Featured Article|Articles in Press, 104466

Clinical “Red Flags” Differentiating Delayed Puberty From Enduring Hypogonadism

Published:October 22, 2022DOI:


      • Delayed pubertal onset is a common reason for endocrine consultation.
      • No gold standard test exists to differentiate self-limited constitutional delay of puberty and abiding hypogonadism (congenital hypogonadotropic hypogonadism).
      • Constitutional delay of puberty and congenital hypogonadotropic hypogonadism can have significant psychosocial sequelae.
      • Identifying red flags of congenital hypogonadotropic hypogonadism can accelerate diagnosis and timely initiation of treatment to improve health and well-being outcomes.


      Delayed puberty affects between 2% and 3% of the population and is a common reason for seeking endocrine consultation. Evaluation involves ruling out pathologic functional conditions disrupting puberty. Adolescents with constitutional delay of puberty (CDP) will initiate puberty spontaneously, albeit later than peers. However, some individuals have congenital hypogonadotropic hypogonadism (CHH) and will neither initiate nor progress in pubertal development. No single gold standard test differentiates CDP from CHH, posing diagnostic challenges for clinicians. This report provides an overview of normal/disrupted puberty, highlights clinical “red flags” facilitating identification of CHH, and emphasizes comprehensive and interprofessional approaches to care.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The Journal for Nurse Practitioners
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Dwyer A.A.
        • Phan-Hug F.
        • Hauschild M.
        • Elowe-Gruau E.
        • Pitteloud N.
        Transition in endocrinology: hypogonadism in adolescence.
        Eur J Endocrinol. 2015; 173: R15-R24
        • Chan Y.M.
        • Feld A.
        • Jonsdottir-Lewis E.
        Effects of the timing of sex-steroid exposure in adolescence on adult health outcomes.
        J Clin Endocrinol Metab. 2019; 104: 4578-4586
        • Dwyer A.A.
        • Smith N.
        • Quinton R.
        Psychological aspects of congenital hypogonadotropic hypogonadism.
        Front Endocrinol. 2019; 10: 353
        • Dwyer A.A.
        Psychosexual effects resulting from delayed, incomplete, or absent puberty.
        Curr Opin Endocr Metab Res. 2020; 14: 15-21
        • Raivio T.
        • Miettinen P.J.
        Constitutional delay of puberty versus congenital hypogonadotropic hypogonadism: genetics, management and updates.
        Best Pract Res Clin Endocrinol Metab. 2019; 33: 101316
        • Herman-Giddens M.E.
        • Slora E.J.
        • Wasserman R.C.
        • et al.
        Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network.
        Pediatrics. 1997; 99: 505-512
        • Herman-Giddens M.E.
        • Steffes J.
        • Harris D.
        • et al.
        Secondary sexual characteristics in boys: data from the Pediatric Research in Office Settings Network.
        Pediatrics. 2012; 130: e1058-e1068
        • Boehm U.
        • Bouloux P.M.
        • Dattani M.T.
        • et al.
        Expert consensus document: European consensus statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment.
        Nat Rev Endocrinol. 2015; 11: 547-564
        • Young J.
        • Xu C.
        • Papadakis G.E.
        • et al.
        Clinical management of congenital hypogonadotropic hypogonadism.
        Endocr Rev. 2019; 40: 669-710
        • Cangiano B.
        • Swee D.S.
        • Quinton R.
        • Bonomi M.
        Genetics of congenital hypogonadotropic hypogonadism: peculiarities and phenotype of an oligogenic disease.
        Hum Genet. 2021; 140: 77-111
        • Swee D.S.
        • Quinton R.
        Current concepts surrounding neonatal hormone therapy for boys with congenital hypogonadotropic hypogonadism.
        Expert Rev Endocrinol Metab. 2022; 17: 47-61
        • Dwyer A.A.
        Minipuberty: a primer for pediatric nurses.
        J Pediatr Nurs. 2020; 50: 138-139
        • Ljubicic M.L.
        • Busch A.S.
        • Upners E.N.
        • et al.
        A biphasic pattern of reproductive hormones in healthy female infants—the COPENHAGEN Minipuberty Study.
        J Clin Endocrinol Metab. 2022; 107: 2598-2605
        • Jonsdottir-Lewis E.
        • Feld A.
        • Ciarlo R.
        • Denhoff E.
        • Feldman H.A.
        • Chan Y.M.
        Timing of pubertal onset in girls and boys with constitutional delay.
        J Clin Endocrinol Metab. 2021; 106: e3693-e3703
        • Varimo T.
        • Miettinen P.J.
        • Kansakoski J.
        • Raivio T.
        • Hero M.
        Congenital hypogonadotropic hypogonadism, functional hypogonadotropism or constitutional delay of growth and puberty? An analysis of a large patient series from a single tertiary center.
        Hum Reprod. 2017; 32: 147-153
        • Davies K.
        • Dwyer A.A.
        Genetic competencies for effective pediatric endocrine nursing practice.
        J Pediatr Nurs. 2019; 48: 127-128
        • Harrington J.
        • Palmert M.R.
        Distinguishing self-limited delayed puberty from permanent hypogonadotropic hypogonadism: how and why?.
        J Clin Endocrinol Metab. 2021; 106: e5264-e5266
        • Mosbah H.
        • Bouvattier C.
        • Maione L.
        • et al.
        GnRH stimulation testing and serum inhibin B in males: insufficient specificity for discriminating between congenital hypogonadotropic hypogonadism from constitutional delay of growth and puberty.
        Hum Reprod. 2020; 35: 2312-2322
        • Chaudhary S.
        • Walia R.
        • Bhansali A.
        • et al.
        FSH-stimulated inhibin B (FSH-iB): a novel marker for the accurate prediction of pubertal outcome in delayed puberty.
        J Clin Endocrinol Metab. 2021; 106: e3495-e3505
        • Chan Y.M.
        • Lippincott M.F.
        • Sales Barroso P.
        • et al.
        Using kisspeptin to predict pubertal outcomes for youth with pubertal delay.
        J Clin Endocrinol Metab. 2020; 105: e2717-e2725
        • Saengkaew T.
        • Howard S.R.
        Genetics of pubertal delay.
        Clinl Endorinol. 2022; 97: 473-482
        • Saengkaew T.
        • Patel H.R.
        • Banerjee K.
        • et al.
        Genetic evaluation supports differential diagnosis in adolescent patients with delayed puberty.
        Eur J Endocrinol. 2021; 185: 617-627
        • Maione L.
        • Dwyer A.A.
        • Francou B.
        • et al.
        Genetics in endocrinology: genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing.
        Eur J Endocrinol. 2018; 178: R55-R80
        • Zhu J.
        • Chan Y.M.
        Adult consequences of self-limited delayed puberty.
        Pediatrics. 2017; 139e20163177
        • Zhu J.
        • Chan Y.M.
        Fertility issues for patients with hypogonadotropic causes of delayed puberty.
        Endocrinol Metab Clin North Am. 2015; 44: 821-834
        • Dwyer A.A.
        • Quinton R.
        The metabolic syndrome in central hypogonadotrophic hypogonadism.
        Front Horm Res. 2018; 49: 156-169
        • Dunkel L.
        • Quinton R.
        Transition in endocrinology: induction of puberty.
        Eur J Endocrinol. 2014; 170: R229-R239
        • Zhu J.
        • Feldman H.A.
        • Eugster E.A.
        • et al.
        Practice variation in the management of girls and boys with delayed puberty.
        Endocr Pract. 2020; 26: 267-284
        • Persani L.
        • Bonomi M.
        • Cools M.
        • et al.
        ENDO-ERN expert opinion on the differential diagnosis of pubertal delay.
        Endocrine. 2021; 71: 681-688
        • Gini G.
        • Espelage D.L.
        Peer victimization, cyberbullying, and suicide risk in children and adolescents.
        JAMA. 2014; 312: 545-546
        • Bhasin S.
        • Cunningham G.R.
        • Hayes F.J.
        • et al.
        Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline.
        J Clin Endocrinol Metab. 2010; 95: 2536-2559
        • Nordenstrom A.
        • Ahmed S.F.
        • van den Akker E.
        • et al.
        Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.
        Eur J Endocrinol. 2022; 186: G9-G49
        • Dwyer A.A.
        • Tiemensma J.
        • Quinton R.
        • Pitteloud N.
        • Morin D.
        Adherence to treatment in men with hypogonadotrophic hypogonadism.
        Clinl Endorinol. 2017; 86: 377-383
        • Rastrelli G.
        • Corona G.
        • Mannucci E.
        • Maggi M.
        Factors affecting spermatogenesis upon gonadotropin-replacement therapy: a meta-analytic study.
        Andrology. 2014; 2: 794-808
        • Dwyer A.A.
        • Raivio T.
        • Pitteloud N.
        Gonadotrophin replacement for induction of fertility in hypogonadal men.
        Best Pract Res Clin Endocrinol Metab. 2015; 29: 91-103
        • Dwyer A.A.
        • Pitteloud N.
        Transition of care from childhood to adulthood: congenital hypogonadotropic hypogonadism.
        Endocr Dev. 2018; 33: 82-98


      Both authors are at Massachusetts General Hospital, Harvard Center for Reproductive Medicine, Boston. Andrew A. Dwyer, PhD, FNP-BC, is also an associate professor at the William F. Connell School of Nursing, Boston, College, Chestnut Hill, MA, and can be contacted at [email protected]


      Yee-ming Chan, MD, PhD, is also with the Division of Endocrinology, Department of Pediatrics, Boston Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, MA.