Although T, FSH, and LH levels were not significantly different in patients and control subjects, inhibin B was higher in patients than in control subjects

ANTONIAZZI, Franco

Camilot M.

Cavarzere P.

Franceschi R

GAUDINO, Rossella

Perlini S.

Tatò L.

Teofoli F.

Vincenzi M.

Tatò L.

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2Paolo CavaMonica ViRossella GRoberto FrSilvia PerlMarta CamFrancescaFranco AnLuciano TaPediatric CVerona,Received Jan2010; publisP.C. has nothnothing to ddisclose. MF.A. has noReprint requesversity of VVerona, Itayahoo.it).FertilitCopyri350Possible andrologic markers in elevatedneonatal 17-hydroxyprogesteroneIn this prospective study, we analyzed 30 male infants with increased neonatal 17-hydroxyprogesterone (17OH-P)(patients) and for comparison 52 age-matched healthy babies (control subjects) with the aim of investigating thehypothalamic-pituitary-testis axis in the first 6 months of life. Although T, FSH, and LH levels were not signifi-cantly different in patients and control subjects, inhibin B was higher in patients than in control subjects. Thereforewe suggest a clinical follow-up of these babies during childhood and puberty to verify the evolution of their con-dition. (Fertil Steril 2010;94:2350–2. 2010 by American Society for Reproductive Medicine.)Key Words: Inhibin B, 17OH-P, newborn, weight, maleDuring the first months of life, the hypothalamic-pituitary-gonadal asymptomatic and untreated neonatal hyper-17OHP-emia canaxis is transiently activated in males, with increased gonadotro-pins, testosterone, and inhibin B levels (1, 2). Peak levels areobserved at around the third month of life. Later on, serumhormone levels significantly decrease, remaining low untilpuberty (3–5).Undetectable levels of inhibin B were observed in infants withbilateral absent testis, and lower levels were seen in infants withcryptorchidism, monorchidism, and testicular damage (4, 6, 7).Recently, low levels of inhibin B were also described inprepubertal boys with congenital adrenal hyperplasia (CAH),even in the absence of testicular adrenal rest (8). Inhibin B levelsin males presenting neonatal increase of 17-hydroxyprogesterone(17OH-P) (40% of all positives at neonatal screening for 21-hy-droxylase deficiency [21-OHD] [9]) are presently unknown. Thisinformation, however, is interesting in view of recent studies re-porting a high rate of infertility in patients with congenital adrenaldisease (10–13). As a matter of fact, it is not known whether anrzere, M.D.ncenzi, Ph.D.audino, M.D.anceschi, M.D.ini, M.D.ilot, Ph.D.Teofoli, Ph.D.toniazzi, M.D.to, M.D.linic, Department of Mother and Child, University ofVerona, Italyuary 4, 2010; revised April 10, 2010; accepted April 16,hed online May 26, 2010.ing to disclose. M.V. has nothing to disclose. R.G. hasisclose. R.F. has nothing to disclose. S.P. has nothing to.C. has nothing to disclose. F.T. has nothing to disclose.thing to disclose. L.T. has nothing to disclose.ts: Paolo Cavarzere, M.D., Department of Pediatrics, Uni-erona, Policlinico G.B. Rossi, Piazzale Scuro 10, 37134ly (FAX: þ39 045 8124302; E-mail: paolocavarzere@y and Sterility Vol. 94, No. 6, November 2010ght ª2010 American Society for Reproductive Medicine, Pmodify the inhibin B secretion, nor its consequences in adulthood.Therefore, the aim of the present prospective study was to inves-tigate the hypothalamic-pituitary-gonadal axis in the first 6 monthsof life in male babies with increased neonatal 17OH-P values, andto compare their data with those obtained in normal infants of thesame age.Thirty newborns with neonatal hyper-17OHP-emia (patients)were analyzed. Inclusion criteria were: male gender, gestationalage (GA) >36 weeks, uncomplicated gestation and delivery, birthweight (BW) >2,500 g, absence of congenital disease, and in-creased 17OH-P levels at neonatal screening for 21-OHD. Exclu-sion criteria were: preterm delivery, classic salt wasting form of21-OHD, and acute illness in the first days of life.For comparison, we enrolled 52 age-matched healthy malebabies (control subjects), with the same inclusion and exclusioncriteria, except for displaying among the inclusion criteria valuesof 17OH-P within the normal reference range.The study was conducted in compliance with the terms of theHelsinki II Declaration, and was approved by the Institutional Re-view Board of Verona. Informed written consents were obtainedfrom the parents of the patients and control subjects.The newborn screening 17OH-P cut-off level for term babieswas set at 40 nmol/L. Positive babies at screening were recalledto confirm the result. For each patient, we recorded GA, BW, birthlength (BL), and state of health. These infants were assessed every3 months from birth to 6 months of life and submitted to completephysical examination. All of them underwent blood withdrawal tomeasure serum 17OH-P, electrolytes, FSH, LH, T, and inhibin Blevels. Testicular volume was assessed using a standard Prader or-chidometer. Testicular ultrasound scanning was performed at thefirst and third evaluations by the same radiologist.For comparison, we assessed T, gonadotropins, and inhibin B incontrol subjects at approximately the same age as the patients.Newborn screening for 21-OHD is based on 17OH-P fluoroim-munoassay on blood spots (AutoDelfia Neonatal 17OH-P Kit;Wallac Oy, Turku, Finland). Serum FSH, LH, and T measurementswere determined by immunometric assay (Immulite 2000;0015-0282/$36.00ublished by Elsevier Inc. doi:10.1016/j.fertnstert.2010.04.040TABLE 1Growth and hormonal data in patients and controlsubjects (mean ± SD).Patients(n[30)Control subjects(n[52)BirthWeight (g) 3,251.5  362.0 3,141.4  460.3Length (cm) 50.3  1.8 50.6  2.0GA (wk) 38.7  1.3 39.1  1.2Screening 17OH-P(nmol/L)133.5  228.2y 11.1  5.4First monthWeight (g) 3,857.2  574.1 3,886.8  550.6Length (cm) 53.1  2.1 53.6  2.1FSH (U/L) 1.4  1.0 1.4  1.6LH (U/L) 3.0  2.1 3.3  2.4T (nmol/L) 8.2  7.2 4.5  5.0Inhibin B (pg/mL) 119.9  50.6* 89.5  37.4Age (d) 25.7  9.2 25.2  11.7Third monthWeight (g) 6,063.4  673.7* 5,076.0  711.7Length (cm) 60.6  1.7y 56.3  3.0FSH (U/L) 1.6  0.8 2.0  1.3LH (U/L) 3.0  2.3 2.8  1.9T (nmol/L) 5.8  3.1 2.7  2.9Inhibin B (pg/mL) 183.1  87.8z 141.7  40.0kAge (d) 90.0  13.2 86.6  26.7Sixth monthWeight (g) 7,742.5  746.2* 6,981.9  1,268.7Length (cm) 67.0  1.5 65.4  3.8FSH (U/L) 0.8  0.5 1.0  1.3LH (U/L) 0.8  0.6 1.2  1.3T (nmol/L) 1.0  1.0 0.1  0.1Inhibin B (pg/mL) 202.2  78.7*,x 117.4  69.1Age (d) 180.8  6.6 180.7  20.9Note: 17OH-P ¼ 17-hydroxyprogesterone; GA ¼ gestational age.* Patients vs. control subjects: P< .05.y Patients vs. control subjects: P< .001.z Patients, first month vs. third month: P< .005.x Patients, first month vs. sixth month: P< .001.k Control subjects, first month vs. third month: P< .001.Cavarzere. Correspondence. Fertil Steril 2010.FSiemens, Erlangen, Germany). Serum 17OH-P was assayed byRIA (DSL-5000 Active 17a-OH Progesterone Coated-TubeRadioimmunoassay; Diasorin, Saluggia, Italy), and serum inhibinB by ELISA (Active Inhibin B ELISA, Diagnostic SystemsLaboratories, Webster, TX).Statistical analyses were performed using SPSS 16.0 for Win-dows (SPSS, Chicago, IL). Comparisons between groups were per-formed by using Student t test or Mann-Whitney U test, andcorrelations by using Spearman or Pearson test, wheneverappropriate.No differences in patients’ and control subjects’ neonatal fea-tures were detected; however, during the clinical follow-up, pa-tients showed a significant increased growth (Table 1). Allpatients’ testicular volumes appeared normal for age, and they re-mained in the normal range for age during the entire follow-up. Nodifferences were reported in their testis size compared with controlsubjects. Testicular ultrasound showed, in all of the subjects, bothtestes in the scrotum. None presented adrenal rest or alterations intesticular parenchyma. Hydrocele was found in 10 babies at firstexamination, bilateral in five of them and persistent in one.All patients showed normal electrolyte values but increased17OH-P serum levels at the first measurement (median 17OH-P:37.5 [range 12.6–210.0] nmol/L). Then, 17OH-P levels decreasedwith age (median 10.1 [5.4–30.0] nmol/L and 2.7 [1.4–36.0] nmol/Lat 3 and 6 months, respectively), reaching the reference range atthe sixth month of life (14, 15). None of them needed treatmentfor hyper-17OHP-emia.Whereas inhibin B was higher in patients than in control sub-jects, no significant differences in testosterone and gonadotropinslevels were found (Table 1).In the patients, we did not find any significant correlation be-tween inhibin B, FSH, and T in the first period of life. Correlationswere found between inhibin B and LH at the first serum evaluation(r ¼ 0.447; P<.05) and between screening 17OH-P levels and in-hibin B levels at the first month of life (r ¼ 0.617; P<.005). Thedecrease of 17OH-P levels between the first and the third evalua-tions correlated with the increase in weight between the third andthe sixth month (r ¼ 0.600; P<.05). In the control subjects, nocorrelations were observed.None of the patients presented conditions explaining their in-creased 17OH-P. No severe enzymatic deficiencies were evidentat birth, and their androgen pattern allowed us to exclude a simplevirilizing form of CAH, although we could not exclude a nonclas-sic form of the disease (9). Consequently, we hypothesized that theneonatal hyper-17OHP-emia was probably due to a slow enzy-matic maturation in the adrenal steroidogenesis process.In agreement with earlier studies (2, 5, 16), we did not find anycorrelation between FSH and inhibin B in the first months of life,whereas patients’ LH and inhibin B, at the first serum evaluation,were positively correlated. These data seem to confirm thehypothesis of a role played by LH in the initial regulation ofinhibin B synthesis and secretion (16, 17).There is no evidence that increased 17OH-P levels in the firstyear of life modify fertility in later years, and data of inhibin Blevels in newborns with congenital adrenal disease are lacking.Nevertheless, some studies described a higher risk of infertilityertility and Sterilityin adult males with CAH, considering inhibin B to be an importantindex of fertility as a marker of Sertoli cell function (10–13, 18).Inhibin B was demonstrated to be a marker of Sertoli cellsduring childhood as well (2–4), and it was hypothesized that itmight be a predictor of future fertility in male newborns (19). Re-cently, low inhibin B levels were described in prepubertal boyswith CAH, suggesting a gonadal dysfunction in these patients,although the impact of this finding on future fertility remainedunknown (8). In contrast, our most intriguing finding was theincreased levels of inhibin B in infants with elevated neonatal17OH-P values compared with control subjects.High inhibin B levels were described in prepubertal patientswith specific disorders in the androgens’ biosynthesis or action.The cause of this finding is still unknown, but it was hypothesizedthat the deficit of testosterone action was the primus movens, fol-lowed by an increased daily production of FSH and/or its insuffi-cient paracrine action on Sertoli cells (20, 21). Another speculative23512interpretation of our data could involve Sertoli cells, which in caseof androgens’ excess might be stimulated by elevated neonatal17OH-P levels, and consequently display a precociousmaturation with active proliferation and increased production ofinhibin B (22, 23). This hypothesis is indirectly confirmed bythe correlation between screening 17OH-P values and inhibin Blevels. However, the role of neonatal hyper-17OHP-emia in thepossible precocious maturation of Sertoli cells and their relation-ship on future fertility remain unclear.Infants with neonatal hyper-17OHP-emia had heavier weightand longer length than control subjects at 3 months of life, andthis finding was confirmed at the sixth-month evaluation only forweight.An earlier study described no differences in the growth duringthe first year of life in children affected by CAH undiagnosed atbirth, suggesting the presence of relative resistance to androgenexcess during this period (24). This finding was supported by theevidence of normal growth in other pathologic conditions with352 Cavarzere et al. Correspondenceelevated androgen levels (25). In contrast, some studies analyzedthe effect in the uterus of androgen excess, reporting that BL ofbabies with CAH was higher than that of the normal population(26, 27). In the present patients, BW and BL were notsignificantly different compared with control subjects, but, overtime, their weight and length exceeded those of the controlsubjects. Therefore, we can hypothesize that neonatal hyper-17OHP-emia influences the growth for some months after birth.The correlation between postnatal decrease of 17OH-P levelsand the increase of weight between the third and the sixth monthsindirectly confirm this hypothesis.In conclusion, we found that male infants with elevated neonatal17OH-P values had higher inhibin B levels and increased weightcompared with a control population until at least 6 months oflife. Whether elevated inhibin B levels in the first months of lifehave an effect on testicular function later in life remains unknown.Further follow-up of these babies during childhood and puberty isuseful to assess the evolution of their clinical condition.REFERENCES1. Winter JS, Hughes IA, Reyes FI, Faiman C.Pituitary-gonadal relations in infancy: 2. Patternsof serum gonadal steroid concentrations in manfrom birth to two years of age. J Clin EndocrinolMetab 1976;42:679–86.2. Andersson AM, Toppari J, Haavisto AM,Petersen JH, Simell T, Simell O, et al. Longitudinalreproductive hormone profiles in infants: peak ofinhibin B levels in infant boys exceeds levels inadultmen. J Clin EndocrinolMetab 1998;83:675–81.3. Chada M, Prusa R, Bronsky J, Kotaka K, Idlova K,Pechova M, et al. Inhibin B, follicle stimulatinghormone, luteinizing hormone and testosteroneduring childhood and puberty in males: changesin serum concentrations in relation to age andstage of puberty. Physiol Res 2003;52:45–51.4. Andersson AM, Skakkebaek NE. Serum inhibin Blevels during male childhood and puberty. MolCell Endocrinol 2001;180:103–7.5. Bergada I, Bergada C, Campo S. Role of inhibins inchildhood and puberty. J Pediatr Endocrinol Metab2001;14:343–53.6. Suomi AM, Main KM, Kaleva M, Schmidt IM,Chellakooty M, Virtanen HE, et al. 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Possible andrologic markers in elevated neonatal 17-hydroxyprogesterone

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Possible andrologic markers in elevated neonatal 17-hydroxyprogesterone

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