1.15-3.99]) and
stroke mortality (odds ratio 3.07 [95% confidence interval, 1.34-7.03]). Several
points concerning morbidity and mortality of patients with POF are worth
considering, as follows:
- A long-lasting hypoestrogenic state at a young age may prevent women from
achieving and maintaining adequate bone density. This may put them at
increased risk for osteoporosis and fractures later in life.
- Women with POF may be at higher risk for cardiovascular diseases, again
due to low estrogen levels.
- Patients with POF may be more inclined to undertake unproven treatments to
restore fertility and, in this way, may be exposed to iatrogenic damage. The
authors recently have observed 2 cases of bone necrosis due to prolonged
treatment with corticosteroids in women with POF and presumed but unconfirmed
- POF can coexist with other endocrine and nonendocrine diseases (eg,
hypothyroidism, Addison disease, type 1 diabetes, pernicious anemia, lupus).
- The diagnosis of POF may have a deleterious psychological impact and may
lead to depression in a young, otherwise healthy woman.
Race: No studies exist regarding race differences in the
incidence of spontaneous POF.
Age: By definition, premature ovarian failure is a condition
of women younger than 40 years.
History: For more information, see
The history of a patient with ovarian failure could be quite variable,
depending on the pathogenesis. In cases of spontaneous ovarian failure, the
typical scenario is a sudden onset of amenorrhea, usually after discontinuation
of oral contraceptives, or after a pregnancy. In as many as 50% of cases, a long
history of oligomenorrhea and polymenorrhea, with or without menopausal
symptoms, is present. In 10% of the affected women, POF presents as primary
amenorrhea. Occasionally, menopausal symptoms appear before the menses have
stopped. In these cases, the physicians could miss the diagnosis easily because
of the young age of the patients and the low index of suspicion. The presenting
symptoms may vary according to the presence of other associated endocrine and
nonendocrine autoimmune diseases.
- The most commonly encountered symptoms are a result of prolonged
hypoestrogenism and include hot flashes, sweats, irritability, dry skin, dry
eyes, vaginal dryness, discomfort and pain during sexual intercourse,
decreased libido, and decreased energy.
- Some of the symptoms may be due to the presence of other endocrine
disorders, such as hypothyroidism, Addison disease, and diabetes. These may
include cold intolerance, dry skin, and bradycardia. Two to six percent of
patients with spontaneous POF may develop Addison disease and may present
with hypotension, hyperpigmentation, orthostatic blood pressure drop, salt
craving, loss of appetite, and abdominal pain.
- Sometimes, patients with autoimmune oophoritis may present with
unexplained episodes of lower abdominal pain or acute pain that may prompt
- Patients should be asked about previous exposure to radiation,
chemotherapy, or toxic environmental agents. The remote possibility of POF
associated with infection should be addressed, especially past or current
viral infections or mumps. History of past or current autoimmune and
endocrine disorders also should be obtained.
- Time of menarche, the previous menstrual pattern, and growth history may
provide clues for the diagnosis of chromosomal or genetic syndromes.
- Surgical procedures involving the pelvic organs, especially the ovaries,
sometimes may result in damage to the ovarian blood supply and, eventually,
decreased ovarian reserve and ovarian insufficiency.
- Evidence of a familial component exists in some cases of POF, including
the finding of an autosomal dominant pattern of inheritance across 4
- Patients who are carriers of fragile X premutation may have a family
history of male mental retardation.
- Patients with POF may have family history of other autoimmune diseases,
including autoimmune endocrine diseases. Whether the presence of autoimmune
disease in first-degree relatives increases the likelihood of autoimmune
ovarian failure is unclear, and studies addressing this question currently
Physical: For more information, see
Generally, women with spontaneous POF have unremarkable clinical findings.
Occasionally, signs of Turner syndrome may be evident (short stature,
shieldlike chest, webbed neck, shortened IV and V metacarpal bones, wide
carrying angle of elbows, low-set ears and low hairline, and Madelung deformity
of the wrists).
In other patients, POF is a part of familial syndromes and unusual clinical
manifestations can be found, such as deafness in Perrault syndrome or
blepharophimosis, eyelid dysplasia, and achondroplasia.
Pay attention to signs of thyroid disease, such as the presence of goiter,
exophthalmos, bradycardia or tachycardia, and cold-and-dry or soft-and-warm
Looking for clinical signs of adrenal insufficiency, such as orthostatic
hypotension, hyperpigmentation, and decreased axillary and pubic hair, is
Other findings associated with the presence of autoimmune diseases may
include vitiligo (often associated with thyroid and adrenal autoimmunity),
premature graying of hair (in thyroid diseases), nail dystrophy and
mucocutaneous candidiasis (in autoimmune polyglandular syndrome type 1), and
alopecia areata and malar rash (in lupus).
Pelvic examination usually reveals atrophic vaginitis. However, some women
have intermittent follicular function and produce enough estradiol to keep the
vaginal mucosa well estrogenized. Usually, the ovaries are small and barely
palpable. Enlarged ovaries could be found occasionally, as in some cases of
The diagnostic approach to patients with ovarian failure is as follows:
- Last spontaneous menstrual cycle
- Prior pelvic surgeries, irradiation, or chemotherapy
- Symptoms of adrenal insufficiency, including the following:
- Orthostatic hypotension
- Skin hyperpigmentation
- Unexplained weakness
- Salt craving
- Abdominal pain
- Symptoms of hypothyroidism
- Family history of POF, male mental retardation, autoimmune disorders
- Enlarged versus nonpalpable ovaries
- Physical stigmata of Turner syndrome or other genetic syndromes,
including the following:
- Short stature
- Webbed neck
- Low position of the ears
- Low posterior hairline
- Cubitus valgus
- Shield chest
- Short IV and V metacarpals
- Signs of autoimmune diseases, Addison disease, and hypothyroidism
- Standard blood chemistry - Fasting glucose, electrolytes, and creatinine
- Test for fragile X chromosome
- Thyroid-stimulating hormone (TSH)
- Antithyroid peroxidase antibody
- Serum adrenal antibodies
- Bone density by dual-energy x-ray absorptiometry (DEXA) scan
classification of premature ovarian failure. For more information, see
Insufficiency. The differential diagnosis of premature ovarian failure
includes the following:
- Differentiate POF from other causes of amenorrhea, such as the following:
- Secondary ovarian insufficiency/failure due to the following:
- Eating disorder
- Extreme physical exercise
- Prolactinoma and other conditions causing hyperprolactinemia
- Pituitary and hypothalamic tumors
- Hypothalamic and pituitary infiltrative and inflammatory processes
- Pituitary hemorrhage
- Systemic diseases, including other endocrine disorders
- Hyperandrogenic conditions due to the following:
- Polycystic ovarian syndrome
- Congenital adrenal hyperplasia
- Ovarian or adrenal androgen-producing tumors
- Ovarian hyperthecosis
- Outflow tract abnormalities
- Pseudo premature ovarian failure due to the following:
- Gonadotropin-producing pituitary adenoma
- Antibodies to gonadotropins
- Differential diagnosis of different forms of POF are as follows:
- Iatrogenic ovarian failure
- Autoimmune, due to the following:
- Associated with adrenal failure/antibodies
- Autoimmune POF without adrenal failure/antibodies
- Miscellaneous rare causes, due to the following:
- Blepharophimosis-epicanthus-ptosis syndrome
- Pure gonadal dysgenesis and syndromes associated with POF, such as
Perrault syndrome and others
- Autosomal recessive syndromes associated with ovarian failure, such as
Cockayne syndrome, Nijmegen breakage syndrome, and Werner syndrome
- Thymic hypoplasia/aplasia or tumor
- Enzyme deficiencies such as 17-alpha-hydroxylase
deficiency/17-20-desmolase deficiency, aromatase enzyme deficiency, and
- Three groups of tests should be performed when ovarian failure is
suspected or has been diagnosed. They include tests that establish the
diagnosis of POF, tests that help clarify the etiology, and screening tests
for other diseases known to have higher prevalence among women with POF.
- A pregnancy test (urine or beta human chorionic gonadotropin [bhCG] in the
blood) should be the first study performed in every woman of reproductive age
who presents with amenorrhea.
- Studies for establishing the diagnosis of POF are as follows:
- Measuring serum FSH level is the core study to establish the diagnosis
of POF after pregnancy has been ruled out. By convention, 2 FSH levels in
the menopausal range for the specific assay (>40 mIU/mL
by radioimmunoassay), measured at least 1 month apart, are diagnostic of POF.
- Measurement of serum LH also is important. In most cases of spontaneous
POF, FSH is higher than LH. If autoimmune oophoritis is present, FSH may be
only mildly elevated, sometimes below the cutoff of 40 mIU/mL,
while LH is markedly elevated.
- A parallel test of serum estradiol is necessary. As a rule, serum
estradiol is low in women with POF and is similar to or less than the early
follicular phase estradiol of women who cycle normally. The combination of
low estradiol and high gonadotropins defines POF.
- Occasionally, women with POF may have spontaneous follicular activity,
and, if hormonal tests are performed during such episodes, levels of FSH, LH,
and estradiol could be in the normal range or FSH and LH could be elevated
only minimally (below the menopausal range). This may lead to an erroneous
rejection of the diagnosis of POF. In these cases, persistent amenorrhea or
oligomenorrhea accompanied by menopausal symptoms necessitates a repeat of
the above tests in 1-2 months.
- Studies to clarify the etiology of ovarian failure are as follows:
- Karyotype: A karyotype should be performed as a part of the routine
evaluation after the diagnosis of POF is established. A history of previous
pregnancies or age older than 35 years should not discourage the test. X
chromosome abnormalities have been described in women who have had normal
puberty, have delivered children without abnormalities, and subsequently
have developed POF. In addition, unexpected karyotype findings may have
important implications for relatives and for future pregnancies. A normal
karyotype may be reassuring to the patient, while an abnormal one could
provide an explanation of the patient's problem.
- Ovarian and other antibodies: Currently, no reliable tests exist for the
diagnosis of autoimmune ovarian failure. The different ovarian antibody
assays that are available commercially are of little diagnostic value
because of problems with specificity and sensitivity.
- The presence of a second autoimmune endocrine or nonendocrine disease
traditionally is used as an argument that the ovarian failure of a
particular patient is of autoimmune etiology. In most cases, this is not
true, the only exception being the combination of Addison disease and POF.
- Screening tests for other associated diseases/conditions are as follows:
- Thyroid: The prevalence of hypothyroidism in patients with spontaneous
POF is higher than in the general female population of the same age, and
screening with a TSH test and thyroid peroxidase antibodies is warranted.
- Elevated thyroid antibodies should be regarded as a risk factor for
hypothyroidism and not as an indicator that the ovaries are affected by an
- Adrenal antibodies: Adrenal antibody test (by immunofluorescent assay)
or 21-hydroxylase antibody test (by enzyme immunoassay) should be performed
as soon as the diagnosis of spontaneous POF has been established.
- Two to five percent of women who present with POF also have autoimmune
adrenal insufficiency. The authors previously have shown that an
autoantibodies test by immunofluorescence is an efficient means to screen
for autoimmune adrenal insufficiency (100% sensitivity and 67% positive
predictive value). Therefore, it should be used early in the diagnostic
- Fragile X chromosome premutation screening: Because the prevalence of
fragile X chromosome premutation is significantly higher among women with
POF compared to women who cycle normally, some authors recommend that a test
for fragile X premutation be a part of the initial workup of patients with
POF. The finding of fragile X premutation may have implications for the
family members and for planned pregnancies.
- Routine tests include serum glucose, electrolytes, and creatinine.
- Tests for secondary ovarian failure are as follows:
- Measure prolactin levels.
- Consider the need for an adrenocorticotropic hormone (ACTH) stimulation
test to evaluate secondary adrenal insufficiency as an additional finding.
- Also consider measuring serum insulinlike growth factor-1 and conducting
an insulin tolerance test to check for growth hormone deficiency.
- Ovarian ultrasound has little practical value in the workup of patients
- An MRI of the pituitary and hypothalamus is indicated in the evaluation of
secondary ovarian failure in the following circumstances:
- Associated headache or visual-field cuts
- Profound estrogen deficiency with otherwise unexplained amenorrhea
Section 6 of 10
Medical Care: Medical treatment of
patients with POF should address the following aspects: ovarian hormone
replacement, restoration of fertility, and psychological well being of the
patient. For women with secondary ovarian failure, the treatment required to
restore ovarian function depends on the specific etiology.
- Management of premature ovarian failure
- Discuss the test results on a special visit (not by phone).
- The diagnosis of POF can be particularly traumatic for young women.
- Use of appropriate terminology is important (use of premature ovarian
failure or insufficiency is preferred instead of premature menopause or
- Explain the nature of the disease and advise the patient of sources of
information and support.
- The ovary is not only a reproductive organ but also is a source of
important hormones that help maintain strong bones. Adequate replacement
of these missing hormones, a healthy lifestyle, and a diet rich in calcium
are essential. DEXA bone scan every 2 years may be needed.
- POF is not menopause. Spontaneous ovarian activity and pregnancies are
- Allow the patient enough time to accept the diagnosis. Discuss
fertility plans later, after the patient has come to terms with her
- No proven therapies exist to restore fertility, and an experimental
treatment should be performed only under a review board–approved research
- Currently available options to resolve infertility include change of
plans, adoption, and ovum donation.
- Replace deficient hormones
- Cyclic/continuous oral/transdermal estrogen and cyclic oral progestin
- Full replacement dose is needed to alleviate symptoms and maintain
age-appropriate bone density.
- Adequacy of hormone replacement therapy (HRT) should be followed
- TSH and adrenal antibodies (expert opinion) should be followed yearly.
- ACTH stimulation test should be performed yearly if the adrenal
antibodies are positive.
- DEXA bone density scan should be performed as needed.
- Hormone replacement therapy: All women with premature ovarian failure
should receive HRT with estrogens and progestins to relieve the symptoms of
estrogen deficiency, to maintain bone density, and to reduce the risk of
cardiovascular diseases. Some women may need HRT even before amenorrhea
develops to alleviate menopausal symptoms.
- Estrogens can be administered orally or transdermally. The appropriate
dose for young women with ovarian failure has not been established in
control studies. According to the authors?clinical judgment, administer
doses twice as high as the recommended dose for HRT for women who are
postmenopausal (conjugated equine estrogens [CEE] 1.25 mg instead of 0.65
mg daily, oral estradiol 2-4 mg instead of 1 mg daily, and transdermal
estradiol 100-150 mcg instead of 50 mcg daily). Such doses usually achieve
adequate estrogenization of the vaginal epithelium in young women with POF
and probably help to maintain age-appropriate bone density.
- The estrogens can be administered continuously or cyclically (21 d on,
7 d off). Because no controlled studies compare the efficacy and safety of
one method over another, the choice of therapy should come after
consideration of the patient's preference and physician's experience.
- Estrogen replacement therapy does not prevent ovulation and conception
in these patients, and they should be informed that they must obtain a
prompt pregnancy test if menstrual bleeding fails to appear when expected.
- Estrogen also can be provided in the form of combination contraceptive
formulations, including oral contraceptives and combination injectable
methods (eg, Lunelle). Even though such estrogen doses may be more than is
needed for symptom abatement and maintenance of appropriate secondary
sexual development, the use of such methods may provide considerable
psychological benefits to those reproductive-aged women who may feel
stigmatized by taking menopausal hormonal preparations.
- Progestins should be administered cyclically, 10-14 days each month,
to prevent endometrial hyperplasia that unopposed estrogen may cause.
Young women with POF have a 5-10% chance of spontaneous pregnancy (unlike
women who are postmenopausal). If an expected withdrawal bleeding is
missing, a pregnancy test should be performed and a diagnosis of pregnancy
should not be delayed.
- The recommended regimens include medroxyprogesterone 10 mg daily for
10-12 days each month or micronized progesterone 200 mg daily for 10-12
days each month.
- The use of combination contraceptives provides appropriate doses of
- Women with ovarian failure have lower levels of free testosterone
compared to normally ovulating age-matched controls, but only a small
percentage have levels below the lower limit of normal.
- Clinical trials are underway to determine whether testosterone
replacement should be a part of the standard therapy for young women with
ovarian failure. Additional information can be obtained by calling the
Section on Women's Health Research at the US National Institute of Child
Health and Human Development, Bethesda, Maryland at (877) 206-0911.
- Until results from these trials are available, androgen replacement
could be considered for women who have persistent fatigue, low libido, and
poor well being despite adequate estrogen replacement and when depression
has been ruled out or adequately treated. This should be performed with
great caution and for relatively short periods until more data are
- Available medications include oral methyl testosterone 1.25-2.5 mg/d,
injectable testosterone esters 50 mg every 6 weeks intramuscularly, and
subcutaneous testosterone pellet implants 50 mg every 3-6 months. A
testosterone transdermal patch, designed to deliver 150 mcg per day,
currently is undergoing a clinical trial.
- Restoration of fertility: No intervention has been proven to increase the
ovulation rate or restore fertility in patients with POF.
- Gonadotropin therapy carries a theoretical risk of exacerbating
autoimmune premature ovarian failure.
- The use of prednisone or dexamethasone in an attempt to restore ovarian
function in suspected autoimmune ovarian failure is not indicated
clinically. Use of these agents carries a risk of osteonecrosis. Their use
in patients with premature ovarian failure should be confined to studies
approved by an institutional review board.
- Unproven treatments to restore fertility should be avoided because they
have the potential of interfering with the development of a spontaneous
- Patients with POF can have successful pregnancy with a donor egg. A
decision to proceed with such a procedure should be made after a fair
discussion of different options. The age of the patient is of less
importance than the age of the egg donor.
- Other possibilities include adoption or change of life plans.
- For women with secondary ovarian failure, the treatment required to
restore fertility depends on the specific etiology.
Surgical Care: Ovarian biopsy is not clinically indicated in
women with ovarian failure, but surgical procedures should be performed in women
with secondary ovarian failure as indicated when hypothalamic or pituitary
lesions are identified.
- Consultation with an endocrinologist may be indicated in some cases
because of concerns of hypothyroidism or adrenal insufficiency.
- Patients with infertility due to POF usually have a grief response after
hearing the diagnosis. They benefit from a baseline psychological evaluation
and appropriate counseling.
- Genetic counseling may be needed in some cases.
Diet: Patients with ovarian failure should consume 1200-1500
mg of elemental calcium per day in their diet. If this is not feasible, calcium
supplementation is appropriate. An adequate intake of vitamin D also is
Activity: Women with POF should be encouraged to engage in
weight-bearing exercises for 30 minutes per day, at least 3 days per week, in
order to improve muscle strength and maintain bone mass. Participation in
outdoor sports is strongly recommended.
Drug Category: Estrogens
-- Used to achieve adequate estrogenization of vaginal epithelium in
young women and to maintain bone density.
|Estradiol transdermal system (Alora) --
Increases synthesis of DNA, RNA, and many proteins in target tissues.
||Apply 0.05, 0.075, or 0.1 mg/d TD patch
thrombophlebitis; undiagnosed vaginal bleeding; pregnancy; breast cancer;
estrogen-dependent neoplasia; chronic liver disease; neurophthalmologic
||May decrease effect of tricyclic
antidepressants and cause worsening of previously well-controlled
depression, which seems to be dose-dependent and is reversible with decrease
or discontinuation of therapy
Effects may decrease during concomitant therapy with carbamazepine and/or
phenytoin, and dose increase may be necessary; estrogens may increase
seizures in patients with previously well-controlled epilepsy
Thyroid replacement or suppressive therapy (eg, levothyroxine,
triiodothyronine) may need adjustment while taking estrogens because the
latter increases SHBG, especially when administered orally, thus leaving
less free T4
Tobacco smoking can have antiestrogenic effect by increasing C-2
hydroxylation of estradiol molecule
Estrogens may reduce hypoprothrombinemic effects of anticoagulants
Estrogen levels may be reduced with coadministration of barbiturates,
rifampin, and other agents that induce hepatic microsomal enzymes; an
increase in corticosteroid levels may occur when administered concurrently
||X - Contraindicated in pregnancy
||Reported endometrial cancer risk among
users of unopposed estrogen is approximately 2- to 12-fold greater than in
nonusers and appears dependent on duration of treatment and dose; greatest
risk appears to be associated with prolonged use (increased risks of 15- to
24-fold for 5-10 y or longer); concurrent progestin therapy may offset risk,
but overall health impact in women who are premenopausal is not known
Some studies suggest possible increased incidence of breast cancer with
higher doses or use for prolonged periods; studies focused on women who are
postmenopausal, and conclusions may not be applicable to young women with
ovarian failure; good counseling should help young women deficient in
estrogen feel comfortable taking estrogens
Therapy during pregnancy is associated with increased risk of fetal
congenital reproductive tract disorders and, possibly, other birth defects
Two studies report 2- to 4-fold increase in risk of gallbladder disease
requiring surgery in women receiving oral estrogen replacement therapy,
similar to 2-fold increase previously noted in users of oral contraceptives;
risk from TD estrogens not established
Occasional BP increases attributed to idiosyncratic reactions; other studies
show slightly lower BP among estrogen users compared to nonusers;
postmenopausal estrogen use does not increase risk of stroke, but BP should
be monitored regularly; recent studies indicate that medroxyprogesterone
acetate may cause adverse changes in lipoprotein metabolism compared to
Ongoing debate over long-term cardioprotective effect of estrogens,
especially in presence of established cardiovascular disease; complete
medical and family histories should be taken before initiating therapy;
should be prescribed for no longer than 1 y without physical examination
Studies have shown that women taking estrogen replacement therapy have
hypercoagulability, primarily related to decreased antithrombin activity;
effect appears dose-dependent and duration-dependent and is less pronounced
than with oral contraceptive use; information on hypercoagulability in women
who have had previous thromboembolic disease is insufficient
Estrogen use may be associated with massive elevations of plasma
triglycerides, leading to pancreatitis and other complications in patients
with familial defects of lipoprotein metabolism
May cause fluid retention, careful observation is required when conditions
that might be influenced by this factor are present (eg, asthma, epilepsy,
migraine, cardiac, renal dysfunction)
Certain patients may develop the following undesirable manifestations of
estrogenic stimulation: abnormal uterine bleeding, mastodynia, and mood
Drug/lab test interactions include accelerated prothrombin time, partial
thromboplastin time, and platelet aggregation time; increased platelet
count; increased factors II, VII antigen, VIII antigen, VIII coagulant
activity, IX, X, XII, VII-X complex, and beta-thromboglobulin; decreased
levels of antifactor Xa and antithrombin III, decreased antithrombin III
activity; increased levels of fibrinogen and fibrinogen activity; increased
plasminogen antigen and activity; increased thyroid-binding globulin (TBG)
leading to increased circulating total thyroid hormone, as measured by
protein-bound iodine (PBI), T4 levels (by column or by
radioimmunoassay), or T3 levels by radioimmunoassay; free T4
and free T3 concentrations are unaltered; other binding proteins
may be elevated in serum (ie, corticosteroid-binding globulin [CBG], sex
hormone-binding globulin [SHBG]) leading to increased circulating
corticosteroids and sex steroids, respectively; free or biologically active
hormone concentrations are unchanged
Other plasma proteins may be increased (eg, angiotensinogen/renin substrate,
|Conjugated equine estrogens (Premarin)
-- Contains a mixture of estrogens obtained exclusively from natural
sources, occurring as the sodium salts of water-soluble estrogen sulfates
blended to represent the average composition of material derived from
pregnant mares' urine. Mixture of sodium estrone sulfate and sodium equilin
sulfate. Contains as concomitant components, sodium sulfate conjugates,
17-alpha-dihydroequilenin, 17-alpha-estradiol, and 17-beta-dihydroequilenin.
Available in 0.3-mg, 0.625-mg, 0.9-mg, 1.25-mg, and 2.5-mg PO tablets.
||1.25 mg/d PO
||<12 years: Not established
12-13 years: 0.3 mg PO qod for as long as 6 mo, increase to adult dose at
>13 years: Administer as in adults
||Documented hypersensitivity; known or
suspected pregnancy; breast cancer; undiagnosed abnormal genital bleeding;
active thrombophlebitis or thromboembolic disorders; history of
thrombophlebitis, thrombosis, or thromboembolic disorders associated with
previous estrogen use (except when used in treatment of breast malignancy or
prostatic malignancy in men)
||May reduce hypoprothrombinemic effect
Coadministration of barbiturates, rifampin, and other agents that induce
hepatic microsomal enzymes may reduce estrogen levels
Pharmacologic and toxicologic effects of corticosteroids may occur as a
result of estrogen-induced inactivation of hepatic P450 enzyme
Loss of seizure control has been noted when administered concurrently with
||X - Contraindicated in pregnancy
||Certain patients may develop
undesirable manifestations of excessive estrogenic stimulation (eg, abnormal
or excessive uterine bleeding or mastodynia)
Estrogens may cause some degree of fluid retention (caution)
Prolonged unopposed estrogen therapy may increase risk of endometrial
Drug Category: Progestins -- When administered
orally in the recommended doses to women adequately exposed to exogenous or
endogenous estrogen, they transform the proliferative endometrium into a
|Medroxyprogesterone (Provera) --
Derivative of progesterone. Androgenic and anabolic effects have been noted,
but apparently is devoid of significant estrogenic activity. Parenterally
administered dosage form inhibits gonadotropin production, which, in turn,
prevents follicular maturation and ovulation. Available data indicate that
this does not occur when the usually recommended PO dose is administered qd.
||10 mg PO qd for 10-12 d monthly
||Documented hypersensitivity; cerebral
apoplexy; undiagnosed vaginal bleeding; thrombophlebitis; liver dysfunction;
known or suspected malignancy of breast or genital organs; missed abortion;
use as a diagnostic test for pregnancy
||May decrease effects of
May cause increased sulfobromophthalein retention and other hepatic function
May cause increase in PT factors VII, VIII, IX, and X
Coadministration with food results in approximate doubling of
medroxyprogesterone maximum concentration and increases area under the
concentration-time curve (AUC) by 20-30% (clinical significance unknown)
May interfere with pregnanediol determination
||X - Contraindicated in pregnancy
||Caution in hepatic impairment,
migraine, seizure disorders, cerebrovascular disorders, breast cancer, and
In case of breakthrough bleeding; as in all cases of irregular vaginal
bleeding, nonfunctional causes (eg, malignancy) should be borne in mind and
adequate diagnostic measures are indicated
Patients who have a history of psychic depression should be carefully
observed and drug discontinued if depression recurs to serious degree
Patients with diabetes should be observed carefully
Because of occurrence of thrombotic disorders (thrombophlebitis, pulmonary
embolism, retinal thrombosis, and cerebrovascular disorders) in patients
taking estrogen-progestin combinations and because the mechanism is obscure,
physician should be alert to earliest manifestations of these disorders;
discontinue medication pending examination if sudden partial or complete
loss of vision occurs or if sudden onset of proptosis, diplopia, or migraine
occurs; if examination reveals papilledema or retinal vascular lesions,
|Progesterone (Prometrium) -- Used to
prevent endometrial hyperplasia in women with a uterus who are receiving
estrogen replacement therapy.
||200 mg PO hs for 12 d sequentially each
||Documented hypersensitivity; cerebral
apoplexy; undiagnosed vaginal bleeding; thrombophlebitis; liver dysfunction;
known or suspected malignancy of breast or genital organs; missed abortion;
use as a diagnostic test for pregnancy
||Ketoconazole may increase
bioavailability (clinical relevance of in vitro findings is unknown)
||X - Contraindicated in pregnancy
||Capsules contain peanut oil and should
never be used by patients allergic to peanuts
May cause fluid retention, and conditions that might be influenced by this (eg,
epilepsy, migraine, asthma, cardiac or renal dysfunction) require careful
Patients who have a history of depression should be observed carefully
Transient dizziness may occur, use caution when driving a motor vehicle or
operating machinery (small percentage of women may experience extreme
dizziness and/or drowsiness during initial therapy)
Drug Category: Androgens -- Responsible for
normal growth and the development and maintenance of secondary sex
characteristics in males. In addition, androgens have exhibited metabolic
activity and may cause retention of nitrogen, sodium, potassium, and phosphorus
and decrease urinary excretion of calcium. In the presence of sufficient caloric
and protein intake, they will improve nitrogen balance. Androgens also have been
reported to stimulate production of RBCs through the enhancement of
erythropoietin production. Also increase muscle mass, improve muscle strength,
and increase libido.
|Methyltestosterone (Android) --
Synthetic testosterone derivative with significant androgen activity.
Tablets are available in 5-mg, 10-mg, and 25-mg strengths.
||1.2-5 mg PO qd
||Documented hypersensitivity; severe
cardiac or renal disease; benign prostatic hypertrophy with obstruction in
men; undiagnosed genital bleeding
||May increase effects of anticoagulants
Concurrent administration of oxyphenbutazone may result in elevated serum
levels of oxyphenbutazone
In patients with diabetes, metabolic effects of androgens may decrease blood
glucose and insulin requirements
||X - Contraindicated in pregnancy
||When administered to pregnant woman,
may cause virilization of external genitalia of female fetus (virilization
includes clitoromegaly, abnormal vaginal development, and fusion of genital
folds to form a scrotallike structure); degree of masculinization related to
amount of drug administered and age of fetus (most likely to occur when
drugs are administered in first trimester); if patient becomes pregnant, she
should be apprised of potential hazard to the fetus
Women should be observed for signs of virilization (deepening of the voice,
hirsutism, acne, clitoromegaly, and menstrual irregularities),
discontinuation at time of evidence of mild virilism is necessary to prevent
irreversible virilization (such virilization is usual following androgen use
at high doses); instruct patients to report any adverse effects (eg,
hoarseness, acne, changes in menstrual periods, more hair on the face,
nausea, vomiting, changes in skin color, ankle swelling)
Because of hepatotoxicity associated with use of 17-alpha-alkylated
androgens, LFTs should be obtained periodically; has been associated with
development of peliosis hepatis and hepatic neoplasms, including
hepatocellular carcinoma (peliosis hepatis can be life-threatening or
fatal); cholestatic hepatitis and jaundice occur with
17-alpha-alkylandrogens at a relatively low dose (if cholestatic hepatitis
with jaundice appears or if LFTs become abnormal, discontinue therapy and
determine etiology); drug-induced jaundice is reversible when medication is
|Testosterone enanthate (Andro LA 200,
Delatestryl, Durathate-200) -- Derivative of the primary endogenous androgen
testosterone. For IM administration. In active form, androgens have a
17-beta-hydroxy group. Esterification of 17-beta-hyroxy group increases
duration of action. Hydrolysis to free testosterone occurs in vivo.
Each mL of sterile colorless-to-pale yellow solution provides 200 mg
testosterone enanthate in sesame oil with 5 mg chlorobutanol (chloral
derivative) as preservative.
||50 mg IM q6wk
||Documented hypersensitivity; severe
cardiac or renal disease; undiagnosed genital bleeding
||May increase effects of anticoagulants
Anabolic effects may enhance hypoglycemia
Elevated serum levels of oxyphenbutazone may result with coadministration
May decrease levels of TBG, resulting in decreased total T4 serum
levels and increased resin uptake of T3 and T4 (free
thyroid hormone levels remain unchanged, however, and no clinical evidence
of thyroid dysfunction)
Caution when coadministering with ACTH or corticosteroids, especially in
patients with hepatic or cardiac disease (enhances tendency toward edema)
||X - Contraindicated in pregnancy
||Observe women for signs of virilization
(eg, deepening of the voice, hirsutism, acne, clitoromegaly, menstrual
irregularities); discontinuation of therapy at time of evidence of mild
virilism is necessary to prevent irreversible virilization (such
virilization is usual following androgen use at high doses and is not
prevented by concomitant use of estrogens)
Because androgens may alter serum cholesterol concentration, caution should
be used when administering these drugs to patients with a history of MI or
coronary artery disease; serial determinations of serum cholesterol should
be made and therapy adjusted accordingly
Further Outpatient Care:
- Patients with ovarian failure should be seen annually to monitor their HRT.
- Symptoms and signs of thyroid disease and adrenal insufficiency should be
sought during the annual follow-up visits.
- TSH levels should be checked every 3-5 years (every year if antiperoxidase
antibody test is positive).
- If a woman with POF has positive adrenal antibodies on her initial
evaluation, even if all adrenal function tests are normal, she is at high risk
of developing adrenal insufficiency and should have an annual ACTH stimulation
test. Whether women with initially negative adrenal antibody tests continue to
carry higher than normal risk for adrenal insufficiency and whether any
follow-up tests are justified is less clear. Until enough evidence is
acquired, the authors suggest that an adrenal antibody test should be
performed every 3-5 years.
- Patients with secondary ovarian failure should be monitored for
manifestations of the underlying hypothalamic/pituitary pathology (progression
of space-occupying lesions and development/progression of hypopituitarism).
- Women with spontaneous POF have a low but real chance of spontaneous
pregnancy. Approximately 10% become pregnant subsequent to the diagnosis of
POF. HRT does not prevent such pregnancies. Paradoxically, even oral
contraceptives, which are designed for pregnancy protection of women without
ovarian abnormalities, may not suppress the rare spontaneous ovulations of
women with POF. Therefore, patients with POF should be well instructed about
their reproductive situation so that they can make informed decisions
- Ovum donation remains the best current option to resolve the infertility,
but patients with POF should not be encouraged hastily because spontaneous
pregnancy is a real possibility and ovum donation is as successful in older
women as it is in younger women.
- Women with POF should be educated on the nature of their disease and the
current research efforts. The mere understanding of the problem helps patients
- Support web sites are available
- Women with POF who desire fertility occasionally opt for unproven
treatments. Of particular concern is the tendency to regard POF as an
autoimmune disease that can be treated successfully with corticosteroids.
Currently, no scientific proof exists that this is true. The anecdotal reports
of restored ovulation or fertility after treatment with prednisone could
represent reporting bias or random phenomena.
- Corticosteroid treatment could lead to severe complications (the authors
have observed 2 cases of osteonecrosis in women with presumed autoimmune POF)
and should be performed only as a part of review board–approved research
protocols. Other unnecessary and expensive treatments or tests also should be
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