Boyce et al. Orphanet Journal of Rare Diseases (2019) 14:90 https://doi.org/10.1186/s13023-019-1057-x RESEARCH ARTICLE Open Access Gynecologic and reproductive outcomes in fibrous dysplasia/McCune-Albright syndrome Alison M. Boyce1* , Rachel K. Casey3,4, Diana Ovejero Crespo1,5,6, Cynthia M. Murdock7,8, Andrea Estrada1,2, Lori C. Guthrie1, Beth A. Brillante1, Veronica Gomez-Lobo3, Lynette K. Nieman7 and Michael T. Collins1 Abstract Background: Autonomous ovarian activation with recurrent estrogen-producing cysts is a hallmark feature of the rare bone and endocrine disorder fibrous dysplasia/McCune-Albright syndrome. Precocious puberty in girls with McCune-Albright syndrome has been well-described, however long-term effects on gynecologic and reproductive function are unknown. Concerningly, case reports have described poor skeletal outcomes associated with pregnancy in women with fibrous dysplasia. Methods: Thirty-nine women with fibrous dysplasia/McCune-Albright syndrome were evaluated as part of a natural history study. Clinical, radiographic, and biochemical data were reviewed. Women were contacted to obtain detailed menstrual and reproductive histories. Results: Abnormal uterine bleeding affected 77% of women (30/39), and was associated with severe anemia requiring blood transfusion in 3 cases. Nine women underwent hysterectomy for management of bleeding, including 67% (6/9) at the unusually young age of less than age 35 years. Infertility affected 43% of women (9/21), including 2 women who developed primary ovarian insufficiency after undergoing surgical treatment of ovarian cysts. Of 25 spontaneous pregnancies in 14 women, 35% (8) were unplanned. Among the 14 pregnancies, pregnancy was associated with no change in bone pain in 7 subjects (53%), increased bone pain in 4 subjects (31%), and decreased bone pain in 2 subjects (15%). No additional skeletal complications were reported during pregnancies. Conclusions: Women with fibrous dysplasia/McCune-Albright syndrome report a high prevalence of gynecologic morbidity and reduced fertility. There is no clear association between pregnancy and poor skeletal outcomes in this population. Keywords: Ovarian cyst, Abnormal uterine bleeding, Gynecology, Fertility, Estrogen Introduction is autonomous estrogen-secreting ovarian cysts [3]. Girls McCune-Albright syndrome (MAS)(ORPHA:562) is a rare typically present in early childhood with signs of episodic disorder arising from somatic gain-of-function mutations estrogen exposure, including breast development, growth in Gαs [1]. Disease presents along a broad spectrum that acceleration, and vaginal bleeding, which resolve in the includes a variable combination of fibrous dysplasia of interval between cysts [4, 5]. Gonadotropin levels are typ- bone (FD), hyperpigmented skin macules, and hyperfunc- ically suppressed when estradiol levels are elevated; how- tioning endocrinopathies [2]. A hallmark feature of MAS ever, prolonged exposure to high estradiol levels can mature the hypothalamic pituitary axis, leading to second- ary gonadotropin-dependent precocious puberty. Treat- * Correspondence: boyceam@mail.nih.gov 1 Skeletal Disorders & Mineral Homeostasis Section, National Institute of ment with aromatase inhibitors, alone or in combination Dental and Craniofacial Research, National Institutes of Health, 30 Convent with gonadotropin releasing hormone agonists, is typically Drive Room 218 MSC 4320, Bethesda, MD, USA Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Boyce et al. Orphanet Journal of Rare Diseases (2019) 14:90 Page 2 of 7 effective at preventing progressive pubertal development Table 1 Subject characteristics during childhood. Number of subjects 39 While the presentation, natural history, and clinical Age at evaluation, median (range) 38 years (15–98) management of MAS-associated precocious puberty has Age at menarche, median (range) 3 years (0.5–13) been well-characterized, ovarian function in adulthood is Fibrous dysplasia 97% (38) poorly understood. It is unknown if women with a history of MAS-associated precocious puberty are at risk for gy- McCune-Albright syndrome features, % (n) necologic disease. Effects of persistent ovarian activation - Precocious puberty 90% (35) on fertility and childbearing, as well as the effects of preg- - Café-au-lait macules 67% (26) nancy on skeletal outcomes, have not been determined. - Hyperthyroidism 38% (15) The obstetrical literature in FD/MAS is limited to case re- - Growth hormone excess 26% (10) ports of skeletal complications during pregnancy, includ- - Hypophosphatemia 44% (17) ing increased FD-related bone pain [6, 7], aneurysmal bone cysts [6, 8, 9], and malignant transformation of FD - Cushing syndrome 0 lesions [10]. This has led some to speculate that pregnancy increases FD activity, placing women at risk for poor skel- using Immulite (Diagnostic Products Corporation, Los etal outcomes [6, 7, 11]. These knowledge gaps in gyneco- Angeles, CA) competitive immunoassay. For LH, logic and reproductive outcomes are a significant source intra-assay coefficient of variation was 3.7%, inter-assay of concern for patients and families affected by FD/MAS. coefficient of variation was 6.7%, and lower limit of detec- The purpose of this study was to evaluate gynecologic tion was 0.1 mIU/mL. For FSH, intra-assay coefficient of and reproductive outcomes in a cohort of adult women variation was 3.2%, inter-assay coefficient of variation was with FD/MAS. 4.8%, and lower limit of detection was 0.1 mIU/mL. Estra- diol was measured using Roche Cobas e601 analyzer Methods (Roche Diagnostics, Indianapolis, IN) electrochemilumi- Subjects were evaluated at the NIH Clinical Center be- nescence immunoassay. Intra-assay coefficient of variation tween 1998 and 2015 as part of a longstanding FD/MAS was 1.9%, inter-assay coefficient of variation was 3.1%, and natural history study. The protocol was approved by the lower limit of detection was 4 pg/mL. For assays run prior NIDCR Institutional Review Board, and informed con- to 2008, LH and FSH were measured using a Microparti- sent/assent was obtained from all subjects and/or their cle Enzyme Immunoassay (Abbott Laboratories, Abbott guardians. Subjects underwent history and physical exam, Park, IL). For FSH, intra-assay coefficient of variation was pelvic ultrasonography, and biochemistries to include LH, 4%, inter-assay coefficient of variation was 3%, and lower FSH, and estradiol. The diagnosis of FD/MAS was made limit of detection was 0.37 mIU/mL. For LH, intra-assay co- on clinical grounds based on the presence of 2 or more efficient of variation was 5%, inter-assay coefficient of vari- characteristic features, with molecular testing as needed, ation was 4%, and lower limit of detection was 0.5 mIU/mL. according to previously published guidelines [2]. Estradiol was measured using Immulite (Diagnostic Products Attempts were made to contact all 90 women who had Corporation, Los Angeles, CA) competitive immunoassay. been seen in the natural history protocol to obtain detailed Intra-assay coefficient of variation was 6.6%, and lower limit gynecologic and reproductive histories, and responses of detection was 15 pg/mL. In pre-menopausal women, were received from 39 subjects. Five interviews were con- levels vary widely according to menstrual cycle, but are typic- ducted at the NIH Clinical Center, and the remainder ally in the range of 15–350 pg/mL for estradiol, 1–24 U/L for were performed by telephone. Subject characteristics are FSH, and 1–100 U/L for LH. reported in Table 1. All subjects met criteria for clinical Statistical tests were performed using GraphPad Prism diagnosis of FD/MAS based on the presence of 2 or more 7.03 (San Diego, CA). Comparisons between groups characteristic features (Table 1). In addition, GNAS muta- were performed using t-tests and Mann-Whitney tests, tion testing from FD tissue was available for 15 subjects; depending on the normality of the distribution. Results in 7 subjects a mutation was identified at the R201C pos- are reported using mean (standard deviation) or median ition, and in 8 subjects a mutation was identified at the (inter-quartile range)(IQR) as described, depending on R201H position. The mean total length of follow-up was the normality of the distribution. 11.5 years (standard deviation 5.1 years, range 0–16 years). Pelvic ultrasounds were reviewed by a single reader Results (DOC). Biochemistries were drawn within 48 h of pelvic Abnormal uterine bleeding ultrasound. Biochemical assays were carried out by the Chronic abnormal uterine bleeding was defined as vaginal Department of Laboratory Medicine at the NIH Clinical bleeding that is abnormal in regularity, volume, frequency, Center. From 2008 to 2015, LH and FSH were measured or duration, and has been present for the majority of at Boyce et al. Orphanet Journal of Rare Diseases (2019) 14:90 Page 3 of 7 least 6 months [12, 13]. Most respondents (77%, 30/39) age 10, and regular menses starting at age 11. Neither had a menstrual history consistent with chronic abnormal woman reported environmental exposures or medica- uterine bleeding. Of these, all 30 women reported bleeding tions associated with ovarian toxicity. No autoimmunity that was abnormally high in frequency and volume, and 9 or additional disorders associated with ovarian insuffi- additionally reported bleeding of abnormally long dur- ciency were identified in either subject. ation. Thirteen women (33%) reported a history of anemia related to abnormal uterine bleeding. Nine of these 13 Obstetrical outcomes women received oral iron supplements for treatment of A total of 25 pregnancies occurred in 14 women. All anemia, and 3 required ≥1 blood transfusion. pregnancies were spontaneous, without the use of The most common treatment for abnormal uterine assisted reproductive technology, and 8 (35%) were un- bleeding was oral contraceptive pills (83%, 25/30 subjects). planned. Four pregnancies (18%) resulted in spontan- This was reported to be effective in most subjects (72%, eous abortion, and 6 (27%) resulted in therapeutic 18/25 treated subjects). Other treatments included levo- abortion. One pregnancy (4%) resulted in fetal demise norgestral intrauterine devices (n = 2, both effective), and due to placental abruption at 27 weeks gestation. A total combination estrogen/progestin patch (n = 1, ineffective). of 14 live births occurred from 10 women. Thirteen of Nine women underwent hysterectomy, all of whom had a these births were full-term, and 1 was pre-term at 36 history of abnormal uterine bleeding. The indications for weeks gestation. Eight live infants were delivered vagi- hysterectomy were abnormal uterine bleeding alone in 6 nally (54%), and 6 were delivered by Caesarian section women, abnormal uterine bleeding in the context of endo- (46%). The indication for Caesarian section was de- metriosis in 2 women, and uterine prolapse in one woman. scribed as fibrous dysplasia-related in 4 deliveries, and The age range at the time of hysterectomy was 27 to 44 fetal status-related in 2 deliveries. years. Of note, 6/9 hysterectomies (67%) were performed in women at the unusually young age of < 35 years. Skeletal complications during menstruation and pregnancy Fertility Menses were associated with no change in bone pain in Fertility was assessed in the subset of women who had 22 subjects (56%), increased bone pain in 12 subjects either achieved pregnancy, or reported ≥12 months of (31%), decreased bone pain in 0 subjects, with 5 subjects unprotected intercourse between ages 15 and 44. Out of unsure. Among the 14 pregnancies, pregnancy was associ- 21 women in whom fertility status could be evaluated, 9 ated with no change in bone pain in 7 subjects (53%), in- (43%) met criteria for infertility. This included 7 women creased bone pain in 4 subjects (31%), decreased bone who failed to achieve spontaneous pregnancy after 12 pain in 2 subjects (15%), with 1 subject unsure. The post- months of unprotected intercourse, and 2 women who partum period was associated with no change in bone carried a medical diagnosis of primary ovarian insuffi- pain in 10 subjects (71%), increased bone pain in 1 subject ciency. 8/9 women who met criteria for infertility (89%) (7%), and decreased bone pain in 3 subjects (21%). had a history of MAS-associated precocious puberty. No additional skeletal complications, including aneurysmal One woman was diagnosed with primary ovarian in- bone cysts or malignant transformation, were reported sufficiency after presenting with secondary amenorrhea during pregnancy. at age 16. Lab work at that time showed FSH 60 U/L, LH 40 U/L, and undetectable estradiol. She had a history Radiographic and biochemical data of precocious puberty presenting at age 7 months, and Of the 39 total subjects, 19 had premenopausal radio- underwent bilateral cystectomy at age 23 months. She graphic and biochemical data available for review. continued to have symptoms of precocious puberty, and Results of simultaneously obtained gonadotropins, estra- was treated with testolactone from ages 3 to 8. After dis- diol levels, and pelvic ultrasonography are shown in continuing testolactone she had irregular menses until Table 2 for the 14 of these subjects who were not receiv- her presentation with secondary amenorrhea at age 16. ing hormonal contraceptives at the time of the studies. Another woman also presented with secondary amen- The presence of follicles/cysts ≥2.5 cm in diameter are orrhea at age 16 years, with a biochemical evaluation noted. Representative ultrasound images are shown in that showed FSH 61 U/L, LH 29 U/L, and undetectable Fig. 1. Six subjects had multiple data points (correspond- estradiol. She had a history of precocious puberty pre- ing to ≥1 admission to the NIH Clinical Center), and 8 senting at age 6 months, at which time she developed by subjects had a single data point. Gonadotropins were a large cyst complicated by ovarian torsion. She under- suppressed to undetectable levels in 6 women at 9 total went unilateral salpingo-oophorectomy, and following timepoints; 8 of these timepoints showed evidence of surgery had no additional symptoms of precocious pu- ovarian cysts/follicles on ultrasound. The median estra- berty, began spontaneous breast development starting at diol levels for subjects with and without ovarian cysts Table 2 Biochemical and ultrasonography findings from pre-menopausal women with McCune-Albright syndrome Admission 1 Admission 2 Admission 3 Admission 4 Age CD LH FSH E2 Pelvic Age CD LH FSH E2 Pelvic Age CD LH FSH E2 Pelvic Age CD LH FSH E2 Pelvic Boyce et al. Orphanet Journal of Rare Diseases (y) (U/L) (U/L) (pg/mL) US (y) (U/L) (U/L) (pg/mL) US (y) (U/L) (U/L) (pg/mL) US (y) (U/L) (U/L) (pg/mL) US 17 7 3.8 4.9 150 L, 9.5 cm 18 21 3.6 4.9 150 nl 20 22 6.4 7.8 64.7 nl 22 31 4.4 6.1 48.2 L, 4.8 cm 21 5 1 <1 202 B, 5 cm 22 9 7 9 313 B, 1.9–4.4 cm 23 30 1 1 107 nl 26 22 <1 <1 86 B, 3.6–4 cm 28 24 <1 <1 21 L, 5.8 cm 41 11 7.3 13 130 nl 32 31 <1 5 191 R, 2.5 cm 33 4 <1 <1 105 R, 3.5 cm 46 40 7.6 11.6 9.6 nl (2019) 14:90 15 36 5.5 2.5 74 nl 16 31 0.7 0.2 447 nl 17 15 2.4 1.4 48.6 nl 16 11 <1 <1 144 B, 3–6 cm 23 27 <1 <1 250 B, 4.3–5 cm 18 13 <1 <1 74 R, 7.5 cm 22 2 2.6 3.3 224 nl 21 25 3 2 134 B, 2.5 cm 21 22 0.2 < 0.1 39.5 nl 26 14 1.6 0.2 <5 nl 35 14 5.2 7.2 87 R, 3.8 cm 36 6 4.9 8.3 75 nl 31 19 2.7 4.7 179 R, 2.8 cm y Years, CD Cycle day, LH Luteinizing hormone, U/L Units per liter, FSH Follicle stimulating hormone, E2 Estradiol, pg/mL Picograms per milliliter, US Ultrasound, B Bilateral ovarian cysts, L Left-sided ovarian cyst, R Right- sided ovarian cyst, cm Centimeters, nl Normal Page 4 of 7 Boyce et al. Orphanet Journal of Rare Diseases (2019) 14:90 Page 5 of 7 Fig. 1 Representative pelvic ultrasound images. a Solitary cyst, measuring 4 cm in diameter. b Septated ovarian cyst, measuring 4 cm in diameter. c Multicystic adnexal mass, measuring 6 cm in diameter. d Multiple cysts involving the right ovary, the largest measuring 3 cm in diameter was 139 pg/mL (IQR 68, 193) and 74 pg/mL (IQR 26, with MAS, potentially decreasing or preventing the need 140), respectively (p = 0.11). The median LH levels for for surgical intervention [19]. subjects with and without ovarian cysts was 1.1 U/L Ovarian cysts persisted into adulthood in this cohort, (IQR 0.9, 3.3) and 2.6 U/L (IQR 0.8, 5.6), respectively resulting in hyperestrogenism and suppression of pituit- (p = 0.17). The corresponding median FSH levels were ary gonadotropin production in some patients. Implica- 1.1 U/L (IQR 0.9, 5.2) and 2.5 U/L (IQR 0.6, 6.6), re- tions of hyperestrogenism in women with MAS are spectively (p = 0.46). unclear. MAS has recently been associated with an in- creased risk of breast cancer, particularly in younger women [20]. Precocious puberty has been identified as a Discussion risk factor for breast cancer within the MAS population, Findings from this large series demonstrate that autono- potentially reflecting the effects of long-term exposure mous ovarian activation in MAS persists into adulthood, to increased circulating estrogen. with significant effects on gynecologic function and This is the largest series to report data on fertility in reproduction. In our cohort, abnormal uterine bleeding women with MAS. Previous reports have been limited to resulted in significant morbidity, including the need for single cases and small series, which have reported both blood transfusions in multiple subjects. This is consistent spontaneous pregnancies [6, 8–10, 21–24] and infertility with previous case reports and small series reporting [16, 17, 25, 26]. Findings from this cohort included an infer- menometrorrhagia [14–17]. Treatment for abnormal uter- tility prevalence of 43%, which is substantially increased ine bleeding in this cohort included primarily oral contra- over the U.S. national average of 10.9% [27]. Thirty-five per- ceptive pills and surgical management. A striking finding cent of pregnancies in this cohort were unplanned, which is was the unusually young age at which hysterectomies were only mildly decreased in comparison to the 49% U.S. na- performed. Most subjects were under age 35 years at the tional average [28]. Taken together, these findings suggest time of surgery, likely reflecting the severity of abnormal that fertility is impaired in women with MAS, however the uterine bleeding. Subjects reported only infrequent use of possibility remains for spontaneous conception. The mech- levonorgestrel intrauterine devices, now considered anism of infertility is likely related in part to anovulatory cy- first-line management for abnormal uterine bleeding in cles resulting from autonomous ovarian activity [29], and it women who do not desire pregnancy [18]. It is possible is possible that conception may not be impaired during in- that increased use of medical therapies that act locally at tervals without ovarian activation. This could potentially ac- the level of the uterine endometrium, such as intrauterine count for the relatively robust prevalence of unplanned devices or ulipristal acetate for women co-morbid leio- pregnancies in this cohort, highlighting the importance of myomas, may improve gynecologic morbidity in women contraceptive care in the MAS population. It should be Boyce et al. Orphanet Journal of Rare Diseases (2019) 14:90 Page 6 of 7 noted that none of the women in this study sought Strengths of this study include the large number of sub- reproductive assistance. Subjects were not specifically jects and extensive follow-up. This is the first cohort study questioned about their decision-making, however con- to establish gynecologic disease as a highly prevalent cerns about skeletal effects of pregnancy and repro- source of morbidity in MAS, to evaluate fertility and re- ductive interventions may have played a role. It is productive outcomes in women with MAS, and to report likely that reproductive assistance may have increased on skeletal outcomes in pregnancy. This is also the first pregnancy rates in this cohort, and should be recom- report of primary ovarian insufficiency as a potential con- mended at an appropriate point to women with MAS sequence of pelvic surgery in MAS, a novel finding that who desire pregnancy. may directly inform gynecologic management. Limitations If anovulation is the primary cause of infertility in include the retrospective nature of the study design. Clin- MAS, ovarian cyst frequency may predict an individual’s ical outcomes data were not collected at same time as degree of fertility impairment. There are 4 reports of radiographic data and biochemical data, and are subjected women with frequent ovarian activation who underwent to recall bias. Interpretation of ultrasound and biochem- unilateral oophorectomy in attempts to improve contra- ical data is limited, because studies were obtained in a lateral ovarian function and fertility [16, 17, 25, 26]. All cross-sectional manner and were not standardized accord- women reported improvement in menses, and 2 ing to menstrual cycles. Additional, prospective studies achieved spontaneous pregnancy. It is important to note are needed to characterize the prevalence and frequency that success with this approach may be predicated on of ovarian cysts, which will provide important context for the laterality of ovarian involvement, and that a unilat- these clinical findings. Prospective studies should correlate eral oophorectomy may be less likely to improve contra- gynecologic data with skeletal outcomes and surrogate lateral function in women with bilateral disease. In endpoints, such as bone turnover markers, to more fully addition, decreased ovarian reserve is an established risk investigate the effects of these hormonal changes on min- of pelvic surgery [30], which is particularly relevant eral metabolism. Selection bias likely resulted in given the frequent and often inappropriate pelvic surger- over-representation of more severely affected patients ies performed in women with MAS [31]. Two women in among respondents. The high prevalence of precocious our series developed primary ovarian insufficiency after puberty among respondents likely reflects this selection ovarian surgery, including one who had resolution of bias. This data should therefore be generalized only to pa- precocious puberty after oophorectomy, suggesting she tients with known MAS ovarian involvement. had unilateral involvement. These findings suggest that unilateral oophorectomy may be helpful for treatment of Conclusions MAS-associated infertility in select cases, however this Abnormal uterine bleeding is common in MAS and may approach should be undertaken with extreme caution result in significant morbidity, including severe anemia with consideration of the potential for harm to fertility, and hysterectomies at an early age. In this series, the and only under the supervision of an experienced repro- prevalence of infertility was substantially increased over ductive specialist. the national average, however the prevalence of un- The effects of menstruation and pregnancy on FD has planned pregnancies was only mildly reduced. Menses been an area of much speculation and concern for pa- and pregnancy were not consistently associated with in- tients. Case reports have described aneurysmal bone cysts creased FD-related bone pain or skeletal complications. and malignant transformation in pregnant women, fueling These findings will inform family planning for patients conjecture that pregnancy hormones may affect adversely with FD/MAS by highlighting both the potential for affect the metabolic activity of FD lesions [6–11]. Osada et spontaneous pregnancy, as well as possibility of impaired al. reported increased bone turnover during pregnancy in fertility and need for reproductive assistance. women with FD, however these changes were consistent with the bone turnover variations typical of pregnancy Abbreviations FD: Fibrous dysplasia; FSH: Follicle stimulating hormone; LH: Luteinizing and the post-partum period [21]. Skeletal complications hormone; MAS: McCune-Albright syndrome; NIDCR: National Institute of are an established morbidity in FD, and it is possible that Dental and Craniofacial Research; NIH: National Institutes of Health their reported association with pregnancy is mediated in part by reporting bias, due to the current literature domi- Acknowledgements None. nated by case reports. In this cohort study, there were no consistent effects of pregnancy or menstruation on bone Funding pain, and no association with skeletal morbidity. Currently This work was supported in part by the intramural programs of the National there is no clear evidence to establish a causative relation- Institute of Dental and Craniofacial Research and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National ship between pregnancy or menstruation and skeletal out- Institutes of Health. The funding bodies played a role in the design, comes in women with FD/MAS. collection, analysis, and interpretation of data. Boyce et al. Orphanet Journal of Rare Diseases (2019) 14:90 Page 7 of 7 Availability of data and materials 9. Bowers CA, et al. Pregnancy-induced cystic degeneration of fibrous The datasets used and/or analyzed during the current study are available dysplasia. Can J Neurol Sci. 2012;39(6):828–9. from the corresponding author on reasonable request. 10. Kanazawa I, et al. Osteosarcoma in a pregnant patient with McCune- Albright syndrome. Bone. 2009;45(3):603–8. Authors’ contributions 11. Bhattacharya S, Mishra RK. Fibrous dysplasia and cherubism. Indian J Plast Study design: DOC, RKC, VG-L, LNK, MTC, AMB. Study conduct: RKC, AE, LCG, Surg. 2015;48(3):236–48. BAB, LCG, CMM, LKN, MTC, AMB. Data collection: DOC, RKC, AE, CMM, LCG, LKN, 12. Munro MG, et al. FIGO classification system (PALM-COEIN) for causes of MTC, AMB. Data analysis: RKC, CMM, VG-L, LKN, MTC, AMB. Data interpretation: abnormal uterine bleeding in nongravid women of reproductive age. Int J RKC, CMM, VG-L, LKN, MTC, AMB. Drafting manuscript: AMB. Revising manuscript Gynaecol Obstet. 2011;113(1):3–13. content: AMB, DOC, LCG, BAB, VG-L, MTC. Approving final version of manuscript: 13. American College of Obstetricians and Gyne-cologists. Practice bulletin no. AMB, DOC, RKC, CMM, LCG, AE, BAB, VG-L, LKN, MTC. AMB takes responsibility 128: diagnosis of abnormal uterine bleeding in reproductive-aged women. for the integrity of the data analysis. Obstet Gynecol. 2012;120(1):197–206. 14. Lala R, et al. Persistent hyperestrogenism after precocious puberty in young Ethics approval and consent to participate females with McCune-Albright syndrome. Pediatr Endocrinol Rev. 2007; The protocol was approved by the NIDCR institutional review board, and 4(Suppl 4):423–8. was conducted in accordance with the Declaration of Helsinki and Good 15. Matarazzo P, et al. McCune-Albright syndrome: persistence of autonomous Clinical Practice. A written informed consent/assent was obtained from all ovarian hyperfunction during adolescence and early adult age. J Pediatr subjects and/or their guardians to participate in the protocol. Endocrinol Metab. 2006;19(Suppl 2):607–17. 16. Laven JS, et al. Management of infertility in a patient presenting with ovarian dysfunction and McCune-Albright syndrome. J Clin Endocrinol Consent for publication Metab. 2004;89(3):1076–8. A written informed consent/assent was obtained from all subjects and/or 17. Chanson P, Salenave S, Young J. Ovarian dysfunction by activating mutation their guardians to publish clinical data. of GS alpha: McCune-Albright syndrome as a model. Ann Endocrinol (Paris). 2010;71(3):210–3. Competing interests 18. American College of Obstetricians and Gyne-cologists. Practice bulletin no. The authors declare that they have no competing interests. 136: management of abnormal uterine bleeding associated with ovulatory dysfunction. Obstet Gynecol. 2013;122(1):176–85. 19. Donnez J, et al. Ulipristal acetate versus leuprolide acetate for uterine Publisher’s Note fibroids. N Engl J Med. 2012;366(5):421–32. Springer Nature remains neutral with regard to jurisdictional claims in 20. Majoor BC, Boyce AM, Bovée JV, Smit VT, Collins MT, Cleton-Jansen A, published maps and institutional affiliations. Dekkers OM, Hamdy NA, Dijkstra PS, Appelman-Dijkstra NM. Increased risk of breast cancer at a young age in women with fibrous dysplasia. J Bone Author details 1 Miner Res. 2018;33:84–90. https://doi.org/10.1002/jbmr.3286. Skeletal Disorders & Mineral Homeostasis Section, National Institute of 21. Osada H, et al. Accelerated bone turnover in pregnant women with Dental and Craniofacial Research, National Institutes of Health, 30 Convent McCune-Albright syndrome. Gynecol Obstet Investig. 2005;60(2):102–7. Drive Room 218 MSC 4320, Bethesda, MD, USA. 2Division of Endocrinology & 22. Wong SC, Zacharin M. Long-term health outcomes of adults with McCune- Diabetes, Children’s National Health System, 111 Michigan Ave NW, Albright syndrome. Clin Endocrinol. 2017;87(5):627–34. Washington, D.C, USA. 3Division of Pediatric and Adolescent Gynecology, 23. Lee PA, Van Dop C, Migeon CJ. McCune-Albright syndrome. Long-term Department of Obstetrics and Gynecology, MedStar Washington Hospital follow-up. JAMA. 1986;256(21):2980–4. Center, Children’s National Health System, Washington, D.C., USA. 4Pediatric 24. Malchoff CD, et al. An unusual presentation of McCune-Albright syndrome and Adolescent Gynecology, Inova Health System, Pediatric Specialists of confirmed by an activating mutation of the Gs alpha-subunit from a bone Virginia, Fairfax, VA, USA. 5Musculoskeletal Research Unit, Hospital del Mar lesion. J Clin Endocrinol Metab. 1994;78(3):803–6. Institute of Medical Investigation (IMIM), Barcelona, Spain. 6National Research 25. Chevalier N, et al. Postpubertal persistent Hyperestrogenemia in McCune- Council, Institute of Clinical Physiology, Lecce, Italy. 7Program in Albright syndrome: unilateral oophorectomy improved fertility but detected Reproductive and Adult Endocrinology, The Eunice Kennedy Shriver National an unexpected borderline epithelial ovarian tumor. J Pediatr Adolesc Institute of Child Health and Human Development, National Institutes of Gynecol. 2015;28(6):e169–72. Health, Bethesda, MD, USA. 8Reproductive Medicine Associates of 26. Lavoue V, et al. Restoration of ovulation after unilateral ovariectomy in a Connecticut, Norwalk, CT, USA. woman with McCune-Albright syndrome: a case report. Eur J Endocrinol. 2008;158(1):131–4. Received: 19 June 2018 Accepted: 8 April 2019 27. Chandra A, Copen CE, Stephen EH. Infertility and impaired fecundity in the United States, 1982-2010: data from the National Survey of family growth. Natl Health Stat Report. 2013;(67):1–18, 1 p following 19. References 28. Finer LB, Zolna MR. Unintended pregnancy in the United States: incidence 1. Weinstein LS, et al. Activating mutations of the stimulatory G protein in the and disparities, 2006. Contraception. 2011;84(5):478–85. McCune-Albright syndrome. N Engl J Med. 1991;325(24):1688–95. 29. Laven JS, et al. Dynamics of ovarian function in an adult woman with 2. Boyce AM, et al. Fibrous dysplasia/McCune-Albright syndrome. In: Adam MP, McCune--Albright syndrome. J Clin Endocrinol Metab. 2001;86(6):2625–30. et al., editors. GeneReviews((R)). Seattle: University of Washington; 1993. 30. Alammari R, Lightfoot M, Hur HC. Impact of cystectomy on ovarian reserve: GeneReviews is a registered trademark of the University of Washington, review of the literature. J Minim Invasive Gynecol. 2017;24(2):247–57. Seattle. All rights reserved.: Seattle (WA). 31. Nabhan ZM, West KW, Eugster EA. Oophorectomy in McCune-Albright 3. Collins MT, Singer FR, Eugster E. McCune-Albright syndrome and the extraskeletal syndrome: a case of mistaken identity. J Pediatr Surg. 2007;42(9):1578–83. manifestations of fibrous dysplasia. Orphanet J Rare Dis. 2012;7(Suppl 1):S4. 4. Schoelwer M, Eugster EA. Treatment of peripheral precocious puberty. Endocr Dev. 2016;29:230–9. 5. Estrada A, et al. Long-term outcomes of letrozole treatment for precocious puberty in girls with McCune-Albright syndrome. Eur J Endocrinol. 2016;175(5):477–83. 6. Kaplan FS, et al. Estrogen receptors in bone in a patient with polyostotic fibrous dysplasia (McCune-Albright syndrome). N Engl J Med. 1988;319(7):421–5. 7. Stevens-Simon C, et al. Exacerbation of fibrous dysplasia associated with an adolescent pregnancy. J Adolesc Health. 1991;12(5):403–5. 8. Mintz MC, Dalinka MK, Schmidt R. Aneurysmal bone cyst arising in fibrous dysplasia during pregnancy. Radiology. 1987;165(2):549–50.