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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-2521
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 6 2223-2229
Copyright © 2008 by The Endocrine Society

Fertility and Obstetrical Complications in Women with LMNA-Related Familial Partial Lipodystrophy

M. C. Vantyghem, D. Vincent-Desplanques, F. Defrance-Faivre, J. Capeau, C. Fermon, A. S. Valat, O. Lascols, A. C. Hecart, P. Pigny, B. Delemer, C. Vigouroux and J. L. Wemeau

Departments of Endocrinology and Metabolism (M.C.V., D.V.-D., F.D.-F., J.L.W.), Diabetology (C.F.), and Biochemistry and Hormones (P.P.), Lille University Hospital, and Institut National de la Santé et de la Recherche Médicale U859 (M.C.V.), 59037 Lille France; UPMC (J.C., OL., C.V.), University of Paris 06, and Institut National de la Santé et de la Recherche Médicale (J.C., OL., C.V.), UMR_S 893Eq9, and Département de Biologie Moléculaire (O.L.), Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, F-75012, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Tenon (J.C., C.V.), Service de Biochimie et Hormonologie, F-75020, Paris, France; Department of Obstetrics (A.S.V.), General Hospital, Lens 62 300, France; and Department of Endocrinology (A.C.H., B.D.), Reims University Hospital, Reims 51092, France

Address all correspondence and requests for reprints to: M. C. Vantyghem, Service d’Endocrinologie-Métabolisme Clinique Linquette, 6 Rue du Pr Laguesse, Centre Hospitalier Régional et Universitaire de Lille F-59037, Lille, France. E-mail: mc-vantyghem{at}chru-lille.fr.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Objective: Familial partial lipodystrophy due to LMNA (lamin A/C) mutations is a rare disorder characterized by a selective loss of adipose tissue and insulin resistance. Dyslipidemia and severe diabetes often occur during its evolution. Only isolated and contradictory case reports have been published on the obstetrical prognosis in lipodystrophy. The aim of our study was to compare the fertility and occurrence of obstetrical complications of women with familial partial lipodystrophy due to LMNA (lamin A/C) mutations with those of nonaffected relatives, women from the general population, and women with polycystic ovary syndrome (PCOS).

Material and Methods: Data were obtained from clinical follow-up of seven families with patients exhibiting mutations in LMNA (five R482W, one R482Q, one R439C) (14 affected among 48 women).

Results: The mean number of live children per woman was 1.7 in affected patients vs. 2.8 in nonaffected relatives. Fifty-four percent of LMNA-mutated women exhibited a clinical phenotype of PCOS, 28% suffered from infertility, 50% experienced at least one miscarriage, 36% developed gestational diabetes, and 14% experienced eclampsia and fetal death. Mean blood leptin level was significantly lower in LMNA-mutated patients than in nonaffected relatives (5.0 ± 3.8 ng/ml vs 14.3 ± 3.6; P < 0.001) despite similar body mass index (21.0 ± 4.2 vs 22.4 ± 2.2; P = 0.49).

Conclusion: In these LMNA-linked lipodystrophic patients, the prevalence of PCOS, infertility, and gestational diabetes was higher than in the general population. Moreover, the prevalence of gestational diabetes and miscarriages was higher in lipodystrophic LMNA-mutated women than previously reported in PCOS women with similar body mass index. Women with lipodystrophies due to LMNA mutations are at high risk of infertility, gestational diabetes, and obstetrical complications and require reinforced gynecological and obstetrical care.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
Lipodystrophies, whether familial or acquired, generalized or partial, are rare disorders characterized by a selective but variable loss of adipose tissue (1, 2). The main subtypes of familial lipodystrophy are autosomal recessive generalized lipodystrophy, linked to mutations in either BSCL2 encoding seipin or BSCL1 encoding 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) genes, and autosomal dominant partial lipodystrophies, due to alterations in the PPARG or LMNA genes. Familial partial lipodystrophy of the Dunnigan type (FPLD2, OMIM 151660) is due to heterozygous mutations in the LMNA gene. It becomes clinically apparent after puberty and is characterized by loss of fat affecting the limbs and trunk, accumulation of fat in the neck and face, and insulin resistance with metabolic alterations such as glucose intolerance or diabetes, dyslipidemia, high blood pressure, and liver steatosis, increasing the risk for coronary heart disease and polycystic ovaries (PCOS). Phenotypes of diseases linked to LMNA alterations, collectively called laminopathies, express great variability. We recently reported that patients with LMNA-linked metabolic syndrome are characterized by severe insulin resistance, which predisposes to PCOS (3). Indeed, it has been shown that laminopathies are an etiological diagnosis of PCOS (4, 5).

Little is known about the fertility and obstetrical prognosis of lipodystrophic women. Isolated publications on acquired or congenital lipodystrophy have reported either complicated (6, 7, 8, 9, 10, 11, 12, 13) or successful (14, 15, 16, 17, 18) pregnancies in such patients. However, because all these case reports except one (9) were published before genetic diagnosis was available, the clinical and metabolic profiles of patients were very heterogeneous, involving partial or generalized, genetic or acquired lipodystrophy with or without signs of autoimmunity and with or without diabetes (6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18).

The aim of this study was to compare the fertility and obstetrical complications of LMNA-linked lipodystrophic women with those of nonaffected relatives, the general population, and women affected by PCOS.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Our study was retrospective, based on data obtained during genetic counseling or follow-up driven by the same clinician (M.C.V.) in the endocrinology and metabolism department of a university hospital between 2000 and 2005. All patients received clinical and biological assessment after a case of lipodystrophy had been diagnosed in their family. Patients belonged to seven families, which were affected by FPLD2 linked to LMNA mutations (five R482W, one R482Q, one R439C) (14 mutated among 48 women). In addition, clinical and biological data were obtained at the beginning of their pregnancy from four probands issued from the seven families.

Comparisons between data from affected and nonaffected subjects were made using a Student t test.


   Results
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 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Fertility and obstetrical data recorded in seven LMNA-linked families (Table 1GoGo)

The seven LMNA-linked families included 48 women and 46 men, 14 and six being affected with LMNA mutations, respectively. The metabolic status of the 14 affected women (when nonpregnant) is reported in Table 1GoGo: nine of 14 had diabetes, three of which required insulin, three had glucose intolerance, and eight exhibited hypertension (19). Mean fasting blood leptin level was 5.0 ± 3.8 in LMNA-mutated patients [body mass index (BMI) 21.0 ± 4.2 kg/m2] and 14.3 ± 3.6 ng/ml in nonmutated relatives with similar BMI (22.4 ± 2.2 kg/m2) (P < 0.001 for leptin values and P = 0.495 for BMI). Fifty-four percent (seven of 13) of LMNA-mutated women whose data were available had a clinical phenotype of PCOS (spaniomenorrhea and hirsutism with no other known cause). Fifty percent of these women had experienced at least one miscarriage, and 28% of their pregnancies ended with a miscarriage. Four of 11 LMNA-mutated women (36%) had gestational diabetes (they were not diabetic before pregnancy), and seven had gestational diabetes and/or fetal macrosomia. Three other women had a known diabetes before pregnancy. Two women with LMNA mutations (14%) experienced eclampsia and fetal death. The mean number of live children per woman was 1.7 in LMNA-mutated patients vs. 2.8 in the 34 nonaffected relatives included in the study (P = 0.06). This number was higher in the mildly affected than in the severely affected patients: LMNA-mutated women with diabetes before pregnancy could not give birth to live children due to infertility or miscarriages.


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  		TABLE 1. Gynecological and obstetrical status in female LMNA-mutated subjects

 

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  		TABLE 1A. Continued

 
Data from four women with LMNA mutations studied before and at the beginning of their pregnancy are given in Table 2Go. Note that all patients became pregnant after the introduction of metformin, associated with a weight loss due to intercurrent surgery in patient M-I-1, insulin discontinuation in patient K-III-1, and diet in patient P-I-1. No weight loss was noticed just before pregnancy in patient H-III-1. Patients M-I-1, P-I-1, and H-III-1 exhibited gestational diabetes, requiring transient insulin therapy in two of them. In patient P-I-1, gestational diabetes was managed with dietary guidelines, but she had a cesarean section for slow labor, possibly related to a myopathic component. Patient K-III-1, who had complicated insulin-requiring diabetes, experienced two spontaneous miscarriages. Her first pregnancy occurred unexpectedly after discontinuation of insulin and introduction of rosiglitazone. Patients M-I-1, P-I-1, and H-III-1 gave birth to apparently normal live children. The female babies (two of three) did not show any signs of virilism. Blood pressure levels remained similar to the prepregnancy values in all four patients, patient K-III-1 being the only one to exhibit slight hypertension (140/90 mm Hg). Liver enzymes remained unchanged in all four patients.


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  		TABLE 2. Case records of four LMNA-mutated women before and at the onset of pregnancy

 
Comparison of fertility and obstetrical complications found in our LMNA-linked lipodystrophic women with those previously reported in the general population and treated and nontreated PCOS women (Table 3Go)

The prevalence of PCOS, infertility, miscarriages, gestational diabetes, and/or macrosomia and eclampsia or fetal death was much higher in LMNA-mutated women than in the general population (20, 21, 22, 23, 24, 25, 26, 27).


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  		TABLE 3. Comparison of fertility and obstetrical complications between LMNA-linked lipodystrophic patients, general population, and treated and nontreated PCOS population

 
In women with PCOS, the prevalence of infertility is correlated with BMI: an estimated 20% in women with a BMI between 17 and 20 kg/m2, and it reaches 50% when BMI is beyond 35 kg/m2 (28). Therefore, the prevalence of infertility of 28.5% in the 14 LMNA-mutated women, whose mean BMI was 21.0 ± 4.2 kg/m2, was higher than that reported in PCOS. The prevalence of miscarriages is controversial in PCOS but was recently measured at 9–19% in metformin-treated PCOS women, regardless of their BMI, which is lower than the range found for our patients (50%) (29, 30). The frequency of eclampsia is also debated, but the reported prevalence of 1.5 of severe forms to 10.5% of mild forms in PCOS is lower than what we observed in LMNA-mutated lipodystrophic patients (14%) (26, 29, 31). Also, the prevalence of gestational diabetes we found (36% increasing to 50% if macrosomia was taken into account) was higher than that observed in PCOS (4.9–20%) (25, 26, 29, 31).


   Discussion
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Fertility was impaired and obstetrical complications were frequent in the 14 studied LMNA-mutated lipodystrophic women: prevalence of PCOS was more than 50%, infertility close to 30%, miscarriages reached 50%, gestational diabetes at least 30%, and preeclampsia and fetal death above 10%. These were all higher than those found in the general population (Table 3Go) (20, 21, 22, 23, 24, 25, 26, 27). Also, the mean number of live children per lipodystrophic woman tends to be lower than in nonaffected relatives and was also lower than the national reference population range, even though this statement has to be taken cautiously due to the small size of our sample for this rare disease (Table 3Go).

PCOS is a well-known risk factor of infertility and is associated with insulin resistance (25, 26, 28, 29, 30, 31). More than half of the studied LMNA-mutated women were affected with PCOS. Therefore, we wished to compare our results with those previously reported in women with PCOS. In the lipodystrophic patients, the rate of infertility was higher than in PCOS women of similar BMI (28). Similarly, miscarriages, gestational diabetes, and eclampsia or fetal death were less prevalent in PCOS, treated or not, than in the LMNA-mutated patients.

Therefore, the prevalence of most infertility and obstetrical issues was not only higher than in general population but also higher than in PCOS.

The poor prognosis of pregnancy in lipodystrophic women has been suggested in some publications (6, 7, 8, 9, 10, 11, 12, 13) and is probably multifactorial, gestational or preexisting diabetes and hypertension being well-known risk factors (32, 33). Indeed, 10 of 14 LMNA-mutated patients were diabetic at the time of pregnancy or had fetal macrosomia, and three of 14 suffered from hypertension during pregnancy.

Increased insulin resistance during pregnancy is a well-known phenomenon but could in this case be reinforced by a specific deleterious effect of estrogens. Indeed, the clinical expression of lipodystrophy due to LMNA mutations occurs at puberty and is more severe in females, suggesting that estrogens could play a role in the expression of the disease (34, 35). Recent data have shown that certain polymorphisms of the estrogen receptor-{alpha} were associated with metabolic syndrome (36). Interactions between estrogens and metabolism could involve the estrogen-dependent regulation of lipin 1, a key regulator of glycerolipid use, which is also a candidate gene for lipodystrophies (37).

Conversely, LMNA mutations could be potentially deleterious for fetal development and viability, as shown in the most severe forms of laminopathy leading to neonatal restrictive dermopathy (38).

The low leptin levels, which are one of the features of FPLD, could play a role in the lower fecundity of lipodystrophic patients. Leptin therapy has been shown to reverse amenorrhea in women with generalized forms of lipoatrophy (39). Nevertheless, high blood leptin levels are associated with infertility in PCOS (40), in which the correlation between leptin, insulin, and visceral fat is lost (41). This divergence in leptin levels between infertile PCOS and FPLD could be attributed to not only fat mass but also fat repartition: it has been recently shown that fat is globally distributed in PCOS, whereas it is supraclavicular and abdominovisceral in FPLD (42, 43).

The pregnancies of the four LMNA-mutated women reported here (five pregnancies, with two miscarriages for the same woman) were all achieved, with the patients taking insulin sensitizers (metformin in four cases, rosiglitazone in one case). The benefits of metformin in improving ovulation and fertility have been well demonstrated (30, 31), and the positive effect of rosiglitazone has recently been emphasized (44). Nevertheless, the lack of deleterious effect on the embryo remains to be shown for rosiglitazone. Three of these pregnancies were uneventful except for gestational diabetes, ending with the delivery of clinically normal babies. All these women had been offered genetic counseling before pregnancy. None of them asked for a prenatal diagnosis despite the fact that one had noticeable hyperandrogenism. The two pregnancies of the oldest patient led to miscarriages (one with metformin plus insulin, one with metformin and rosiglitazone). Besides the different factors possibly involved in this outcome and listed above, increased androgens after the occurrence of pregnancy could have interfered, as already demonstrated (45). Nevertheless, the level of total androgens was similar in this patient than to that of the two other patients who gave birth to live female children with no signs of virilization, probably due to the concomitant increase of sex-hormone binding protein. Note that metformin and rosiglitazone administration induced a marked, albeit transient, decrease of serum testosterone (Table 2Go).

In conclusion, fertility and obstetrical complications were found to be highly prevalent in LMNA-linked lipodystrophic women. These results suggest that patients suffering from metabolic laminopathies should receive reinforced gynecological and obstetrical care.


   Acknowledgments
 
We thank the European Commission (Specific Targeted Research Project FP6 "Eurolaminopathies") for its support.


   Footnotes
 
Disclosure Statement: The authors have nothing to disclose.

First Published Online March 25, 2008

Abbreviations: BMI, Body mass index; FPLD2, familial partial lipodystrophy of the Dunnigan type; PCOS, polycystic ovary syndrome.

Received November 13, 2007.

Accepted March 13, 2008.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals