Inheritance in idiopathic premature ovarian failure: analysis of 71 cases.
Inheritance in idiopathic premature ovarian failure: analysis of 71 cases*
Walter Vegetti 2
Maria Grazia Tibiletti 1
Giovanna Testa 0
Luciana De Lauretis Yankowski 2
Federica Alagna 2
Elena Castoldi 0
Monica Taborelli 1
Tiziano Motta 2
Pier Francesco Bolis 0
Leda Dalpr a` 3
Pier Giorgio Crosignani 2
0 Obstetrics and Gynaecology Unit, Department of Clinical and Biological Sciences, University of Pavia , Varese
1 Laboratory of Pathology, Department of Clinical and Biological Sciences, Ospedale di Circolo , Varese
2 First Department of Obstetrics and Gynaecology, University of Milan
3 Department of Biology and Genetics for Medical Sciences, University of Milan , Italy
4 Presented in part at the 13th Annual Meeting of ESHRE , Edinburgh, UK, June 22-25, 1997
5To whom correspondence should be addressed European Society for Human Reproduction and Embryology
Premature ovarian failure is defined as cessation of ovarian
function under the age of 40 years and affects ~1% of
women in the general population. The aetiology of this
disorder is still unknown in most cases. Although there
have been some reports of familial premature ovarian
failure, very little is known about the incidence and
inheritance pattern of its idiopathic form. The aims of this study
were to investigate the incidence and inheritance pattern
of familial premature ovarian failure in a homogeneous
group of patients with premature idiopathic menopause
and to identify possible clinical differences between patients
with the familial and the sporadic form of premature
ovarian failure. A total of 71 women were recruited into
the study. Clinical assessments and genetic counselling
showed that 22 (31%) patients had familial premature
ovarian failure, this high incidence strongly suggesting that
the disorder is a recognizable heritable entity. There was
a statistically significant (P , 0.05) difference in the median
age of precocious menopause in patients with sporadic and
familial premature ovarian failure (31.0 and 37.5 years of
age in the two groups, respectively). Pedigree analysis
strongly suggests the existence of a familial pattern of
premature ovarian failure with a dominant maternal and/
or paternal transmission and incomplete penetrance. In
the presence of familial history of premature ovarian
failure, reproductive counselling is recommended.
Key words: familial/idiopathic/premature ovarian
Cessation of ovarian function under the age of 40 years has
been defined as premature ovarian failure and affects ~1% of
women in the general population (Coulam et al., 1986). The
condition can be associated to autoimmune (Aiman et al.,
1985; Blumenfeld et al., 1993; Wheatcroft et al., 1997) or
genetic (Mattison et al., 1984) disorders, ovarian surgery and
iatrogenic causes. Thus this disorder is highly heterogeneous,
but in most cases the aetiology of premature ovarian failure
is still unknown.
A familial pattern of premature ovarian failure, suggesting
autosomal dominant or X-linked inheritance, has been
described in the past (Mattison et al., 1984; Coulam et al.,
1998). In addition, several authors have reported the correlation
between premature ovarian failure and different chromosome
X abnormalities (Schmidt and Du Sart, 1992; Beck et al.,
1995; Seller et al., 1995). So far, two critical regions on Xq,
which are essential for normal ovarian function, have been
identified: Xq13.3-q21.1 (Powell et al., 1994; Sala et al., 1997)
and Xq26-28 (Skibsted et al., 1984; Delon et al., 1997).
The postulated X-linked inheritance was demonstrated in
another premature ovarian failure pedigree and was associated
with interstitial deletion of the long arm of the X chromosome
(Krauss et al., 1987). More recently a correlation between
premature menopause and fragile X carriers has been suggested
(Partington et al., 1996; Vianna-Morgante et al., 1996).
Cytogenetic data and the correlation between premature ovarian
failure and fragile X carriers again suggest a possible X
localization of the premature ovarian failure gene or genes.
Some forms of ovarian failure associated with other gene
defects have been reported. In 1994 and 1995 Aittomaki et al.
described cases of primary amenorrhoea with FSH receptor
gene mutation in the Finnish population. Amati et al. (1996)
reported two families with premature ovarian failure-related
eyelid malformations and localized this disease to chromosome
Although there have been some reports of the familial form
of the disorder (Coulam et al., 1983; Mattison et al., 1984)
and recent epidemiological evidence that supports the familial
association between menopausal age of mothers and daughters
(Cramer et al., 1995; Torgerson et al., 1997), very little is
known about the incidence and inheritance pattern of the so
called idiopathic premature ovarian failure.
The aims of this study were to investigate the incidence and
inheritance pattern of familial premature ovarian failure in a
homogeneous group of patients with idiopathic premature
ovarian failure and to identify possible clinical differences
between patients with the familial and the sporadic form of
premature ovarian failure.
Materials and methods
ductive Endocrinology Services, Department of Obstetrics and
Gynaecology in Milan and Varese. Both centres followed a pre-established
protocol for patient selection. For the purpose of this study, secondary
hypergonadotrophic amenorrhoea was defined as cessation of menses
for a duration of 6 months or longer before the age of 40 years and
follicle stimulating hormone (FSH) concentrations .40 IU/l. Patients
with amenorrhoea due to known causes or associated with autoimmune
diseases were excluded from the study.
All patients underwent the following clinical assessments: complete
medical history; complete gynaecological history including age at
menarche and previous menses; complete obstetrics history, with
previous pregnancy outcome; history of cigarette-smoking, alcohol
consumption and diet; clinical gynaecological examination; ultrasound
pelvic evaluation using a 56.5 MHz vaginal probe (Ansaldo 538);
serum gonadotrophin assessment; non-organ specific autoantibody
(against nucleus, mitochondria, ribosomes, DNA) by the standard
indirect immunofluorescence on cryostat tissue sections as reported
by Preziati et al. (1995) and organ-specific serum autoantibody
assessments on sections of human pancreas, monkeys ovary, testis
and adrenal gland and rat stomach.
Peripheral blood lymphocyte cultures were set up conventionally and
incubated for 72 h and, in order to obtain high resolution chromosomal
spreads (.550 bands), 103 M methotrexate (MTX) supplied by
Sigma, Italy, was added in cultures for 17.3 h and replaced, after
washing, with 1.2 104 M thymidine (Sigma, St Louis, MO, USA)
for an additional 4 h. Colcemid (Boehringer Mannheim, Germany)
at a final concentration of 0.1 g/ml was added for 10 min to the
culture. Chromosome spreads and QFQ banding were prepared
according to the standard methods. The karyotype reconstructed
followed the guidelines expressed in International System for
Chromosome Nomenclature 95 (ISCN, 1995). For each karyotype a minimum
of 20 cells were analysed and an additional 50 cells were assessed
to exclude sex chromosome mosaicism. A family history was reviewed
during genetic counselling and family members were traced back
Eighty-one patients with secondary hypergonadotrophic amenorrhoea
were initially considered eligible for study entry. No-one presented
clinical evidence of autoimmune disorders. After screening 10 patients
were excluded from the study due to premature ovarian failure
phenotype-related clinical conditions. Of the 10 excluded patients,
three were withdrawn due to previous ovarian surgery, one due to
galactosaemia, one due to previous chemotherapy for the treatment
of Hodgkins disease and five because they presented abnormal
Two of the five patients with abnormal karyotypes had a
previous diagnosis of trisomy 21 and trisomy 18 at mosaic,
respectively, while X chromosome abnormalities were found in the
remaining three at premature ovarian failure screening. In particular,
the following karyotypes were identified: 46,XX,del(X) (q22.3;
q26.3); 46,XX,del(X) (q22qter); 45,X/46,Xisodic(X) (q23qter).
Seven patients reported a dysthyroidism (six in the sporadic and
one in the familial group): four of the seven had thyroid disease some
years after premature ovarian failure, two showed hypothyroidism 1
and 7 years before the onset of premature ovarian failure, respectively,
and the patient with familial premature ovarian failure was diagnosed
with hyperthyroidism 14 years before the onset of premature ovarian
48 (2555) 49 (4155) 40 (2555)
failure. Since thyroid assessment at study entry was normal, all these
patients were considered eligible.
In summary a total of 71 (Milan, n 5 41; Varese, n 5 30)
phenotypically and chromosomally normal women with a diagnosis
of idiopathic premature ovarian failure were entered into the study.
The mean value of serum FSH levels was 77.33 6 23.68 UI/l.
No serum autoantibodies were found in the first 20 patients
specifically tested. The median age at menarche in both groups
was similar (13 years in the sporadic group and 12 years in
the familial group).
Menstrual history showed that 44 patients had eumenorrhoea
before the onset of premature ovarian failure (30 patients in
the sporadic group and 14 in the familial group); 24 patients
had episodes of eumenorrhoea/oligomenorrhoea before the
onset of premature ovarian failure (19 and five in the sporadic
and familial groups, respectively), while eight patients had
oligomenorrhoea since menarche (six in the sporadic and two
in the familial premature ovarian failure group).
Twenty-two (44.9%) pregnancies were recorded in the
sporadic group compared to 18 (81.8%) in the familial group
(P , 0.05, Fishers exact test). On ultrasound examination,
all ovaries showed an afollicular pattern with no sign of
ovarian activity and an endometrial thickness 5 mm. Table I
reports the age at menopause for the patients and their mothers.
Thirteen patients (26.5 %) in the sporadic group and four
(18.2 %) in the familial group were habitual smokers.
Results obtained from genetic counselling showed that 22 of
the 71 index cases (31.0%) had familial premature ovarian
failure, while the remaining 49 had the sporadic form of the
disorder. In the familial premature ovarian failure group,
pedigree analysis showed another 37 cases of premature
ovarian failure, for a total of 59 affected females.
All patients included in this study appeared to be
phenotypically normal on physical examination (normal height,
weight and habitus). No family showing blepharophimosis or
Figure 1. Pedigree of four premature ovarian failure families. A black circle indicates premature ovarian failure features and the Arabic
numbers in bold type the age at menopause.
with conditions related to cancer cluster nor families presenting
cases showing fragile X syndrome or other forms of mental
retardation were found. Figure 1 shows four of the most
significant familial premature ovarian failure pedigrees.
Pedigree analysis showed a vertical transmission of premature
ovarian failure in both centres, suggesting a dominant pattern
of inheritance. No families sharing only affected sibship were
Transmission was through either maternal (13 families) (see
family 1 in Figure 1 as example) or paternal (four families)
(see family 2 in Figure 1 as example) relatives. In addition,
five families (see family 3 in Figure 1) had both maternal and
paternal transmission. All transmitting males were
phenotypically normal and no consanguineous matings were reported.
Our pedigree analysis suggests either an autosomal or
Xlinked dominant sex-limited pattern of inheritance, irrespective
of maternal or paternal transmission. It is known that in cases
with an X-linked inheritance, all transmitting males will have
affected females. However, we recorded two families in which
the transmitting males had unaffected daughters over the age
of 45 years. This may be explained by incomplete penetrance
(see family 4 in Figure 1). In another family the transmitting
male had two daughters: one showing the premature ovarian
failure phenotype and the other undergoing menopause at the
age of 41 years.
Not all probands had premature ovarian failure mothers,
therefore the penetrance in our study was not complete (79.1%)
considering only female subjects. Interestingly, among the
non-penetrant group, two females from two different families
underwent early menopause at 44 and 45 years of age,
In addition, in the sporadic premature ovarian failure group,
we found eight index cases with mothers showing early
menopause between the ages of 41 and 45 years. Similar
genetic characteristics (percentage of familial cases and pattern
of inheritance) were recorded in both centres.
A clinical and genetic investigation was conducted in 71
patients with a diagnosis of idiopathic premature ovarian
failure. All patients were phenotypically and chromosomally
normal. Although other authors (Coulam et al., 1983, 1986;
Krauss et al., 1987; Riva et al., 1996; Sala et al., 1997) report
genetic information on premature ovarian failure patients, the
populations considered were not homogeneous. As far as we
know this is the first study performed in a homogeneous group
of patients with idiopathic premature ovarian failure.
Premature ovarian failure has been often considered as an
immunological disorder (Hoek et al., 1997), associated with
Addison or autoimmune thyroid diseases (Alper et al., 1985).
Moreover, premature ovarian failure patients with serological
evidence of autoimmunity and no sign of autoimmune disease
are frequently described (Wheatcroft, 1994). In a recent report,
Wheatcroft et al. (1997) showed the different results obtained
by the use of two different methods of antibody detection
(indirect immunofluorescence versus enzyme-linked
immunosorbent assay). Their results call into question the specificity
of ovarian antibodies as a marker for autoimmune premature
ovarian failure. Fenichel et al. (1997) also indicated the poor
prognostic value of the antibodies found in patients without
autoimmune disease. In our study no patient showed clinical
evidence of autoimmune diseases. The screening test performed
with the indirect immunofluorescence method in the first 20
subjects studied indicated uniformly negative results.
Genetic counselling performed in our study showed that
31% of the patients had familial premature ovarian failure and
this confirms that premature ovarian failure is a recognizable
heritable entity. A vertical transmission of the disease through
either maternal or paternal relatives was observed in this
population, suggesting either an autosomal or X-linked,
sexlimited dominant pattern of inheritance. Incomplete penetrance
may interfere with inheritance pattern assessments. In fact,
families having transmitting males with both normal and
affected daughters may be compatible either with an autosomal
dominant pattern or an X-linked pattern. Interestingly, two
non-penetrant females underwent menopause at 44 and 45
years of age, respectively.
The age of onset of ovarian failure may be variable,
suggesting a different pattern of expression of the same disease.
Moreover, the anticipation phenomenon should also be taken
into consideration. Anticipation is defined as a phenomenon
in which the age of onset of a disorder is reduced and/or the
severity of the phenotype is increased in successive generations
(Strachan and Read, 1996). The occurrence of anticipation
may be masked by expression variability. A recent study
(Conway et al., 1995) showed a correlation between
anticipation and FRAXA amplification, detected in a family showing
the premature ovarian failure phenotype. In our study no
family presenting cases showing fragile X syndrome or other
forms of mental retardation were found.
The pedigrees reported in this study strongly suggest the
existence of a familial pattern of premature ovarian failure
showing a dominant transmission in all cases. Nevertheless,
incomplete penetrance makes it difficult to distinguish an
autosomal pattern of inheritance from an X-linked one. Both
patterns share an obvious sex-limited transmission of the
Contrary to the study conducted by Aittomaki et al. (1995)
no pedigrees showing an autosomal recessive pattern of
inheritance were reported in our series. Nevertheless, the gene
mutation reported in the selected Finnish population with
primary amenorrhoea is a very rare condition.
Our findings on pedigrees sharing maternal and/or paternal
inheritance indicate the need for proper genetic counselling.
Theoretically, there is a similar genetic risk involved in the
recurrence of the disorder with both autosomal and X-linked
patterns of inheritance. In families with maternal transmission,
the risk of recurring premature ovarian failure is 50% (39.5%
corrected by penetrance), regardless of whether the pattern of
inheritance is X-linked or autosomal. On the contrary, in
families with paternal transmission, the risk is 100% (79.1%
corrected by penetrance) when the disorder has an X-linked
pattern of inheritance, but decreases to 50% (39.5% corrected
by penetrance) when the dominant pattern of inheritance is
autosomal. On this basis, pedigree analysis seems important
in assessing the reproductive risk.
Ovarian failure started later and the fertile period was longer
in the familial compared with the sporadic group. These data
show that patients with familial premature ovarian failure have
a better reproductive chance as compared to patients with
sporadic premature ovarian failure and strongly suggest the
need for a specific reproductive counselling.
The authors are indebted to Professor Pier Luigi Meroni and Doctor
Luisa Guidali for performing autoantibody assays. We would also
Aiman , J. and Smentek , C. ( 1985 ) Premature ovarian failure . Obstet. Gynecol., 66 , 9 - 14 .
Aittomaki, K. ( 1994 ) The genetics of XX gonadal dysgenesis . Am. J. Hum. Genet ., 54 , 844 - 851 .
Aittomaki, K. , Lucena , J.L. , Pakarinen , P. et al. ( 1995 ) Mutation in the folliclestimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure . Cell , 82 , 959 - 968 .
Alper , M.M. and Garner , P.R. ( 1985 ) Premature ovarian failure: its relationship to autoimmune disease . Obstet. Gynecol., 66 , 27 - 30 .
Amati , P. , Gasparini , P. , Zlotogora , J. et al. ( 1996 ) A gene for premature ovarian failure associated with eyelid malformation maps to chromosome 3q22-q23 . Am . J. Hum . Genet., 58 , 1089 - 1092 .
Beck , J. , Enders , H. , Schliephaeke , M. et al. ( 1994 ). X;1 translocation in a female Menkes patient characterization by fluorescent in situ hybridization . Clin. Genet ., 46 , 295 - 298 .
Blumenfeld , Z. , Halachmi , S. , Peretz , B.A. et al. ( 1993 ) Premature ovarian failure-the prognostic application of autoimmunity on conception after ovulation induction . Fertil. Steril., 59 , 750 - 755 .
Conway , G. , Hettiarachchi , S. , Murray , A. and Jacobs , P.A. ( 1995 ). Fragile X premutation in familial premature ovarian failure . Lancet , 346 , 309 - 310 .
Coulam , C.B. , Stringfellow , S. and Hoefnagel , D. ( 1983 ) Evidence for a genetic factor in the etiology of premature ovarian failure . Fertil. Steril., 40 , 693 - 695 .
Coulam , C.B. , Adamson , S.C. and Annagers , J.F. ( 1986 ) Incidence of premature ovarian failure . Obstet. Gynecol., 67 , 604 - 606 .
Cramer , D.W. , Huijuan , X. and Harlow , B.L. ( 1995 ) Family history as a predictor of early menopause . Fertil. Steril., 64 , 740 - 745 .
Delon , B. , Lallaoui , H. , Abel-Lablanche , C. et al. ( 1997 ) Fluorescent in situ hybridization and sequence-tagged sites for delineation of an X:Y translocation in a patient with secondary amenorrhoea . Mol. Hum. Reprod. , 3 , 439 - 443 .
Fenichel , P. , Sosset , C. , Barbarino-Monnier , P. et al. ( 1997 ) Prevalence, specificity and significance of ovarian antibodies during spontaneous premature ovarian failure . Hum. Reprod., 12 , 2623 - 2628 .
Hoek , A. , Schoemaker , J. and Drehage , H.A. ( 1997 ) Premature ovarian failure and ovarian autoimmunity . Endocr. Rev. , 18 , 107 - 134 .
ISCN ( 1995 ) Mittelman , F. (ed.), An International System for Human Cytogenetic Nomenclature Karger , Basel.
Krauss , C.M. , Turksoy , R.N. , Atkins , L. et al. ( 1987 ) Familial premature ovarian failure due to an interstitial deletion of the long arm of the X chromosome . N. Eng . J. Med., 317 , 125 - 131 .
Mattison , D.R. , Evans , M.I. , Schwimmer , W.B. et al. ( 1984 ) Familial premature ovarian failure . Am. J. Hum. Genet ., 36 , 1341 - 1348 .
Partington , M.W. , Moore , D.Y. and Turner , G.M. ( 1996 ) Confirmation of early menopause in fragile X carriers . Am. J. Med. Genet ., 64 , 370 - 372 .
Powell , C.M. , Taggart , R.T. , Drumheller , T.C. et al. ( 1994 ) Molecular and cytogenetic studies of an X; autosome translocation in a patient with premature ovarian failure and review of the literature . Am. J. Med. Gen. , 52 , 19 - 26 .
Preziati , D. , La Rosa , L. , Covini , G. et al. ( 1995 ) Autoimmunity and thyroid function in patients with chronic active hepatitis treated with recombinant interferon alpha-2a . Eur. J. Endocrinol. , 132 , 587 - 593 .
Riva , P. , Magnani, I. , Conti , A.M. et al. ( 1996 ) FISH characterization of the Xq21 breakpoint in a translocation carrier with premature ovarian failure . Clin. Genet ., 49 , 1 - 3 .
Sala , C. , Arrigo , G. , Torri , G. et al. ( 1997 ) Eleven X chromosome breakpoints associated with premature ovarian failure (POF) map to a 15-Mb YAC contig spanning Xq21 . Genomics , 40 , 123 - 131 .
Sankila , E.M. , Lehvaslaiho , H. , Engel , A.R . et al. ( 1995 ) Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure . Cell , 82 , 959 - 968 .
Schmidt , M. and Du Sart , D. ( 1992 ) Functional disomies of the X-chromosome influence the cell selection and hence the inactivation pattern in females with balanced X-autosome translocations: a review of 122 cases . Am. J. Med. Genet ., 42 , 161 - 169 .
Seller , M.J. , Kalyani , P. , Horsley , S. et al. ( 1995 ) A fetus with an X;1 balanced reciprocal translocation and eye disease . J. Med. Genet ., 32 , 557 - 560 .
Skibsted , L. , Westh , H. and Niebuhr , E. , ( 1984 ) X long arm deletions: a review of non-mosaic cases studied with banding techniques . Hum. Genet., 67 , 1 - 5 .
Strachan , T. and Read , A.P. ( 1996 ) Human Molecular Genetics . Wiley-Liss, New York, p. 589 .
Torgerson , D.J. , Thomas , R.E. and Reid , D.M. ( 1997 ) Mothers and daughters menopausal ages: is there a link? Eur . J. Obstet . Gynecol. Reprod. Biol., 74 , 63 - 66 .
Vianna-Morgante , A.M. , Costa , S.S. , Peres , A.S. and Verreschi , I. ( 1996 ) Fraxa premutation associated with premature ovarian failure . Am. J. Med. Genet ., 64 , 373 - 375 .
Wheatcroft , N.J. , Toogood , A.A. , Li , T.C. et al. ( 1994 ) Detection of autoantibodies to ovarian antigens in women with premature failure . Clin. Exp. Immunol. , 96 , 122 - 128 .
Wheatcroft , N.J. , Salt , C. , Milford-Ward , A. et al. ( 1997 ) Identification of ovarian antibodies by immunofluorescence, enzyme-linked immunosorbent assay or immunoblotting in premature ovarian failure . Hum. Reprod., 12 , 2617 - 2622 .
Received on October 20 , 1997 ; accepted on April 8, 1998