1 Department of Obstetrics and Gynaecology, Medical Center Alkmaar, Wilhelminalaan 12, 1815 JD Alkmaar, 2 Department of Obstetrics and Gynaecology and 3 Department of Human Genetics, University Hospital Nijmegen, and 4 Department of Obstetrics and Gynaecology, University Hospital Utrecht, The Netherlands
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Abstract |
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Key words: familial/idiopathic premature ovarian failure/incidence/inheritance
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Introduction |
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Genetic factors may play a role in premature ovarian failure (Coulam et al., 1983). One such factor might be located on the X-chromosome in a so-called critical region ranging from Xq13 to Xq26. This interval is based on cases with cytogenetic abnormalities concerning deletions in Xq or X-autosome translocations (Therman et al., 1990
; Powell et al., 1994
; Sala et al., 1997
). Mutation in the genes on the X-chromosome, such as the fragile X-premutation, can coincide with premature ovarian failure, although the mechanism is still unknown (Conway et al., 1998
).
The familial form of idiopathic premature ovarian failure offers the opportunity to study the mode of inheritance. The incidence of familial idiopathic premature ovarian failure seems to be quite low, around 4% (Starup and Sele, 1973; Conway et al., 1996
). Recently a much higher incidence of 31% in a group of 71 idiopathic premature ovarian failure patients has been reported (Vegetti et al., 1998
). Epidemiological studies also suggest a higher incidence of approximately 30% (Cramer et al., 1995
; Torgerson et al., 1997
). Furthermore there is evidence of a strong genetic factor determining age of menopause (Snieder et al., 1998
).
In these two studies we attempted to elucidate the genetic aspects of premature ovarian failure. The incidence study focused on the incidence of familial cases among idiopathic premature ovarian failure, whereas the pedigree study evaluated the mode of inheritance within the affected families.
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Materials and methods |
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Patients: pedigree study
Detailed pedigree studies were performed on families with at least two relatives with premature ovarian failure, excluding the index patient, to determine the mode of inheritance.
In order to increase the number of severely affected families, we also recruited families by advertising in the main national newspapers.
All index patients were diagnosed as having idiopathic premature ovarian failure. The definition of idiopathic premature ovarian failure was identical to that used in the incidence study. In the pedigree study the index patients were karyotyped, and screened for fragile X according to the routine procedure. Relatives of older than 40 years were diagnosed as having premature ovarian failure if their last menstrual period had been before or at the age of 40 years. In the relatives still under the age of 40 years, the same definition was applied as that used for the index patient. Age at menopause of between 41 and 45 years was referred to as early menopause.
Procedure
To avoid recall bias, we checked every family history in the incidence study with the index patient. When possible all alleged affected relatives were checked in person.
For the mode of inheritance study, all relevant relatives, affected and non-affected, were approached personally. A complete medical history was taken and a general physical examination was performed. The subjects gave informed consent for us to access their medical histories. Pedigrees were made based on the family history given by the index patient, after confirmation of the data by the relatives.
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Results |
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In total eight families were available for pedigree research. All index patients had a normal karyotype. No fragile X premutations were found in the index patients.
The pedigrees of families 2, 3, 4, 6, 7 and 8 are shown in Figure 1. The pedigrees of families 1 and 5 are not depicted, as evaluation of these families showed that they were not affected by premature ovarian failure. In order to maintain clarity, not all relatives are depicted.
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Family no. 2 (recruited from the incidence study)
The index patient experienced menopause at age 31 years. The age of menopause of her oldest sister could not be determined, as she had been put on continuous progestagens at around age 40 years. The second sister underwent total hysterectomy at age 40, while still having cycles. She developed climacteric symptoms around age 41. The third sister experienced menopause at age 38. The fourth sister experienced menopause at age 47. The last sister died in a car accident at age 17. The age of their mother at menopause (39 years) could not be confirmed, as she had died. The maternal aunts had also died. No information was available on their age at menopause. The brothers and the parents of the father of the index patient had died. The only sister could not be traced.
Co-morbidity in this family was a hearing impairment, which was not co-segregating with premature ovarian failure.
Family no. 3 (advertisement)
The respondent experienced menopause at age 29 years. Her elder sister is still having regular cycles at age 35. Her mother had two sisters. All three sibs experienced menopause at age 3536. All three women developed blepharoptosis, occurring in the fourth or fifth decade of life. Two of these women, and the index patient, suffered from congenital cataract. Only one of the affected aunts underwent early cataract surgery to improve sight.
Family no. 4 (advertisement)
The respondent was diagnosed as having premature ovarian failure at age 35 years. Her two sisters still have regular menstrual periods at age 32 and 31. Her mother experienced menopause at age 39. The age of menopause of the maternal grandmother is reported to be 38, but cannot be confirmed. The maternal aunt underwent total hysterectomy at age 37. She developed climacteric symptoms at age 41. The maternal grandmother had two brothers and three sisters. One of these grandmaternal sisters had seven children, five sons and two daughters. Another grandmaternal sister had three sons and the eldest grandmaternal sister only had one daughter, who died at a young age from meningitis.
Family no. 5 (advertisement)
The index patient was diagnosed as having premature ovarian failure at age 33 years. This family was reported to have seven affected relatives, apart from the index patient. When contacted none of the women appeared to have had a premature or early menopause (five members). Two relatives had died. We concluded that the respondent represented a sporadic case of premature ovarian failure.
Family no. 6 (advertisement)
The respondent experienced menopause at age 37 years. Two of her four sisters were affected. The older maternal generation had three unaffected sisters and two brothers. The father of the index patient had died. He had five brothers and four sisters. The only living sister was not willing to co-operate. There was no contact between the index patient or her siblings and the offspring of their father's siblings, so further evaluation could not be performed.
Family no. 7 (referred by the University Hospital of Utrecht)
The index patient was diagnosed as having premature ovarian failure at age 36 years. She had three brothers and seven sisters of whom four were affected. Her mother experienced menopause at age 47. She belonged to a family of 14 children, five men and nine women. One brother and one sister had died. Two of her sisters experienced menopause at normal age (48+ and 50 years). Her other five sisters were not willing to co-operate. The father of the index patient had four sisters of whom three had died. The only sister still living reported no history of premature ovarian failure. She had eight sons and two daughters, neither of whom was affected.
Family no. 8 (recruited from the incidence study)
The index patient was diagnosed as having premature ovarian failure at age 37 years. Her only sister is still having regular menstrual periods at age 39. Her mother and one of the three maternal aunts experienced premature menopause between the age of 35 and 38. The age of menopause of the maternal grandmother is unknown and cannot be determined, because of dementia. The maternal grandmother only had one brother. This brother had five daughters, of whom two participated in the pedigree study. One experienced menopause at age 53, while the other daughter was still having menstrual periods at age 52. The maternal grandfather only had one sister, who underwent a hysterectomy prior to age 40. She never had children.
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Discussion |
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The definition of premature ovarian failure varied widely between the studies. Some use the most restricted definition with an upper age limit of 30 years (Starup and Sele, 1973), others include patients until the age of 40 years with an amenorrhoea that exceeded 6 months with FSH levels of above 10 U/l (Conway et al., 1996
). Most authors use a definition based on an upper age limit of 40 years and FSH levels of above 40 U/l.
A definition of idiopathic premature ovarian failure was not explicitly mentioned in any of the studies. Thus, some authors give the incidence of familial cases based on the total premature ovarian failure population and others based on a selected population of idiopathic premature ovarian failure patients.
Given the minor differences in the above-mentioned definitions between the study by Vegetti et al. (Vegetti et al., 1998) and the present one, we postulate that recall bias may play an important role in explaining the differences in incidence of familial premature ovarian failure. The present study clearly showed positive recall bias. We did not find any evidence of the opposite, i.e. negative recall bias, in families with familial premature ovarian failure. However, we did not investigate the families of sporadic cases in detail. Positive recall bias might indicate an overestimation of familial premature ovarian failure in epidemiological studies in which most of the data were based on recollection. Finally, geographical location may have caused the variation in incidence of familial premature ovarian failure, because all the studies were carried out in different countries.
Families 1 and 5 are not informative on the subject of inheritance. However, since they underline the importance of direct confirmation of premature ovarian failure with the alleged affected relatives they are included in the results. The six informative families are not conclusive for patterns of inheritance. All modes of inheritance are possible, although not all are likely. Table II shows the likelihood of each mode of inheritance per family. Assuming there is one common mode of inheritance in the pathophysiology of familial premature ovarian failure, it is highly unlikely that this will be mitochondrial inheritance. In these pedigrees paternal transmission could not be excluded, which is a prerequisite to accept mitochondrial inheritance. Moreover, the pedigrees of families 4, 5 and 6 are suggestive of paternal transmission. Autosomal recessive inheritance as a common mode of inheritance is unlikely since many families show affected relatives in more than one generation. Thus, a common mode of inheritance would most likely be a dominant trait, either autosomal or X-linked. However, to accept X-linked inheritance in all families, incomplete penetrance has to be assumed in families 6 and 7. Incomplete penetrance might be caused by skewed X-inactivation.
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Fragile X premutations have been reported to be a significant risk factor in premature ovarian failure development (Allingham-Hawkins et al., 1999). Premature ovarian failure was shown to cosegregate with the fragile X premutation in families with the fragile X premutation. All index patients in the present study had normal FMR1 (fragile X mental retardation gene) repeat tract lengths. Therefore it is unlikely that premature ovarian failure is related to a fragile X premutation in these families.
In summary, the pattern of inheritance in this study is compatible with either X-linked or autosomal-dominant sex-limited, paternal and maternal, transmission. This is in agreement with previous studies (Starup and Sele, 1973; Coulam et al., 1983
; Mattison et al., 1984
; Vegetti et al., 1998
). Previously, autosomal dominant sex-limited transmission was thought to be the most likely mode of inheritance (Coulam et al., 1983
; Mattison et al., 1984
). Other authors favoured the concept of an X-linked transmission with incomplete penetrance (Vegetti et al., 1998
). We feel the data of our study do not support a greater likelihood of X-linked inheritance over autosomal dominant inheritance or vice versa. Still, considering the wide variety of X-chromosomal aberrations coinciding with premature ovarian failure, an X-linked trait would seem to be the most attractive option.
The large critical region for premature ovarian failure on the X-chromosome is almost incompatible with a single gene, so it has been postulated that premature ovarian failure is a multigenetic trait (Therman et al., 1990; Sala et al., 1997
). This may seem in conflict with evidence from the pedigree studies that indicate a dominant trait. However, if every gene were required for normal reproduction, these data would be in agreement. It would also explain why the average age of menopause within premature ovarian failure families tends to stay within a certain range, but differs between families.
Unfortunately we were not able to perform linkage analysis. The families were too small to obtain sufficient meioses. Most members of the older generations had died and many of the youngest generation were not yet informative. With the delay in childbirth seen in our country, there will be a tendency for premature ovarian failure patients not to reproduce at all unless they use oocyte donation. In this study only eight out of the 63 patients (12.6%) had one child or more. Therefore, if we want to perform linkage analysis, we have to study these families now. Registration and follow-up may still give us the missing information.
We conclude that the familial form of idiopathic premature ovarian failure is not as common as has been suggested by recent studies. This study showed the importance of meticulous screening of every premature ovarian failure patient and her alleged affected relatives. In families with premature ovarian failure the risk of other females developing premature ovarian failure will depend on the mode of inheritance and the mode of transmission. With autosomal dominant inheritance the risk of premature ovarian failure will be 50% with either maternal or paternal transmission. However, with X-linked inheritance and paternal transmission this risk may be as high as 100%. These risks will be smaller with incomplete penetrance. If a premature ovarian failure patient appears to be a sporadic case, the risk of other female relatives developing premature ovarian failure will probably be equal to the risk of the general population, around 1%. At present we can only advise females in affected families to have children at an early age (probably several years before the earliest age of menopause reported in the family). In the near future oocyte storage, in-vitro maturation, in-vitro fertilization, and intracytoplasmic sperm injection may become available.
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Notes |
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References |
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Submitted on April 6, 1999; accepted on June 25, 1999.