The idiopathic forms of premature menopause and early menopause show the same genetic pattern

Human Reproduction, Nov 1999

Genetic factors may influence the timing of menopause. Premature ovarian failure (POF) has recently been identified as a genetic entity, but no genetic data are available on early menopause (EM). We investigated 36 patients with EM (age of menopause between 40 and 45 years of age) using cytogenetic and pedigree analysis. In 30 patients of this study the EM was idiopathic and 15 subjects (50%) had a familial condition of EM or POF. Pedigree analysis revealed a dominant pattern of inheritance of EM through maternal or paternal relatives. Our data reveal that POF and EM patients show the same genetic features and we postulate that these conditions may be a variable expression of the same genetic disease.

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The idiopathic forms of premature menopause and early menopause show the same genetic pattern

M.G.Tibiletti 2 G.Testa 1 W.Vegetti 0 F.Alagna 0 M.Taborelli 2 L.Dalpra 3 P.F.Bolis 1 P.G.Crosignani 0 0 First Department of Obstetrics and Gynaecology, University of Milan , Via della Commenda 12, 20122 Milan 1 Obstetrics and Gynaecology Unit, Department of Clinical and Biological Sciences, University of Insubria , V.le Borri 57, 20121 Varese 2 Department of Clinical and Biological Sciences, University of Insubria, Ospedale di Circolo , V.le Borri 57, 20121 Varese 3 Department of Biology and Genetics for Medical Sciences, University of Milan , Via Viotti 3/5, 20133 Milan , Italy 5To whom correspondence should be addressed Genetic factors may influence the timing of menopause. Premature ovarian failure (POF) has recently been identified as a genetic entity, but no genetic data are available on early menopause (EM). We investigated 36 patients with EM (age of menopause between 40 and 45 years of age) using cytogenetic and pedigree analysis. In 30 patients of this study the EM was idiopathic and 15 subjects (50%) had a familial condition of EM or POF. Pedigree analysis revealed a dominant pattern of inheritance of EM through maternal or paternal relatives. Our data reveal that POF and EM patients show the same genetic features and we postulate that these conditions may be a variable expression of the same genetic disease. Introduction Over the past few decades, the timing of menopause has remained unchanged: the median age at menopause is currently around 50 years in Western industrialized society (Ginsburg, 1991; Sowers and La Pietra, 1995). Few surveys have reported the distribution of age at menopause in the general population (Coulam et al., 1986). Recently it was reported that the mean age at menopause is over 45 years in 8 8 % of women, under 45 in 9.7% (early menopauseEM), and under 40 years (premature ovarian failurePOF) in only 1.9% (Torgerson et al., 1997). In a large Italian study, Vegetti et al. (1998) showed that in one-third of the idiopathic POF patients this condition was an inheritable entity with a dominant maternal and/or paternal transmission characterized by incomplete penetrance. In addi tion three sporadic POF patients in that study shared an Xq interstitial deletion spanning from q22.3 to q26.3 (one case) and from q22-23 to qter (two cases). This finding confirms that a critical region of the X chromosome plays an important causative role in POF pathogenesis (Powell etal, 1994). Other authors reported familial and sporadic POF patients carrying Xq abnormalities and in particular large deletions spanning from q22-25 to qter and deletions in Xq26-27 (Krauss et al., 1987; Veneman etal., 1991; Tharapel etal., 1993; Ishizuka et al., 1997). Moreover recent and detailed cytogenetic studies have identified the region q21 on the X chromosome (Sala et al., 1997) as being critical and the Diaphanous gene mapping in Xq21.3 has very recently been proposed as a candidate gene for POF (Bione et al., 1998). On the contrary, very few data are reported in the literature on the EM condition. During a case-control study (Cramer et al., 1995), an association was observed between family history and EM, suggesting the presence of genetic factors as a cause of EM. In a study on patients with POF, EM, and menopause over the age of 45 (Torgerson et al., 1997), it was reported that a significant relationship existed between the menopausal age of mothers and daughters. A brilliant twin study (Snieder et al., 1998) demonstrated that genetic factors are determinants of age at menopause. Nevertheless, little is known of the genetic factors involved in EM. Because the menopause occurred between the ages of 40 and 45 in several female relatives of the POF index cases in the Italian study previously described (Vegetti et al., 1998), the authors decided to examine the families of patients with early menopause. The aim of this study therefore, was to investigate the presence of genetic factors that may influence the timing of menopause in EM patients. Materials and methods Between May 1996 and December 1998, we observed 81 POF patients (reported in Vegetti et al., 1998) and 36 patients who entered menopause between the ages of 40 and 45 years. The patients were recruited by the Reproductive Endocrinology Services, Department of Obstetrics and Gynecology 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 at least 6 months between the ages of 40 and 45 and follicle stimulating hormone (FSH) concentrations > 4 0 IU/l on at least two occasions. 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 obstetric history with previous pregnancy outcome, history of cigarette-smoking, alcohol consumption, and diet, clinical gynaecological examination, ultra sound pelvic evaluation and serum gonadotrophin assessment. For karyotyping, peripheral blood lymphocyte cultures were set up conventionally and incubated for 72 h. In order to obtain high resolution chromosomal spreads ( > 5 0 0 bands), 1 0 - 3 mmol/l methotrexate (MTX; Sigma, Italy) was added to cultures for 17 h and replaced, after washing, with 1.2 X 1 0 - 4 mmol/l thymidine (Sigma, St Louis, MO, USA) for an additional 4 h. Colcemid (Boehringer Mannheim, Mannheim, Germany) at a final concentration of 0.1 |ig/ ml was added for 10 min to the culture. Chromosome spreads and QFQ banding were prepared according to the standard methods. The reconstructed karyotypes followed the guidelines expressed in the International System for Chromosome Nomenclature 1995 (ISCN, 1995). For each karyotype a minimum of 20 cells was analysed and an additional 50 cells were assessed to exclude sex chromosome mosaicism. Family history was reviewed during genetic counselling and family members were traced back three generations. To avoid recall bias, each family history was carefully reviewed with the index patients and all affected members, when possible, were visited in person. Results Thirty-six patients with secondary hypergonadotrophic amenorrhoea between the ages of 40 and 45 years were identified. After screening, six patients were excluded from the study because of EM phenotype-related clinical conditions. Of the six excluded patients, four were withdrawn because of previous ovarian surgery, one because of congenital hypothyroidism and one because of an Xq deletion [karyotype: 46,XX, del(q21-q25)], revealed by chromosome analysis. A total of 30 patients was defined as idiopathic and analysed. The mean age at menopause was 42.3 1.2 years (range 41-44), the mean FSH concentration was 67.1 19.8 IU/l (41.2-105), the mean age at menarche was 12.6 1.6 years (9-15) and the mean duration of menstrual cyclicity was 29.3 2.3 years (22-34). Patients had a mean body weight of 60.0 7.4 kg (45-75) and a mean height of 159.1 5.2 cm (150-170). Twenty-four patients had had at least one previous conception and 20 of them delivered at least one child. Four patients had had a previous conception that had ended in mis carriage. Of the 30 patients, 10 were regular consumers of alcohol and 13 were smokers (more than five cigarettes per day). Medical history showed a previous dysthyroidism in two patients and two cases of cancer (breast cancer and chondrosarcoma) treated only with surgery. The mean maternal age at menopause was 45.8 5.5 (36-54) and pedigree analysis showed that 15 out of 30 index cases (50%) had a familial condition of EM. In addition, some relatives with POF were also recorded. Six of the families had relatives showing EM only, and nine had relatives showing both EM and POF, as summarized in Table I. Pedigree analysis revealed a dominant pattern of inheritance of EM through maternal (12 families) or paternal (three families) relatives. Figure 1 shows three pedigree examples with maternal (family 1) and paternal (family 2) transmission of EM. Family 3, shown in the same figure, reveals EM and POF conditions in the same pedigree. In all but one family, individuals showing EM or POF appeared to be phenotypically normal on physical examination. One EM index case showed congenital deafness, and so did the mother and one sister but they were of physiological age at menopause. Patient no. EM = early menopause. POF = premature ovarian failure. NA = not available, patient deceased before menopause. aThe number of EM and POF relatives indicates the number of females in the same family of the index case showing EM or POF features. bSurgical menopause. Discussion Physiological age at menopause is considered to be between 45 and 55 years. Much evidence has shown that menopausal age is influenced by environmental and genetic factors (Ginsburg, 1991). The hypothesis that a strong genetic factor may deter mine the occurrence of POF has been suggested in the literature (van Starup and Sele, 1973; Coulam et al., 1983; Mattison et al., 1984; Snieder etal., 1998). Two recent epidemiological studies have suggested that EM may have genetic determinants (Cramer etal., 1995; Torgerson etal., 1997). In a previous study (Vegetti et al., 1998) a group of POF patients showed E M relatives. This finding prompted us to examine the EM patients more carefully. Fifty per cent of the EM cases examined in the present study had a familial condition of EM and pedigree analysis suggested a dominant X-linked or an autosomal pattern of inheritance. Both patterns shared an obvious sex-limited transmission of the disorder. In this study we found the presence of a familial pattern of EM, as well as the concomitant condition of POF and EM in the same family. This latter finding strongly suggests that there is a genetic relationship between EM and POF. Because EM patients have genetic features similar to those observed in patients with POF, this may suggest that E M is Genetics of early menopause Family 3 due to the same genetic causes as POF. This hypothesis is in agreement with preliminary observations (Cramer et al., 1995; Torgerson etal., 1997) from which a correlation was postulated between family history and the occurrence of early menopause. In a population of 344 women with menopause before the age of 46 years, it was found that 37.5% of cases were familial (POF and EM patients were analysed together) (Cramer et al., 1995). These workers obtained an odds ratio of 6.1 (95% CI 4.0-9.3) for the disease associated with family history of the same condition. It has been found, in a population of patients with premature and physiological menopause, that age at menopause depended on the maternal age at menopause (Torgerson et al., 1997). The present study is the first that examines and characterizes families showing the recurrence of EM. The high percentage of familial cases (50%) found in this study is probably due to the small sample size. Nevertheless, all the affected relatives were visited in person in order to avoid recall bias. From a clinical point of view, we did not find any difference in clinical and gynaecological history between POF (Vegetti et al., 1998) and EM patients in this study. As expected, patients with EM showed a more favourable reproductive performance due to the later onset of menopause compared to POF patients: 80% of EM patients (24 out of 30) experienced at least one previous pregnancy compared with the 56.3% already reported (Vegetti et al., 1998) in POF patients. The percentage of patients who experienced at least one miscarriage is similar: 2 5 % in EM patients and 24.6% in POF patients. In conclusion, this study suggests that idiopathic POF and EM, differing only in age of menopause onset, may represent a variable expression ofthe same genetic disease. The different age of menopause onset in these patients may be explained by genetic heterogeneity and/or by different environmental factors. Otherwise these results suggest that the timing of menopause is controlled by different genes probably located on the X chromosome. Genetic mutations (chromosome dele tions or molecular mutations) of one or more genes may explain the premature or early onset of menopause. A linkage analysis in POF and E M families is currently in progress and preliminary results on haplotype-sharing are in agreement with an X-linked mode of inheritance. Acknowledgements This work was supported by grants from I.S.S., 93/G/T28. The authors would like to thank Yvonne Pomposo for her assistance in the preparation of the manuscript.


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M.G. Tibiletti, G. Testa, W. Vegetti, F. Alagna, M. Taborelli, L. Dalprà, P.F. Bolis, P.G. Crosignani. The idiopathic forms of premature menopause and early menopause show the same genetic pattern, Human Reproduction, 1999, 2731-2734, DOI: 10.1093/humrep/14.11.2731