Persistent autonomous ovarian dysfunction in McCune-Albright syndrome
      (MAS) patients is associated with the development of multiple dominant
      follicles, premature luteinization, cyst formation, and anovulatory
      infertility. Due to the mosaic distribution of the mutation, ovaries may
      be unequally affected. In the current patient, the least affected ovary
      became quiescent upon GnRH agonist-induced gonadotropin suppression.
      Normoovulatory cycles were restored after subsequent removal of the
      affected right ovary, and a pregnancy was established within 3 months. A
      healthy unaffected girl was born at term after an uneventful pregnancy.
      The placental tissue was normal, and the mutation was not detected in the
      placenta, umbilical cord structures, or umbilical cord blood. GnRH analog
      administration may help to identify those MAS patients who might benefit
      from unilateral ovariectomy. Because a healthy baby was born, evidence is
      provided suggesting that MAS is not passed on to the children from the
      parents

Fauser, B.C.J.M. (Bart)

Laven, J.S.E. (Joop)

Lumbroso, S.

Sultan, C.

Erasmus University Digital Repository

Management of Infertility in a Patient Presenting withOvarian Dysfunction and McCune-Albright SyndromeJOOP S. E. LAVEN, SERGE LUMBROSO, CHARLES SULTAN, AND BART C. J. M. FAUSERDivision of Reproductive Medicine, Department of Obstetrics and Gynecology (J.S.E.L, B.C.J.M.F.), Erasmus MedicalCenter, 3015 GD Rotterdam, The Netherlands; Department of Hormonology (S.L.), University Hospital Montpellier, 34295Montpellier, France; and Department of Hormonology and Unit of Pediatric Endocrinology and Gynecology, Department ofPediatrics (C.S.), University Hospital Montpellier, 34295 Montpellier, FrancePersistent autonomous ovarian dysfunction in McCune-Albright syndrome (MAS) patients is associated with the de-velopment of multiple dominant follicles, premature lutein-ization, cyst formation, and anovulatory infertility. Due to themosaic distribution of the mutation, ovaries may be unequallyaffected. In the current patient, the least affected ovary be-came quiescent upon GnRH agonist-induced gonadotropinsuppression. Normoovulatory cycles were restored after sub-sequent removal of the affected right ovary, and a pregnancywas established within 3 months. A healthy unaffected girlwas born at term after an uneventful pregnancy. The placen-tal tissue was normal, and the mutation was not detected inthe placenta, umbilical cord structures, or umbilical cordblood. GnRH analog administration may help to identify thoseMAS patients who might benefit from unilateral ovariectomy.Because a healthy baby was born, evidence is provided sug-gesting that MAS is not passed on to the children from theparents. (J Clin Endocrinol Metab 89: 1076–1078, 2004)POLYOSTOTIC FIBROUS DYSPLASIA, cafe´ au lait spots,sexual precocity, and hyperfunction of multiple endo-crine glands constitute the key features of McCune-Albrightsyndrome (MAS). The syndrome is due to a somatic muta-tion in the GNAS1 gene (1, 2). Missense point mutations atcodon 201 substituting Arg with either Cys or His give riseto abnormal Gs proteins that reduce the intrinsic guanosinetriphosphatase activity, thereby constitutively activating theGs protein (3–5). The extent and nature of the abnormality arehighly variable, depending on the specific tissues involveddue to the mosaic distribution of the GNAS1 mutation (3).The most commonly encountered endocrine dysfunctionin MAS is gonadal hyperfunction. Precocious puberty rep-resents the usual initial manifestation of MAS in girls. Ovar-ian cysts may be found upon pelvic ultrasound (6, 7). Otherendocrine abnormalities include hyperfunction of the thy-roid and adrenal cortex as well as excessive GH secretion.The majority of patients have abnormally elevated sex ste-roids with low or undetectable gonadotropin levels. Al-though pregnancies have been described later in life (8–10),polymenorrhea and amenorrhea due to continued gonado-tropin-independent estrogen production have also beenreported (6, 11). However, clinical information regardingovarian dysfunction in McCune-Albright patients during ad-olescent and adult life is scant.In a recent paper, we provided evidence for persistentautonomous unilateral ovarian dysfunction in an adultwoman suffering from MAS. Because MAS patients show atypical unilateral involvement of symmetrical tissues, themutation is usually only present or more abundant in eitherone of the ovaries. Increased FSH and LH signaling gave riseto the development of multiple dominant follicles, prematureluteinization, anovulation, and cyst formation in the affectedovary. As a result of the sex steroid-rich endocrine environ-ment, gonadal function in the unaffected contralateral ovaryis usually also disturbed. Endometrial function may be alsodisrupted presumably due to elevated progesterone levelsthroughout the cycle, implying that embryo implantationmight be severely compromised, representing an additionalfactor in infertility (11). Hence, removal of the affected ovarymight restore a normal endocrine environment, and subse-quently normal ovarian function might be restored in theremaining gonad, rendering these patients fertile.Case ReportA 22-yr-old patient previously diagnosed as having MAS attendedour outpatient clinic for fertility counseling. She exhibited the classicalclinical triad of polyostotic fibrous dysplasia, along with large cafe´ aulait spots in the lumbosacral region and a history of precocious pubertyand irregular menstrual bleeding. DNA analysis revealed a mutation(201 Arg to His) present in the right ovary only, as well as in theendometrium (11). As previously described, increased FSH and LHsignaling gave rise to the development of multiple dominant follicles,premature luteinization, anovulation, and cyst formation in the affectedovary. The function in the contralateral unaffected ovary was also dis-turbed due to continuously elevated sex steroid levels (11).In an attempt to suppress the function of the unaffected ovary, aGnRH agonist (Zoladex, AstraZeneca, Zoetermeer, The Netherlands)known to induce suppression of pituitary gonadotropin release wasadministered for 1 month. This investigation was performed to test thehypothesis that the unaffected ovary would be rendered quiescent dueto the lack of tropic support, whereas the affected ovary would continueto function autonomously. Weekly transvaginal ultrasound showed aprogressive disappearance of ovarian cysts in the left ovary duringGnRH agonist administration, indicating that this ovary is normallyresponsive to FSH and LH. In contrast, the affected ovary on the rightside did not respond and continued to function abnormally.These results as well as the experimental nature of the proposedunilateral ovariectomy were discussed extensively in our team and withAbbreviation: MAS, McCune-Albright syndrome.JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the en-docrine community.0021-972X/04/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 89(3):1076–1078Printed in U.S.A. Copyright © 2004 by The Endocrine Societydoi: 10.1210/jc.2003-0312451076 on November 7, 2006 jcem.endojournals.orgDownloaded from the patient. Moreover, the local Institutional Review Board was in-formed before the investigations had been carried out. Because only onefully informed patient was involved, a research protocol approval wasnot required. Subsequently, unilateral ovariectomy was performedthrough laparoscopy under general anesthesia. Upon laparoscopy, anenlarged (5 5 8-cm) cystic ovary was easily removed. Care was takento leave the fallopian tube on the right side intact. The left ovary had anormal appearance, as had the remaining internal genital organs. Sec-tions of the left ovary were prepared as previously described (11). Uponmicroscopic examination, primordial, primary, and secondary folliclesalong with Graaffian structures were found. Although all stages offollicular development were present, larger follicles were luteinizedwithout exception. The mutation was readily detectable throughout theremoved ovary. Again, both canonical and mutant sequences presentwere indicative of the mosaic nature of the disease.The patient recovered rapidly after the operation, and a regular men-strual cycle (28–30 d) was immediately restored. During the third cycle,she spontaneously conceived after a previous 4-yr period of infertility.After an uneventful pregnancy, at 40 wk a healthy daughter weighing3800 g was delivered vaginally. The placenta appeared normal (650 g),and the baby displayed no external stigmata of MAS. The placentaltissue was normal on microscopic examination. No evidence of theGNAS1 mutation was found in the placenta, umbilical cord, or cordblood (Fig. 1). The daughter is now 11⁄2 yr old, and her developmentremains normal.DiscussionThe current findings suggest that it may be useful to applyan in vivo test using a GnRH agonist to investigate whetherthe least or nonaffected ovary in MAS patients is normallyresponsive to diminished stimulation by gonadotropins.Moreover, the current case history provides evidence to sup-port the concept that in adult MAS patients with persistentunilateral autonomous ovarian activity, ovarian and endo-metrial function can be restored through removal of theaffected ovary. Finally, because an unaffected healthydaughter was born, this report provides further evidence thatMAS is caused by an autosomal dominant lethal gene that iscompatible with viability of the conceptus only when it oc-curs in the mosaic state. Hence, MAS results from a somaticmutation and therefore may not be inherited through anaffected parent.Our patient showed a typical unilateral involvement oftissue because the mutation was only found in the rightpolycystic ovary. This might be due to either a reducednumber or an absence of mutated cells present in the leftovary not being detected by DNA analysis (11). Neverthe-less, this difference in expression of the mutation seems to becompatible with normal monofollicular growth in the leftovary. However, this potentially normal ovary was still dys-functional as a result of the abnormal sex steroid-rich endo-crine environment induced by its affected counterpart. Re-moval of the right ovary might restore normal function of theremaining left ovary and should be considered. Testingwhether this is a feasible approach may be done using an invivo GnRH agonist test. If the unaffected ovary becomesquiescent under GnRH analog administration, it may bejustified to remove the affected ovary. The abnormal endo-crine environment, which may also affect both oocyte andendometrial function and, consequently, the outcome of invitro fertilization, cannot be otherwise corrected. Hence,ovariectomy may constitute the only treatment option insymptomatic adult MAS women (11).It has been postulated that the presence of mutated cellsin the endometrium might also compromise endometrialreceptivity and natural fertility (11). Surprisingly, this seemsnot to be the case because the patient conceived readily afterovariectomy. Because the mutated endometrial cells wereonly found in the anterior lining of the uterus, the remainingendometrium was apparently functionally normal. More-over, nidation and placentation, as observed by ultrasoundscans during early pregnancy, took place in the posteriornonaffected endometrial lining.Happle (3) made the intriguing suggestion that this dis-order is caused by an autosomal dominant lethal gene thatis compatible with viability of the conceptus only when itoccurs in the mosaic state, having arisen by somatic muta-tion. MAS has been reported to occur in one set of monozy-gotic twin girls of whom only one showed major signs ofMAS whereas the other showed only mild radiological signsof the disease (12). However, the lack of fully convincingfamilial cases is consistent with the mosaic mutation hypoth-esis. In the present case, the daughter displayed no signs ofMAS. Because the mutation analysis was also negative, sheis unlikely to be affected. This provides further evidence forthe Happle hypothesis, hereby excluding any possibility oftransmission from the parents.In conclusion, the present report shows that normal ovar-ian and reproductive function in MAS patients can be re-stored through unilateral ovariectomy, provided the unaf-fected ovary is successfully suppressed upon GnRH agonistFIG. 1. Direct DNA sequencing showed the presence of a guanine toadenine transversion (G/A*) leading to an Arg-His substitution atposition 201 in the right ovary. Both canonical and mutant sequenceswere present, the latter with a weaker intensity (green) indicating amosaicism of normal and abnormal cells. The mutation was not de-tectable in the left ovary or in the placental tissue.Laven et al. • McCune-Albright Syndrome and Infertility J Clin Endocrinol Metab, March 2004, 89(3):1076–1078 1077 on November 7, 2006 jcem.endojournals.orgDownloaded from administration. Furthermore, evidence is provided that MASmight not be passed on to children by their parents.AcknowledgmentsReceived July 18, 2003. Accepted November 21, 2003.Address all correspondence and requests for reprints to: Joop S. E.Laven, M.D., Ph.D., Division of Reproductive Medicine, Department ofObstetrics and Gynecology, Erasmus Medical Center, Dr. Molewater-plein 40, 3015 GD Rotterdam, The Netherlands. E-mail: j.laven@erasmusmc.nl.References1. Albright S, Butler AM, Hampton AO, Smith P 1937 Syndrome characterizedby osteitits fibrosa disseminata, areas of pigmentation and endocrine dys-function, with precocious puberty in females. N Engl J Med 216:727–7462. McCune DJ, Bruch H 2000 Osteodystrophia fibrosa. Am J Dis Child 54:806–8483. Happle R 1986 The McCune-Albright syndrome: a lethal gene surviving bymosaicism. Clin Genet 29:321–3244. Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM1991 Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med 325:1688–16955. Schwindinger WF, Francomano CA, Levine MA 1992 Identification of amutation in the gene encoding the  subunit of the stimulatory G protein ofadenylyl cyclase in McCune-Albright syndrome. Proc Natl Acad Sci USA89:5152–51566. Kaufman FR, Costin G, Reid BS 1986 Autonomous ovarian hyperfunctionfollowed by gonadotrophin-dependent puberty in McCune-Albright syn-drome. Clin Endocrinol (Oxf) 24:239–2427. Escobar ME, Gryngarten M, Domene H, Ropelato G, Lopez MR, Bergada C1997 Persistence of autonomous ovarian activity after discontinuation of ther-apy for precocious puberty in McCune-Albright syndrome. J Pediatr AdolescGynecol 10:147–1518. Malchoff CD, Reardon G, MacGillivray DC, Yamase H, Rogol AD, MalchoffDM 1994 An unusual presentation of McCune-Albright syndrome confirmedby an activating mutation of the Gs -subunit from a bone lesion. J ClinEndocrinol Metab 78:803–8069. Lee PA, Van Dop C, Migeon CJ 1986 McCune-Albright syndrome. Long-termfollow-up. JAMA 256:2980–298410. Murram D, Dewhurst J, Grant DB 1984 Precocious puberty: a follow up study.Arch Dis Child 59:77–7811. Laven JS, Lumbroso S, Sultan C, Fauser BC 2001 Dynamics of ovarian func-tion in an adult woman with McCune-Albright syndrome. J Clin EndocrinolMetab 86:2625–263012. Lemli L 1977 Fibrous dysplasia of bone. Report of female monozygotic twinswith and without the McCune-Albright syndrome. J Pediatr 91:947–949JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving theendocrine community.1078 J Clin Endocrinol Metab, March 2004, 89(3):1076–1078 Laven et al. • McCune-Albright Syndrome and Infertility on November 7, 2006 jcem.endojournals.orgDownloaded from 

Management of infertility in a patient presenting with ovarian dysfunction and McCune-Albright syndrome

Laven, Joop

Lumbroso, S

Sultan, C

Fauser, BCJM (Bart)

EUR Research Repository

Management of Infertility in a Patient Presenting withOvarian Dysfunction and McCune-Albright SyndromeJOOP S. E. LAVEN, SERGE LUMBROSO, CHARLES SULTAN, AND BART C. J. M. FAUSERDivision of Reproductive Medicine, Department of Obstetrics and Gynecology (J.S.E.L, B.C.J.M.F.), Erasmus MedicalCenter, 3015 GD Rotterdam, The Netherlands; Department of Hormonology (S.L.), University Hospital Montpellier, 34295Montpellier, France; and Department of Hormonology and Unit of Pediatric Endocrinology and Gynecology, Department ofPediatrics (C.S.), University Hospital Montpellier, 34295 Montpellier, FrancePersistent autonomous ovarian dysfunction in McCune-Albright syndrome (MAS) patients is associated with the de-velopment of multiple dominant follicles, premature lutein-ization, cyst formation, and anovulatory infertility. Due to themosaic distribution of the mutation, ovaries may be unequallyaffected. In the current patient, the least affected ovary be-came quiescent upon GnRH agonist-induced gonadotropinsuppression. Normoovulatory cycles were restored after sub-sequent removal of the affected right ovary, and a pregnancywas established within 3 months. A healthy unaffected girlwas born at term after an uneventful pregnancy. The placen-tal tissue was normal, and the mutation was not detected inthe placenta, umbilical cord structures, or umbilical cordblood. GnRH analog administration may help to identify thoseMAS patients who might benefit from unilateral ovariectomy.Because a healthy baby was born, evidence is provided sug-gesting that MAS is not passed on to the children from theparents. (J Clin Endocrinol Metab 89: 1076–1078, 2004)POLYOSTOTIC FIBROUS DYSPLASIA, café au lait spots,sexual precocity, and hyperfunction of multiple endo-crine glands constitute the key features of McCune-Albrightsyndrome (MAS). The syndrome is due to a somatic muta-tion in the GNAS1 gene (1, 2). Missense point mutations atcodon 201 substituting Arg with either Cys or His give riseto abnormal Gs proteins that reduce the intrinsic guanosinetriphosphatase activity, thereby constitutively activating theGs protein (3–5). The extent and nature of the abnormality arehighly variable, depending on the specific tissues involveddue to the mosaic distribution of the GNAS1 mutation (3).The most commonly encountered endocrine dysfunctionin MAS is gonadal hyperfunction. Precocious puberty rep-resents the usual initial manifestation of MAS in girls. Ovar-ian cysts may be found upon pelvic ultrasound (6, 7). Otherendocrine abnormalities include hyperfunction of the thy-roid and adrenal cortex as well as excessive GH secretion.The majority of patients have abnormally elevated sex ste-roids with low or undetectable gonadotropin levels. Al-though pregnancies have been described later in life (8–10),polymenorrhea and amenorrhea due to continued gonado-tropin-independent estrogen production have also beenreported (6, 11). However, clinical information regardingovarian dysfunction in McCune-Albright patients during ad-olescent and adult life is scant.In a recent paper, we provided evidence for persistentautonomous unilateral ovarian dysfunction in an adultwoman suffering from MAS. Because MAS patients show atypical unilateral involvement of symmetrical tissues, themutation is usually only present or more abundant in eitherone of the ovaries. Increased FSH and LH signaling gave riseto the development of multiple dominant follicles, prematureluteinization, anovulation, and cyst formation in the affectedovary. As a result of the sex steroid-rich endocrine environ-ment, gonadal function in the unaffected contralateral ovaryis usually also disturbed. Endometrial function may be alsodisrupted presumably due to elevated progesterone levelsthroughout the cycle, implying that embryo implantationmight be severely compromised, representing an additionalfactor in infertility (11). Hence, removal of the affected ovarymight restore a normal endocrine environment, and subse-quently normal ovarian function might be restored in theremaining gonad, rendering these patients fertile.Case ReportA 22-yr-old patient previously diagnosed as having MAS attendedour outpatient clinic for fertility counseling. She exhibited the classicalclinical triad of polyostotic fibrous dysplasia, along with large café aulait spots in the lumbosacral region and a history of precocious pubertyand irregular menstrual bleeding. DNA analysis revealed a mutation(201 Arg to His) present in the right ovary only, as well as in theendometrium (11). As previously described, increased FSH and LHsignaling gave rise to the development of multiple dominant follicles,premature luteinization, anovulation, and cyst formation in the affectedovary. The function in the contralateral unaffected ovary was also dis-turbed due to continuously elevated sex steroid levels (11).In an attempt to suppress the function of the unaffected ovary, aGnRH agonist (Zoladex, AstraZeneca, Zoetermeer, The Netherlands)known to induce suppression of pituitary gonadotropin release wasadministered for 1 month. This investigation was performed to test thehypothesis that the unaffected ovary would be rendered quiescent dueto the lack of tropic support, whereas the affected ovary would continueto function autonomously. Weekly transvaginal ultrasound showed aprogressive disappearance of ovarian cysts in the left ovary duringGnRH agonist administration, indicating that this ovary is normallyresponsive to FSH and LH. In contrast, the affected ovary on the rightside did not respond and continued to function abnormally.These results as well as the experimental nature of the proposedunilateral ovariectomy were discussed extensively in our team and withAbbreviation: MAS, McCune-Albright syndrome.JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the en-docrine community.0021-972X/04/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 89(3):1076–1078Printed in U.S.A. Copyright © 2004 by The Endocrine Societydoi: 10.1210/jc.2003-0312451076 on November 7, 2006 jcem.endojournals.orgDownloaded from the patient. Moreover, the local Institutional Review Board was in-formed before the investigations had been carried out. Because only onefully informed patient was involved, a research protocol approval wasnot required. Subsequently, unilateral ovariectomy was performedthrough laparoscopy under general anesthesia. Upon laparoscopy, anenlarged (5  5  8-cm) cystic ovary was easily removed. Care was takento leave the fallopian tube on the right side intact. The left ovary had anormal appearance, as had the remaining internal genital organs. Sec-tions of the left ovary were prepared as previously described (11). Uponmicroscopic examination, primordial, primary, and secondary folliclesalong with Graaffian structures were found. Although all stages offollicular development were present, larger follicles were luteinizedwithout exception. The mutation was readily detectable throughout theremoved ovary. Again, both canonical and mutant sequences presentwere indicative of the mosaic nature of the disease.The patient recovered rapidly after the operation, and a regular men-strual cycle (28–30 d) was immediately restored. During the third cycle,she spontaneously conceived after a previous 4-yr period of infertility.After an uneventful pregnancy, at 40 wk a healthy daughter weighing3800 g was delivered vaginally. The placenta appeared normal (650 g),and the baby displayed no external stigmata of MAS. The placentaltissue was normal on microscopic examination. No evidence of theGNAS1 mutation was found in the placenta, umbilical cord, or cordblood (Fig. 1). The daughter is now 11⁄2 yr old, and her developmentremains normal.DiscussionThe current findings suggest that it may be useful to applyan in vivo test using a GnRH agonist to investigate whetherthe least or nonaffected ovary in MAS patients is normallyresponsive to diminished stimulation by gonadotropins.Moreover, the current case history provides evidence to sup-port the concept that in adult MAS patients with persistentunilateral autonomous ovarian activity, ovarian and endo-metrial function can be restored through removal of theaffected ovary. Finally, because an unaffected healthydaughter was born, this report provides further evidence thatMAS is caused by an autosomal dominant lethal gene that iscompatible with viability of the conceptus only when it oc-curs in the mosaic state. Hence, MAS results from a somaticmutation and therefore may not be inherited through anaffected parent.Our patient showed a typical unilateral involvement oftissue because the mutation was only found in the rightpolycystic ovary. This might be due to either a reducednumber or an absence of mutated cells present in the leftovary not being detected by DNA analysis (11). Neverthe-less, this difference in expression of the mutation seems to becompatible with normal monofollicular growth in the leftovary. However, this potentially normal ovary was still dys-functional as a result of the abnormal sex steroid-rich endo-crine environment induced by its affected counterpart. Re-moval of the right ovary might restore normal function of theremaining left ovary and should be considered. Testingwhether this is a feasible approach may be done using an invivo GnRH agonist test. If the unaffected ovary becomesquiescent under GnRH analog administration, it may bejustified to remove the affected ovary. The abnormal endo-crine environment, which may also affect both oocyte andendometrial function and, consequently, the outcome of invitro fertilization, cannot be otherwise corrected. Hence,ovariectomy may constitute the only treatment option insymptomatic adult MAS women (11).It has been postulated that the presence of mutated cellsin the endometrium might also compromise endometrialreceptivity and natural fertility (11). Surprisingly, this seemsnot to be the case because the patient conceived readily afterovariectomy. Because the mutated endometrial cells wereonly found in the anterior lining of the uterus, the remainingendometrium was apparently functionally normal. More-over, nidation and placentation, as observed by ultrasoundscans during early pregnancy, took place in the posteriornonaffected endometrial lining.Happle (3) made the intriguing suggestion that this dis-order is caused by an autosomal dominant lethal gene thatis compatible with viability of the conceptus only when itoccurs in the mosaic state, having arisen by somatic muta-tion. MAS has been reported to occur in one set of monozy-gotic twin girls of whom only one showed major signs ofMAS whereas the other showed only mild radiological signsof the disease (12). However, the lack of fully convincingfamilial cases is consistent with the mosaic mutation hypoth-esis. In the present case, the daughter displayed no signs ofMAS. Because the mutation analysis was also negative, sheis unlikely to be affected. This provides further evidence forthe Happle hypothesis, hereby excluding any possibility oftransmission from the parents.In conclusion, the present report shows that normal ovar-ian and reproductive function in MAS patients can be re-stored through unilateral ovariectomy, provided the unaf-fected ovary is successfully suppressed upon GnRH agonistFIG. 1. Direct DNA sequencing showed the presence of a guanine toadenine transversion (G/A*) leading to an Arg-His substitution atposition 201 in the right ovary. Both canonical and mutant sequenceswere present, the latter with a weaker intensity (green) indicating amosaicism of normal and abnormal cells. The mutation was not de-tectable in the left ovary or in the placental tissue.Laven et al. • McCune-Albright Syndrome and Infertility J Clin Endocrinol Metab, March 2004, 89(3):1076–1078 1077 on November 7, 2006 jcem.endojournals.orgDownloaded from administration. Furthermore, evidence is provided that MASmight not be passed on to children by their parents.AcknowledgmentsReceived July 18, 2003. Accepted November 21, 2003.Address all correspondence and requests for reprints to: Joop S. E.Laven, M.D., Ph.D., Division of Reproductive Medicine, Department ofObstetrics and Gynecology, Erasmus Medical Center, Dr. Molewater-plein 40, 3015 GD Rotterdam, The Netherlands. E-mail: j.laven@erasmusmc.nl.References1. Albright S, Butler AM, Hampton AO, Smith P 1937 Syndrome characterizedby osteitits fibrosa disseminata, areas of pigmentation and endocrine dys-function, with precocious puberty in females. N Engl J Med 216:727–7462. McCune DJ, Bruch H 2000 Osteodystrophia fibrosa. Am J Dis Child 54:806–8483. Happle R 1986 The McCune-Albright syndrome: a lethal gene surviving bymosaicism. Clin Genet 29:321–3244. Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM1991 Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med 325:1688–16955. Schwindinger WF, Francomano CA, Levine MA 1992 Identification of amutation in the gene encoding the  subunit of the stimulatory G protein ofadenylyl cyclase in McCune-Albright syndrome. Proc Natl Acad Sci USA89:5152–51566. Kaufman FR, Costin G, Reid BS 1986 Autonomous ovarian hyperfunctionfollowed by gonadotrophin-dependent puberty in McCune-Albright syn-drome. Clin Endocrinol (Oxf) 24:239–2427. Escobar ME, Gryngarten M, Domene H, Ropelato G, Lopez MR, Bergada C1997 Persistence of autonomous ovarian activity after discontinuation of ther-apy for precocious puberty in McCune-Albright syndrome. J Pediatr AdolescGynecol 10:147–1518. Malchoff CD, Reardon G, MacGillivray DC, Yamase H, Rogol AD, MalchoffDM 1994 An unusual presentation of McCune-Albright syndrome confirmedby an activating mutation of the Gs -subunit from a bone lesion. J ClinEndocrinol Metab 78:803–8069. Lee PA, Van Dop C, Migeon CJ 1986 McCune-Albright syndrome. Long-termfollow-up. JAMA 256:2980–298410. Murram D, Dewhurst J, Grant DB 1984 Precocious puberty: a follow up study.Arch Dis Child 59:77–7811. Laven JS, Lumbroso S, Sultan C, Fauser BC 2001 Dynamics of ovarian func-tion in an adult woman with McCune-Albright syndrome. J Clin EndocrinolMetab 86:2625–263012. Lemli L 1977 Fibrous dysplasia of bone. Report of female monozygotic twinswith and without the McCune-Albright syndrome. J Pediatr 91:947–949JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving theendocrine community.1078 J Clin Endocrinol Metab, March 2004, 89(3):1076–1078 Laven et al. • McCune-Albright Syndrome and Infertility on November 7, 2006 jcem.endojournals.orgDownloaded from 

English

Management of infertility in a patient presenting with ovarian dysfunction and McCune Albright Syndrome

EUR Research Information PortalManagement of infertility in a patient presenting with ovarian dysfunction and McCuneAlbright SyndromePublished in:Journal of Clinical Endocrinology and MetabolismPublication status and date:Published: 01/01/2004DOI (link to publisher):10.1210/jc.2003-031245Document VersionPublisher's PDF, also known as Version of recordCitation for the published version (APA):Laven, J., Lumbroso, S., Sultan, C., & Fauser, BCJM. (2004). Management of infertility in a patient presenting with ovariandysfunction and McCune Albright Syndrome. Journal of Clinical Endocrinology and Metabolism, 89(3), 1076-1078.https://doi.org/10.1210/jc.2003-031245Link to publication on the EUR Research Information PortalTerms and Conditions of UseExcept as permitted by the applicable copyright law, you may not reproduce or make this material available to any third partywithout the prior written permission from the copyright holder(s). Copyright law allows the following uses of this materialwithout prior permission:            • you may download, save and print a copy of this material for your personal use only;            • you may share the EUR portal link to this material.In case the material is published with an open access license (e.g. a Creative Commons (CC) license), other uses may beallowed. Please check the terms and conditions of the specific license.Take-down policyIf you believe that this material infringes your copyright and/or any other intellectual property rights, you may request itsremoval by contacting us at the following email address: openaccess.library@eur.nl. Please provide us with all the relevantinformation, including the reasons why you believe any of your rights have been infringed. In case of a legitimate complaint,we will make the material inaccessible and/or remove it from the website.Management of Infertility in a Patient Presenting withOvarian Dysfunction and McCune-Albright SyndromeJOOP S. E. LAVEN, SERGE LUMBROSO, CHARLES SULTAN, AND BART C. J. M. FAUSERDivision of Reproductive Medicine, Department of Obstetrics and Gynecology (J.S.E.L, B.C.J.M.F.), Erasmus MedicalCenter, 3015 GD Rotterdam, The Netherlands; Department of Hormonology (S.L.), University Hospital Montpellier, 34295Montpellier, France; and Department of Hormonology and Unit of Pediatric Endocrinology and Gynecology, Department ofPediatrics (C.S.), University Hospital Montpellier, 34295 Montpellier, FrancePersistent autonomous ovarian dysfunction in McCune-Albright syndrome (MAS) patients is associated with the de-velopment of multiple dominant follicles, premature lutein-ization, cyst formation, and anovulatory infertility. Due to themosaic distribution of the mutation, ovaries may be unequallyaffected. In the current patient, the least affected ovary be-came quiescent upon GnRH agonist-induced gonadotropinsuppression. Normoovulatory cycles were restored after sub-sequent removal of the affected right ovary, and a pregnancywas established within 3 months. A healthy unaffected girlwas born at term after an uneventful pregnancy. The placen-tal tissue was normal, and the mutation was not detected inthe placenta, umbilical cord structures, or umbilical cordblood. GnRH analog administration may help to identify thoseMAS patients who might benefit from unilateral ovariectomy.Because a healthy baby was born, evidence is provided sug-gesting that MAS is not passed on to the children from theparents. (J Clin Endocrinol Metab 89: 1076–1078, 2004)POLYOSTOTIC FIBROUS DYSPLASIA, café au lait spots,sexual precocity, and hyperfunction of multiple endo-crine glands constitute the key features of McCune-Albrightsyndrome (MAS). The syndrome is due to a somatic muta-tion in the GNAS1 gene (1, 2). Missense point mutations atcodon 201 substituting Arg with either Cys or His give riseto abnormal Gs proteins that reduce the intrinsic guanosinetriphosphatase activity, thereby constitutively activating theGs protein (3–5). The extent and nature of the abnormality arehighly variable, depending on the specific tissues involveddue to the mosaic distribution of the GNAS1 mutation (3).The most commonly encountered endocrine dysfunctionin MAS is gonadal hyperfunction. Precocious puberty rep-resents the usual initial manifestation of MAS in girls. Ovar-ian cysts may be found upon pelvic ultrasound (6, 7). Otherendocrine abnormalities include hyperfunction of the thy-roid and adrenal cortex as well as excessive GH secretion.The majority of patients have abnormally elevated sex ste-roids with low or undetectable gonadotropin levels. Al-though pregnancies have been described later in life (8–10),polymenorrhea and amenorrhea due to continued gonado-tropin-independent estrogen production have also beenreported (6, 11). However, clinical information regardingovarian dysfunction in McCune-Albright patients during ad-olescent and adult life is scant.In a recent paper, we provided evidence for persistentautonomous unilateral ovarian dysfunction in an adultwoman suffering from MAS. Because MAS patients show atypical unilateral involvement of symmetrical tissues, themutation is usually only present or more abundant in eitherone of the ovaries. Increased FSH and LH signaling gave riseto the development of multiple dominant follicles, prematureluteinization, anovulation, and cyst formation in the affectedovary. As a result of the sex steroid-rich endocrine environ-ment, gonadal function in the unaffected contralateral ovaryis usually also disturbed. Endometrial function may be alsodisrupted presumably due to elevated progesterone levelsthroughout the cycle, implying that embryo implantationmight be severely compromised, representing an additionalfactor in infertility (11). Hence, removal of the affected ovarymight restore a normal endocrine environment, and subse-quently normal ovarian function might be restored in theremaining gonad, rendering these patients fertile.Case ReportA 22-yr-old patient previously diagnosed as having MAS attendedour outpatient clinic for fertility counseling. She exhibited the classicalclinical triad of polyostotic fibrous dysplasia, along with large café aulait spots in the lumbosacral region and a history of precocious pubertyand irregular menstrual bleeding. DNA analysis revealed a mutation(201 Arg to His) present in the right ovary only, as well as in theendometrium (11). As previously described, increased FSH and LHsignaling gave rise to the development of multiple dominant follicles,premature luteinization, anovulation, and cyst formation in the affectedovary. The function in the contralateral unaffected ovary was also dis-turbed due to continuously elevated sex steroid levels (11).In an attempt to suppress the function of the unaffected ovary, aGnRH agonist (Zoladex, AstraZeneca, Zoetermeer, The Netherlands)known to induce suppression of pituitary gonadotropin release wasadministered for 1 month. This investigation was performed to test thehypothesis that the unaffected ovary would be rendered quiescent dueto the lack of tropic support, whereas the affected ovary would continueto function autonomously. Weekly transvaginal ultrasound showed aprogressive disappearance of ovarian cysts in the left ovary duringGnRH agonist administration, indicating that this ovary is normallyresponsive to FSH and LH. In contrast, the affected ovary on the rightside did not respond and continued to function abnormally.These results as well as the experimental nature of the proposedunilateral ovariectomy were discussed extensively in our team and withAbbreviation: MAS, McCune-Albright syndrome.JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the en-docrine community.0021-972X/04/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 89(3):1076–1078Printed in U.S.A. Copyright © 2004 by The Endocrine Societydoi: 10.1210/jc.2003-0312451076 on November 7, 2006 jcem.endojournals.orgDownloaded from the patient. Moreover, the local Institutional Review Board was in-formed before the investigations had been carried out. Because only onefully informed patient was involved, a research protocol approval wasnot required. Subsequently, unilateral ovariectomy was performedthrough laparoscopy under general anesthesia. Upon laparoscopy, anenlarged (5  5  8-cm) cystic ovary was easily removed. Care was takento leave the fallopian tube on the right side intact. The left ovary had anormal appearance, as had the remaining internal genital organs. Sec-tions of the left ovary were prepared as previously described (11). Uponmicroscopic examination, primordial, primary, and secondary folliclesalong with Graaffian structures were found. Although all stages offollicular development were present, larger follicles were luteinizedwithout exception. The mutation was readily detectable throughout theremoved ovary. Again, both canonical and mutant sequences presentwere indicative of the mosaic nature of the disease.The patient recovered rapidly after the operation, and a regular men-strual cycle (28–30 d) was immediately restored. During the third cycle,she spontaneously conceived after a previous 4-yr period of infertility.After an uneventful pregnancy, at 40 wk a healthy daughter weighing3800 g was delivered vaginally. The placenta appeared normal (650 g),and the baby displayed no external stigmata of MAS. The placentaltissue was normal on microscopic examination. No evidence of theGNAS1 mutation was found in the placenta, umbilical cord, or cordblood (Fig. 1). The daughter is now 11⁄2 yr old, and her developmentremains normal.DiscussionThe current findings suggest that it may be useful to applyan in vivo test using a GnRH agonist to investigate whetherthe least or nonaffected ovary in MAS patients is normallyresponsive to diminished stimulation by gonadotropins.Moreover, the current case history provides evidence to sup-port the concept that in adult MAS patients with persistentunilateral autonomous ovarian activity, ovarian and endo-metrial function can be restored through removal of theaffected ovary. Finally, because an unaffected healthydaughter was born, this report provides further evidence thatMAS is caused by an autosomal dominant lethal gene that iscompatible with viability of the conceptus only when it oc-curs in the mosaic state. Hence, MAS results from a somaticmutation and therefore may not be inherited through anaffected parent.Our patient showed a typical unilateral involvement oftissue because the mutation was only found in the rightpolycystic ovary. This might be due to either a reducednumber or an absence of mutated cells present in the leftovary not being detected by DNA analysis (11). Neverthe-less, this difference in expression of the mutation seems to becompatible with normal monofollicular growth in the leftovary. However, this potentially normal ovary was still dys-functional as a result of the abnormal sex steroid-rich endo-crine environment induced by its affected counterpart. Re-moval of the right ovary might restore normal function of theremaining left ovary and should be considered. Testingwhether this is a feasible approach may be done using an invivo GnRH agonist test. If the unaffected ovary becomesquiescent under GnRH analog administration, it may bejustified to remove the affected ovary. The abnormal endo-crine environment, which may also affect both oocyte andendometrial function and, consequently, the outcome of invitro fertilization, cannot be otherwise corrected. Hence,ovariectomy may constitute the only treatment option insymptomatic adult MAS women (11).It has been postulated that the presence of mutated cellsin the endometrium might also compromise endometrialreceptivity and natural fertility (11). Surprisingly, this seemsnot to be the case because the patient conceived readily afterovariectomy. Because the mutated endometrial cells wereonly found in the anterior lining of the uterus, the remainingendometrium was apparently functionally normal. More-over, nidation and placentation, as observed by ultrasoundscans during early pregnancy, took place in the posteriornonaffected endometrial lining.Happle (3) made the intriguing suggestion that this dis-order is caused by an autosomal dominant lethal gene thatis compatible with viability of the conceptus only when itoccurs in the mosaic state, having arisen by somatic muta-tion. MAS has been reported to occur in one set of monozy-gotic twin girls of whom only one showed major signs ofMAS whereas the other showed only mild radiological signsof the disease (12). However, the lack of fully convincingfamilial cases is consistent with the mosaic mutation hypoth-esis. In the present case, the daughter displayed no signs ofMAS. Because the mutation analysis was also negative, sheis unlikely to be affected. This provides further evidence forthe Happle hypothesis, hereby excluding any possibility oftransmission from the parents.In conclusion, the present report shows that normal ovar-ian and reproductive function in MAS patients can be re-stored through unilateral ovariectomy, provided the unaf-fected ovary is successfully suppressed upon GnRH agonistFIG. 1. Direct DNA sequencing showed the presence of a guanine toadenine transversion (G/A*) leading to an Arg-His substitution atposition 201 in the right ovary. Both canonical and mutant sequenceswere present, the latter with a weaker intensity (green) indicating amosaicism of normal and abnormal cells. The mutation was not de-tectable in the left ovary or in the placental tissue.Laven et al. • McCune-Albright Syndrome and Infertility J Clin Endocrinol Metab, March 2004, 89(3):1076–1078 1077 on November 7, 2006 jcem.endojournals.orgDownloaded from administration. Furthermore, evidence is provided that MASmight not be passed on to children by their parents.AcknowledgmentsReceived July 18, 2003. Accepted November 21, 2003.Address all correspondence and requests for reprints to: Joop S. E.Laven, M.D., Ph.D., Division of Reproductive Medicine, Department ofObstetrics and Gynecology, Erasmus Medical Center, Dr. Molewater-plein 40, 3015 GD Rotterdam, The Netherlands. E-mail: j.laven@erasmusmc.nl.References1. Albright S, Butler AM, Hampton AO, Smith P 1937 Syndrome characterizedby osteitits fibrosa disseminata, areas of pigmentation and endocrine dys-function, with precocious puberty in females. N Engl J Med 216:727–7462. McCune DJ, Bruch H 2000 Osteodystrophia fibrosa. Am J Dis Child 54:806–8483. Happle R 1986 The McCune-Albright syndrome: a lethal gene surviving bymosaicism. Clin Genet 29:321–3244. Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM1991 Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med 325:1688–16955. Schwindinger WF, Francomano CA, Levine MA 1992 Identification of amutation in the gene encoding the  subunit of the stimulatory G protein ofadenylyl cyclase in McCune-Albright syndrome. Proc Natl Acad Sci USA89:5152–51566. Kaufman FR, Costin G, Reid BS 1986 Autonomous ovarian hyperfunctionfollowed by gonadotrophin-dependent puberty in McCune-Albright syn-drome. Clin Endocrinol (Oxf) 24:239–2427. Escobar ME, Gryngarten M, Domene H, Ropelato G, Lopez MR, Bergada C1997 Persistence of autonomous ovarian activity after discontinuation of ther-apy for precocious puberty in McCune-Albright syndrome. J Pediatr AdolescGynecol 10:147–1518. Malchoff CD, Reardon G, MacGillivray DC, Yamase H, Rogol AD, MalchoffDM 1994 An unusual presentation of McCune-Albright syndrome confirmedby an activating mutation of the Gs -subunit from a bone lesion. J ClinEndocrinol Metab 78:803–8069. Lee PA, Van Dop C, Migeon CJ 1986 McCune-Albright syndrome. Long-termfollow-up. JAMA 256:2980–298410. Murram D, Dewhurst J, Grant DB 1984 Precocious puberty: a follow up study.Arch Dis Child 59:77–7811. Laven JS, Lumbroso S, Sultan C, Fauser BC 2001 Dynamics of ovarian func-tion in an adult woman with McCune-Albright syndrome. J Clin EndocrinolMetab 86:2625–263012. Lemli L 1977 Fibrous dysplasia of bone. Report of female monozygotic twinswith and without the McCune-Albright syndrome. J Pediatr 91:947–949JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving theendocrine community.1078 J Clin Endocrinol Metab, March 2004, 89(3):1076–1078 Laven et al. • McCune-Albright Syndrome and Infertility on November 7, 2006 jcem.endojournals.orgDownloaded from 

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Management of infertility in a patient presenting with ovarian dysfunction and McCune-Albright syndrome

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