Use of Serum FSH to Identify Perimenopausal Women with Pituitary hcg

Transcription

1 Cliical Chemistry 54: (2008) Edocriology ad Metabolism Use of Serum FSH to Idetify Perimeopausal Wome with Pituitary hcg A M. Groowski, 1* Corie R. Fatz, 2 Curtis A. Parvi, 1 Lori J. Sokoll, 3 Carme L. Wiley, 4 Mark H. Weer, 5 ad David G. Greache 6 BACKGROUND: Huma chorioic goadotropi (hcg) tests are performed o may female patiets before performig medical procedures or admiisterig medicatios that may harm a fetus. hcg of pituitary origi has bee show to icrease with age. Therefore, mild icreases i serum hcg i a older patiet ca be of pituitary origi ad does ot ecessarily idicate pregacy. The iability to rule out pregacy i perimeopausal wome ca create cliical cofusio ad may delay eeded therapies. Our objective was to determie the diagostic utility of serum follicle-stimulatig hormoe (FSH) cocetratios to rule out hcg of placetal origi i perimeopausal wome with a low cocetratio of serum hcg ( IU/L). METHODS: Seve testig ceters performed physicia-ordered serum quatitative hcg tests over a 15- moth period. From these, 100 samples from wome years of age with serum hcg cocetratios 5 14 IU/L were idetified. We performed FSH testig ad patiet chart review for each sample. RESULTS: Twety-three patiets were foud to have hcg of placetal origi (pregacy, resolvig abortio, or gestatioal trophoblastic disease), ad i those cases serum FSH was IU/L. A FSH cutoff of 45.0 IU/L idetified hcg of placetal origi with 100% sesitivity ad 75% specificity. FSH 45 IU/L was ever observed whe hcg was of placetal origi (egative predictive value). CONCLUSIONS: These data idicate that quatitative serum FSH ca be used to rule out pregacy ad hcg of placetal origi i wome years of age with mild icrease i serum hcg cocetratios America Associatio for Cliical Chemistry It has become stadard practice at most istitutios to determie the huma chorioic goadotropi (hcg) 7 status (urie or serum) o all female patiets before ay medical itervetio that could potetially harm a fetus, eve i older patiets who are likely peri- or postmeopausal. Although the majority of determiatios o these older, opregat patiets are egative, umerous studies idicate that low cocetratios of hcg ca be preset i these older cohorts of wome eve i the absece of pregacy (1 3). Positive results from qualitative tests or quatitative serum results that exceed a threshold of 5.0 IU/L ca create cliical cofusio ad delay eeded therapies. Aside from its sythesis durig ormal pregacy, gestatioal trophoblastic disease, or some maligacies, a small amout of hcg is ormally produced by the pituitary glad i cojuctio with the structurally similar glycoprotei hormoes luteiizig hormoe (LH), follicle-stimulatig hormoe (FSH), ad thyroid-stimulatig hormoe (4, 5). Studies have demostrated that pituitary productio of hcg icreases durig meopause (2, 3). Recetly, Cole et al. (2) reported that 2 weeks of treatmet with estroge-progesteroe hormoe-replacemet therapy could be used to suppress serum hcg cocetratios ad cofirm that it is of pituitary origi. However, this method is ot useful i emerget situatios whe pregacy must be ruled out quickly before diagostic procedures or treatmet. Several years before meopause, there is a icrease i circulatig cocetratios of FSH ad a decrease i estradiol. LH cocetratios geerally remai similar to those i youger wome. The use of FSH quatificatio to help idetify meopause-associated low-positive hcg cocetratios has bee suggested (6). We previously suggested that wome years 1 Divisio of Laboratory ad Geomic Medicie, Washigto Uiversity School of Medicie, St. Louis, Missouri; 2 Departmet of Pathology ad Laboratory Medicie, Emory Uiversity, Atlata, Georgia; 3 Departmet of Pathology, Johs Hopkis Medical Istitutios, Baltimore, Marylad; 4 Divisio of Laboratory Medicie ad Pathology, Marshfield Cliic, Marshfield, Wiscosi; 5 Departmet of Laboratory Medicie, Uiversity of Washigto, Seattle, Washigto; 6 Departmet of Pathology ad Laboratory Medicie, Uiversity of North Carolia School of Medicie, Chapel Hill, North Carolia, ow at Departmet of Pathology, Uiversity of Utah Health Scieces Ceter, Salt Lake City, Utah. * Address correspodece to this author at: Washigto Uiversity School of Medicie, Departmet of Pathology, Box 8118, 660 S. Euclid, St. Louis, MO groowski@wustl.edu. Received November 9, 2007; accepted Jauary 15, Previously published olie at DOI: /clichem Nostadard abbreviatios: hcg, huma chorioic goadotropi; FSH, folliclestimulatig hormoe. 652

2 FSH to Exclude hcg of Placetal Origi Table 1. Specime collectio period, umber of specimes icluded, ad testig methods for quatitative hcg ad FSH measuremet at each testig ceter. Testig ceters Ceter code A B C D E F G hcg method FSH method ADVIA Cetaur (Bayer Diagostics) ADVIA Cetaur (Bayer Diagostics) Roche Elecsys (Roche Diagostics) Vitros ECi (Ortho-Cliical Diagostics) (Beckma Coulter) (Beckma Coulter) (Beckma Coulter) (Beckma Coulter) Dimesio (Dade Behrig) (Beckma Coulter) AIA (Tosoh Biosciece) AIA (Tosoh Biosciece) AxSYM (Abbott Laboratories) DxI (Beckma Coulter) Immulite 2000 (Diagostic Products Corporatio) Totals Specime collectio period 2/10/06 to 5/14/07 3/22/06 to 4/4/07 3/22/06 to 1/4/07 3/22/06 to 4/2/07 3/22/06 to 4/2/07 3/21/06 to 3/5/07 3/22/06 to 4/16/07 2/10/06 to 5/14/07 Quatitative serum hcg tests performed From wome years old From wome years old ad hcg 5.0 IU/L From wome years old ad hcg IU/L Samples excluded Isufficiet sample volume No chart Icoclusive pregacy status Patiet duplicate Samples icluded Cliical Chemistry 54:4 (2008) 653

3 Physicia-ordered hcg tests Male Females <40 or > 55 years Females years = hcg <5 or >14 IU/L hcg 5 14 IU/L Chart review ot available (6) Isufficiet specime volume for FSH testig (41) Specime from same patiet already icluded i study (7) Pregacy status ucertai (5) Fig. 1. Algorithm for specime iclusio ad exclusio. (perimeopausal) with a serum hcg betwee 5.0 ad 14.0 IU/L have reflex FSH testig performed to help exclude a diagosis of pregacy (1). However, that study was limited because it icluded oly 3 opregat patiets, years of age, with serum hcg 5.0 IU/L. A larger cohort of perimeopausal wome was eeded to cofirm a cliically useful diagostic cutoff for FSH. This study uses a populatio of wome betwee the ages of 41 ad 55 years with a low cocetratio of serum hcg ( IU/L) to determie the diagostic utility of serum FSH cocetratios to rule out hcg of placetal origi. Materials ad Methods STUDY POPULATION This multiceter, prospective, cohort study used leftover samples set to the laboratory over a approximate 15-moth period betwee February 10, 2006, ad May 14, 2007, for physicia-ordered hcg testig (study recruitmet periods varied slightly betwee sites; see Table 1). The study period was defied as the time required to collect 100 specimes that met the iclusio criteria (see below). Testig ceters icluded Washigto Uiversity, St. Louis, MO; Uiversity of North Carolia, Chapel Hill, NC; Emory Uiversity, Atlata, GA; Marshfield Cliic, Marshfield, WI; Marshfield Cliic Regioal Ceter Cliics, rural Wiscosi; Johs Hopkis Medical Istitutios, Baltimore, MD; ad Uiversity of Washigto, Seattle, WA (Table 1). The study desig is show i Fig. 1. Durig the study period, specimes had quatitative hcg testig performed (excludig proficiecy testig ad quality cotrol specimes). Specimes were icluded i the study if the serum hcg cocetratio from wome years of age was IU/L. Specimes were excluded if from a male patiet, if a patiet chart was uavailable for review, if pregacy status was ucertai ad source of the hcg could ot be determied, if there was isufficiet sample to perform FSH testig, or if a sample from the patiet was already icluded i the study (Fig. 1). Chart review was performed o all patiets. The presece of hcg of placetal origi was determied based o physicia otes, subsequet hcg testig, ad pathology reports. This study received approval from the Istitutioal Review Board of each istitutio. 654 Cliical Chemistry 54:4 (2008)

4 FSH to Exclude hcg of Placetal Origi ANALYSIS OF COLLECTED SPECIMENS All specimes used i the study had quatitative hcg ad FSH testig performed. Because the goal was to develop guidelies that ca be widely used, testig ceters were selected to reflect a variety of quatitative hcg immuoassay methods curretly i use (Table 1). All testig was performed i CLIA-approved laboratories accordig to maufacturer s istructios. hcg testig was performed upo receipt of the specime i the laboratory. Samples were refrigerated for up to 3 days or froze for up to 3 weeks before FSH testig was performed. STATISTICS The study size of 100 patiets was determied assumig that true sesitivity, specificity, ad positive ad egative predictive values were approximately 0.80 or above, which would produce cofidece iterval estimates that were expected to be approximately 10% or less. A ROC curve was computed usig Graph-Pad Prism, v (GraphPad Software). Exact 95% CIs for sesitivity, specificity, ad positive ad egative predictive values were computed usig Stata, release 9 (StataCorp). Results I this study populatio, 11% (4415/39 742) of the serum hcg tests were performed o wome years of age (Fig. 1). I this subset of wome, the prevalece of hcg cocetratios 5.0 IU/L, IU/L, ad 14.0 IU/L was 85.8% (3787/4415), 3.6% (159/4415), ad 10.6% (469/4415), respectively (Table 1). Of the 77 patiets who had hcg of oplacetal origi, the vast majority ( 68) were beig tested because they had bee or were goig to be subject to agets that could harm a fetus (24 presurgical/medicatio/radiology; 20 cacer patiets; 11 real failure; 5 drug abuse; 4 cogestive heart failure; 2 psychotic disorder or suicide; 1 stroke; 1 seizure). Four patiets were evaluated for vomitig or abdomial pai ad 3 for vagial bleedig or missed meses. Oe patiet was a boe marrow door, ad oe was a healthy research study patiet. Of the 23 patiets with hcg of placetal origi, 17 had resolvig abortio/miscarriage, 4 had gestatioal trophoblastic disease, ad two were early i pregacy. These data are show i Supplemetal Table 1 i the Data Supplemet that accompaies the olie versio of this article at org/cotet/vol54/issue4. The distributio of FSH cocetratios i patiets with hcg of placetal origi ad oplacetal origi is show i Fig. 2. I cotrast to the wide variatio i the FSH cocetratios i patiets with hcg of oplacetal origi, FSH did ot exceed 45 IU/L whe hcg origiated from placetal FSH IU/L hcg IU/L Fig. 2. Scatter plot of hcg vs FSH cocetratios. Ope circles represet oplacetal hcg; 77. Closed circles represet placetal hcg; 23. The dashed lie represets a FSH cutoff of 45 IU/L. tissue. A ROC curve for FSH to rule out hcg of placetal origi is show i Fig. 3. The area uder the curve is (95% CI ). A cutoff of 45 IU/L was selected from the ROC curve to rule out hcg of placetal origi. Serum FSH 45 IU/L has a sesitivity of 100% (95% CI 87.8% 100%) to idetify specimes with hcg of placetal origi ad a specificity of 75.3% (95% CI 64.2% 84.4%). A value above the cutoff is also 100% predictive (95% CI 95.0% 100%) that the hcg is ot of placetal origi (i.e., egative predictive value 100% for FSH 45 IU/L), ad a value below the cutoff is 54.8% predictive (95% CI 38.7% 70.2%) that hcg was of placetal origi (positive predictive value). Fig. 3. ROC curve for FSH to rule out hcg of placetal origi. The area uder the curve was (95% CI ) ad differed sigificatly from 0.50 (P ). Cliical Chemistry 54:4 (2008) 655

5 Discussio The results preseted here support our previous fidigs ad idicate that serum FSH has cliical utility to rule out pregacy as the hcg source ad ca facilitate medically ecessary treatmet i wome of perimeopausal age. We suggest reflex FSH testig be cosidered i all patiets betwee 41 ad 55 years of age with serum hcg cocetratios IU/L if the possibility of pregacy is beig evaluated. It is ot ecessary i patiets betwee years of age with hcg 5.0 IU/L, as pregacy is ulikely. I patiets betwee 41 ad 55 years of age, a hcg 14.0 IU/L should be cosidered cosistet with pregacy uless otherwise determied, as eve postmeopausal wome with hcg of prove pituitary origi ucommoly (17%) exceed 14 IU/L (2). If reflex FSH testig is performed after hcg test results of IU/L i this age group, hcg results could be reported with the followig iterpretatios. Whe FSH is 45 IU/L, FSH was determied to be 45 IU/L. It is ulikely that the hcg is due to pregacy. Whe FSH is 45 IU/L, FSH was determied to be 45 IU/L. The hcg may be due to pregacy. Note that this algorithm is iteded exclusively for hcg tests that have bee ordered to rule out pregacy, ad test results eed to be iterpreted with regard to cliical evaluatio. I our prelimiary study, we had established 20 IU/L as a cutoff for FSH (1). I this larger study, use of this threshold resulted i 78% sesitivity ad 84% specificity for rulig out pregacy. Because FSH testig will be used to evaluate potetial pregacy, we believe it is essetial that a cutoff with 100% sesitivity to rule out hcg of placetal origi be used, as failure to do so may result i iappropriate treatmets i pregat patiets. The differece betwee the FSH cutoff established i this study ad our previous publicatio is likely due to the small umber ( 3) of opregat, perimeopausal wome with positive hcg i our previous publicatio. Serum FSH is ofte used to help evaluate the meopausal status of wome. Iterestigly, FSH cocetratios vary widely i postmeopausal wome ad therefore are ot recommeded for use i diagosig meopause. Likewise here, FSH cocetratios 45 Refereces IU/L should ot be used to diagose meopause, but rather these cocetratios idicate that the presece of hcg is ulikely due to pregacy or of placetal origi. I this study, the prevalece of wome years of age who had hcg testig performed ad had hcg cocetratios 5 14 IU/L was 0.4% (159/39 742). This is similar to the 0.2% prevalece estimated i our previous report (1). At this low prevalece, implemetig reflex testig should ot create ecoomic or logistical burdes for the laboratory. Although the exact source of hcg was ot kow for the wome with hcg of oplacetal origi, the evidece suggests a pituitary origi. Cocetratios of pituitary hcg have bee show to icrease durig perimeopause (2, 3), ad as stated earlier, these hcg cocetratios ted to be low ( 16 IU/L) (2). We suggest that our approach is most useful i situatios where rulig out pregacy is urgetly eeded. If the FSH cocetratio is 45 IU/L, the pregacy is ulikely ad the procedure or treatmet should proceed. Later, if the hcg remais icreased, ad there is cocer about the source of the hcg, the hormoe replacemet therapy ca be iitiated to idetify a pituitary source as advocated by Cole et al. (2). If the hcg does ot suppress, other sources of hcg should be ivestigated. Oe potetial caveat to this study is that the cutoff of 45 IU/L was established based o data from 5 differet istrumets. Because FSH assays are ot well stadardized, it is possible that use of the 45 IU/L cutoff may provide slightly differet sesitivity ad specificity for differet assays. However, we should ote that at the coclusio of this study all samples were performed usig the Vitros ECi (except 7, which had isufficiet quatity for retestig). Usig the 45 IU/L cutoff, the sesitivity ad specificity remaied at 100% ad 75%, respectively. Grat/Fudig Support: Noe declared. Fiacial Disclosures: Noe declared. Ackowledgmets: We thak the medical techologists, laboratory persoel, ad iformatio techologists at each istitutio that helped to retrieve specimes, perform FSH testig, ad collect hcg data. 1. Syder J, Haymod S, Parvi C, Groowski A, Greache D. Diagostic cosideratios i the measuremet of huma chorioic goadotropi i agig wome. Cli Chem 2005;51: Cole L, Sasaki Y, Muller C. Normal productio of huma chorioic goadotropi i meopause. N Egl J Med 2007;356: Stema U, Alftha H, Rata T, Vartiaie E, Jalkae J, Seppala M. Serum levels of huma chorioic goadotropi i opregat wome ad me are modulated by goadotropi-releasig hormoe ad sex steroids. J Cli Edocriol Metab 1987;64: Odell W, Griffi J. Pulsatile secretio of chorioic goadotropi durig the ormal mestrual cycle. J Cli Edocriol Metab 1989;69: Birke S, Maydelma Y, Gawiowicz M, Poud A, Liu Y, Hartree S. Isolatio ad characterizatio of huma pituitary chorioic goadotropi. Edocriology 1996;137: Stema U, Alftha H, Hotakaie K. Huma chorioic goadotropi i cacer. Cli Biochem 2004; 37: Cliical Chemistry 54:4 (2008)