Document Type : Review Article
Authors
1 Obstetrics and Gynecology Department, Women’s (Mirza Koochak Khan) Hospital, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran;Obstetrics and Gynecology Department, Faculty of Medicine
2 Obstetrics and Gynecology Department, Women’s (Mirza Koochak Khan) Hospital, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
Abstract
Keywords
Premature ovarian failure (POF) is a mysterious
disorder. It is defined by the association of
amenorrhea, sex steroid deficiency and elevated
(menopausal) levels of serum gonadotropins before
the age of 40 years. It is not a rare condition;
its incidence is estimated to be as great as 1 in 100
by the age of 40, and 1 in 1000 by the age of 20
years (
In women with primary amenorrhea, the prevalence
is 10-28% and in those with secondary
amenorrhea, POF occurs in 4-18% of patients (
At one time, POF had been considered irreversible
on the basis of early studies, which suggested that a
serum follicle stimulating hormone (FSH) level of
more than 40 IU/ L is associated with permanent
cessation of ovarian function due to ovarian follicle
depletion (
Although most cases of POF are idiopathic, with no
identifiable etiology even after a thorough evaluation
(
Etiological factors of premature ovarian failure
X chromosomal abnormalities |
X monosomy (Turner’s syndrome) |
X Trisomy |
X- autosomal translocation |
X- chromosomal deletion |
Fragile X syndrome |
Mosaic karyotype |
Bone morphogenetic protein 15 (BMP15) gene mutation |
Autosomal disorders |
Galactosemia |
Blepharophimosis- ptosis- epichanthus inversus syndrome (BPES) |
Autoimmune polyendocrinopathy- candidiasis-ectodermal dystrophy (APECED) |
Steroidogenic enzyme defect |
Gonadotropin receptor dysfunction |
Inhibin gene mutation |
Noggin mutation |
Pelvic surgery |
Irradiation |
Chemotherapy |
Varicella |
Mumps |
Cytomegalovirus |
Tuberculosis |
Malaria |
Shigella |
To the best of our knowledge, this study is the first review article about POF in Iranian literature. This review presents the causes and pathogenesis related to POF, obtained by Medline, Pub Med, Google Scholar, the Cochrane Library, Iran Medex and hand searches of pertinent references of English literature on POF, cited between the year 1900 and May 2010.
The observation of familial cases with POF indicates
the role of genetic aberrations in its pathogenesis
(
Various genetic mechanisms implicated in the
pathogenesis of POF include reduced gene dosage
and non-specific chromosome effects that impair
meiosis. These can lead to ovarian failure by causing
a decrease in the pool of primordial follicles,
increased atresia of the ovarian follicles due to apoptosis,
or failure of follicle maturation (
Genetically, ovarian failure is associated with X
chromosomal abnormalities. These abnormalities
could include a small defect in chromosomal arrangement
such as deletions, isochromosomes and
balanced X chromosome-autosomal translocations.
However, complete deletion of one X (Turner’s
syndrome) has also been recorded (
Complete or near-complete absence of one X chromosome
is the most common chromosomal defect
in humans (
However, the identification of genes or critical
regions responsible for individual Turner’s syndrome
features has turned out to be problematic.
Cytogenetic data indicate the reduced dosages of
genes on the short arms of the X (Xp) and Y (Yp)
chromosomes (2. 6Mb Xp-Yp pseudoautosomal
region) tends to be associated with short stature
and somatic anomalies (
Association between trisomy X and POF have
been reported (
Adolescent girls with Turner’s syndrome or other
chromosomal abnormalities who still have follicles
in their ovaries could be candidates for oocyte or/
and ovarian tissue cryopreservation, to save their
ovaries for future fertilization by ovarian reimplantation
(
Fragile X syndrome is an X-linked dominant condition
with incomplete penetration and a prevalence
of 1/4000 in males and 1/6000 in females (
The prevalence of the
Approximately 14% of women with familial POF
have a premutation in the
Individuals seeking reproductive counseling who have a family history of Fragile X syndrome or undiagnosed intellectual disability.
Fetuses of mothers or fathers with premutations or full mutations.
Young women with elevated levels of FSH hormone, especially with a family history of premature ovarian failure, Fragile X syndrome, or a relative of either sex with undiagnosed intellectual disability.
Actually, there is a need for each woman diagnosed
with spontaneous POF to be informed of
her increased risk of carrying a premutation in the
The associations of POF and other abnormalities
of the X chromosome have been extensively reported
in literature (
We found only one study in Iranian literature about
chromosomal abnormalities in Iranian women with
POF, which has showed definite abnormal X chromosomes
in 17. 65% of these patients (
Abnormal karyotypes are detected in 13-50% of
patients who develop primary or secondary amenorrhea
due to POF. Thus, cytogenetic analysis
should be performed as a part of basic evaluation
of women diagnosed with POF. Having this information
may influence the family planning decisions
of family members (
Galactosemia is a rare autosomal recessive disorder
which occurs due to a deficiency in the enzyme
galactose-1-phosphate uridyltransferase (GALT).
The GALT gene maps to chromosome 9p13. These
patients develop hepatocellular, ocular, renal, and
neurological damage as a result of the accumulation
of galactose and its metabolites. The prevalence of
POF is 60-70% in female patients with galactosemia
(
GALT 188Q is a genetic marker which has been
identified in some patients with galactosemia. Premature
ovarian dysfunction has not been diagnosed
in individuals heterozygous for GALT188Q mutations.
(
BPES is an autosomal dominant, sex-limited condition
with a distinctive eyelid phenotype. Two
forms have been described: in type I, POF related
infertility is an adjunct to the condition, and type
II is not associated with POF (
AIRE gene, is responsible for autoimmune polyendocrinopathy-
candidiasis-ectodermal dystrophy
syndrome (APECED) (
Several congenital enzyme defects can disrupt estrogen
synthesis; these defects result in low estrogen,
delayed puberty, amenorrhea, and high serum
FSH concentration levels despite the existence of
normal-appearing primordial follicles in the ovary.
Defects in the steroidogenic acute regulatory
enzyme (StAR), CYP17, and aromatase enzymes
cause these clinical and histological abnormalities
(
FSH and luteinizing hormone (LH) have important
roles in the recruitment, development, and maturation
of ovarian follicles. FSH and LH receptor
genes map to 2p21. Some studies have reported
inactivating mutations of the FSH or LH receptor
genes in connection with primary or secondary
amenorrhea and hypergonadotropic ovarian failure
(
Breetherick et al. suggested that estrogen receptor-α (
The glycoprotein inhibin plays an important role
in the recruitment and development of ovarian follicles by the negative feedback control of FSH. Inhibin
α (
Proximal symphalangism (SYM1) is an autosomal
dominant disorder with characteristic skeletal abnormalities
and conductive deafness. This disease
has been shown to result from haploinsufficiency
of the
A recent study has shown that four polymorphisms
in the protein L- isoaspartyl-0-methytransferase
(
Some cases of POF may be due to an abnormal
self-recognition by the immune system. The exact
mechanism remains obscure (
Presence of lymphocytic oophoritis (
Demonstration of ovarian autoantibodies (
Associated autoimmune disorders (
Antiovarian antibodies in POF have been reported in several studies, but their specificity and pathogonomic roles are questionable. Some antigenic targets for antibody-mediated autoimmune damage in POF were identified:
Steroid producing cells (hillar cells, granulosa
cells, theca internal and corpus luteum). Autoantibodies
to steroid producing cells are widely present in POF associated with Addison’s disease (
3β-hydroxysteroid dehydrogenase (3β-HSD).
This enzyme is involved in the steroid metabolic
pathway. 3β-HSD autoantibodies were found in
2-21% patients with isolated POF (
Gonadotropin receptor blocking antibodies.
Tang et al. (
Other ovarian antigens. The oocyte, zona pellucida,
and corpus luteum are other possible targets
for autoantibody-induced damage (
The published incidence of antiovarian antibodies
in patients with POF ranges widely (7-67%) due to
the heterogeneity of investigation methods, multiple
ovarian antibody targets (including antibodies
against steroidogenic enzymes, gonadotropins and
their receptors, the corpus luteum, zona pellucida
and oocytes), the transient appearance of antiovarian
antibodies, different stages of disease, as well
as variations in antibody test format and antigen
presentation (
Approximately 3% of women with POF have an
associated endocrine dysfunction known as autoimmune
polyglandular syndrome (APS), types
I and II. The type I syndrome is a rare autosomal
recessive disorder in young children, characterized
by multiple organ-specific autoimmunity secondary to a variety of autoantibodies directed
against key intracellular enzymes. POF in the form
of primary amenorrhea develops in 60% of these
patients. APS type II is an autosomal dominant disorder,
and is associated with gonadal failure in 4%
of patients (
Circulating 21-hydroxylase antibodies are the best
immune markers of autoimmune adrenal insufficiency
(
Several other autoimmune disorders have been
associated with POF; hypothyroidism is the most
common. Both endocrine (thyroid, hypoparathyroid,
diabetes mellitus, hypophsitis) and non-endocrine
disorders (chronic candidiasis, idiophatic
thrombocytopenic purpura, vitiligo, alopecia, autoimmune
hemolytic anemia, pernicious anemia,
SLE, rheumatoid arthritis, Crohn’s disease, Sjogren
syndrome, primary billiary cirrhosis and chronic
active hepatitis) were observed in association with
autoimmune POF (
Ashrafi et al. (
Autoimmune hypothyroidism is a disease commonly associated with POF, so screening by the measurement of TSH, free T4, anti-thyroid-peroxidase and anti-thyroglobuline antibodies levels is recommended.
The gold standard for detecting autoimmune POF
is ovarian biopsy, which is not recommended due
to unknown clinical value, expense, and risks (
In autoimmune ovarian failure, the elevated serum
gonadotropin hormones result from the dysfunction
of the ovarian follicles rather than follicular
depletion. Also, the lymphatic infiltration is
confined to secondary and antral follicles while
primordial follicles are spared, so resumption of
ovarian function with or without conception can be
found in a substantial number of affected patients
(
Chemotherapy and radiotherapy can lead to POF
in patients developing malignant disease (
The exact mechanisms involved in chemotherapyinduced
ovarian failure are not known; however the functions of granulosa cells and oocytes may be
affected by chemotherapeutic agents (
Although several investigators have demonstrated
that GnRH agonist may inhibit chemotherapyinduced
ovarian failure in animal models, it is a
controversial issue in humans (
Ovarian suppression by GnRH agonist was offered
to every referred female patient before chemotherapy
for malignant diseases (
Ovarian or egg cryopreservation and transplantation
of the thawed tissue are not yet clinically established;
however there is no contraindication for
cryopreservation combined with GnRH agonist
administration (
Some studies have reported the spontaneous return
of ovarian function after several years in women
with chemotherapy- or radiotherapy-induced ovarian
failure (
Although no prospective studies of ovarian function
and gonadotropin levels before and after
pelvic-adnexal surgeries have been done, these
procedures have the potential to damage the ovary
by affecting its blood supply or causing inflammation
in the pelvic area (
Uterine artery embolization has a potential to result
in POF by compromising the vascular supply
to the ovary (
Mumps oophoritis has been considered to be a
cause of POF. True incidence of post-oophritis
ovarian failure is unknown. In the vast majority of
affected women, return of ovarian function occurs
following recovery (
There are also anecdotal reports of viral and microbial
infection, such as tuberculosis, varicella,
cytomegalovirus, malaria, and shigella being followed
by POF (
Smoking is the most widely studied toxin that alters
ovarian function, and on average, the female
smokers experience menopause earlier than nonsmokers
suggesting a possible detrimental effect
of cigarette smoking on ovarian function (
POF is defined by the association of amenorrhea,
sex steroid deficiency and menopausal levels of
serum gonadotropins before the age of 40 years.
Intermittent and unpredictable ovarian function,
and even spontaneous pregnancy have been reported
in young women with spontaneous POF
subsequent to diagnosis (
Although most cases of POF are idiopathic (
Adolescent girls with Turner’s syndrome or other
chromosomal abnormalities who still have follicles
in their ovaries could be candidates for oocyte or/
and ovarian tissue cryopreservation, to save their
ovaries for future fertilization (
Fragile X syndrome is an X-linked dominant condition
with incomplete penetration, (
Carriers of the
There is a need for each woman diagnosed with
spontaneous POF to be informed of her increased
risk for carrying a premutation in the
An increasing number of studies have documented
autosomal involvement in ovarian dysfunction.
Heterozygous mutation of the bone morphogenetic
protein 15 (
POF related infertility is an adjunct to BPES type
I. In previous reports, all mutations were exclusively
localized in the
Defects in the steroidogenic acute regulatory enzyme
(StAR), CYP17, and aromatase enzymes
cause primary amenorrhea and POF (
Some studies reported inactivating mutations of
the FSH or LH receptor genes in connection with
primary or secondary amenorrhea and hypergonadotropic
ovarian failure (
A recent study among the Iranian population has
showed that inhibin α-subunit (
Karyotypes should be performed as a part of basic
evaluation of women diagnosed with POF due
to frequent abnormal karyotypes (13-50%) in this
condition. Having this information may influence
the family planning decisions of family members
(
Some cases of POF may be due to an abnormal
self-recognition by the immune system. The exact
mechanism remains obscure (
Antiovarian antibodies in POF have been reported in several studies, but their specificity and pathogonomic
roles are questionable. Antiovarian antibodies
do not correlate with the presence or severity of
oophritis, so the measurement of these antibodies is
not recommended. The measuring of CD8 density
on T cells could provide a reliable indicator of the
involvement of the immune system in POF (
Autoimmune Polyglandular Syndrome (APS) type I is a rare autosomal recessive disorder in young children, characterized by multiple organ-specific autoimmunity secondary to a variety of autoantibodies directed against key intracellular enzymes. POF in the form of primary amenorrhea develops in 60% of these patients.
Autoimmunity against the adrenal gland has been
shown in 2-10% of POF cases (
Autoimmune hypothyroidism is the disease most commonly associated with POF, so screening by measurement of TSH, free T4, anti-thyroid-peroxidase and anti-thyroglobuline antibody levels is recommended.
The gold standard for detecting autoimmune POF
is ovarian biopsy, which is not recommended due to
unknown clinical value, expense, and risks (
Placebo-controlled randomized clinical trials, using
corticosteroids as immunosuppressive therapy,
failed to show a change in the course of autoimmune
POF (
Iatrogenic POF has increased over time (
The serum anti-mullerian hormone, as a biochemical
marker of ovarian reserve, may be useful for
evaluating the gonadotoxicity of chemotherapy
regimens (
The usefulness of GnRH agonist for inhibiting
chemotherapy-induced ovarian failure is a controversial
issue in humans (
Some studies have reported the spontaneous return
of ovarian function after several years in women
with chemotherapy- or radiotherapy-induced ovarian
failure (
Predictive factors for ovarian recovery after chemotherapy-
or radiotherapy-induced ovarian failure
include younger age at first chemotherapy administration
and absence of concomitant radiotherapy
(
There is an increase in miscarriage, small for gestational
age offspring, and reduction in live births
in women treated with chemotherapy (
Uterine artery embolization has a potential for
POF by compromising the vascular supply of the
ovary (
Mumps oophoritis has been considered to be a
cause of POF. Return of ovarian function has been
shown in the vast majority of affected patients (
In conclusion, although in the majority of POF cases the underlying cause is not identified, several etiological factors can affect normal ovarian function and lead to permanent or transient ovarian failure. Thorough screening for associated autoimmune disorders and cytogenetic analysis should be performed as a part of the diagnostic work-up. There is no value in ovarian biopsy for diagnosis.