Recent advances in the understanding and management of delayed puberty

Delayed puberty, especially in boys, is a common presentation in paediatrics. Recent advances have improved our understanding of the neuroendocrine, genetic and environmental factors controlling pubertal development, and hence inform the pathophysiology of delayed puberty. The discovery of kisspeptin signalling through its receptor identified neuroendocrine mechanisms controlling the gonadotrophin-releasing hormone (GnRH) pulse generator at the onset of puberty. Genetic mechanisms from single gene mutations to single nucleotide polymorphism associated with delayed puberty are being identified. Environmental factors, including nutritional factors and endocrine disruptors, have also been implicated in changes in secular trends and abnormal timing of puberty. Despite these advances, the key clinical question is to distinguish delayed puberty associated with an underlying pathology or hypogonadism from constitutional delay in growth and puberty, which remains challenging as biochemical tests are not always discriminatory. The diagnostic accuracies of newer investigations, including 36-hour luteinising hormone releasing hormone (LHRH) tests, GnRH-agonist tests, antimullerian hormone and inhibin-B, require further evaluation. Sex hormone replacement remains the main available treatment for delayed puberty, the choice of which is largely dictated by clinical practice and availability of the various sex steroid preparations. Spontaneous reversal of hypogonadism has been reported in boys with idiopathic hypogonadotrophic hypogonadism after a period of sex steroid treatment, highlighting the importance of reassessment at the end of pubertal induction. Novel therapies with a more physiological basis such as gonadotrophins or kisspeptin-agonist are being investigated for the management of hypogonadotrophic hypogonadism. Careful clinical assessment and appreciation of the normal physiology remain the key approach to patients with delayed puberty.

Download Full-text

An Update on Aetiopathology, Various Genetic Causes and Management of Delayed Puberty-A Minireview

Journal of Pediatrics & Neonatal Biology ◽

10.33140/jpnb.04.02.04 ◽

2019 ◽

Vol 4 (2) ◽

Keyword(s):

Environmental Factors ◽

Normal Population ◽

Pubertal Development ◽

Hormone Replacement ◽

Hypogonadotropic Hypogonadism ◽

Clinical Signs ◽

Sex Steroid ◽

Delayed Puberty ◽

Main Question ◽

Releasing Hormone

Delayed Puberty (DP), especially in boys, is a common presentation in paediatrics. By definition DP is defined as the presentation of clinical signs of puberty 2-2.5SD later than in the normal population. With the recent advances in understanding of the neuroendocrine, genetic and environmental factors controlling pubertal development it has become easier to understand the pathophysiology of DP. The discovery of kisspeptin signaling through its receptor identified neuroendocrine mechanisms controlling the gonadotropin releasing hormone (GnRH) pulse generator at the onset of puberty. Genetic mechanisms from single gene mutations to single nucleotide polymorphisms associated with DP are being identified. Environmental factors, including nutritional factors, besides endocrine disruptors, have been associated with the secular trends and abnormal timing of puberty. Inspite of these advances, the main question remains how to differentiate DP associated with underlying pathology of hypogonadism from constitutional delay in growth and puberty (CDP) that remains challenging as biochemical tests do not always discriminate the 2.The diagnostic accuracies of newer investigations which include the 36-hour luteininzing hormone releasing hormone(LHRH) tests, GnRH agonist tests, antimullerian hormone and inhibin B, need further evaluation. Sex hormone replacement remains the main therapy that is available for DP, whose choice is based on clinical practice and the availability of the various sex steroid preparations. Spontaneous reversal of hypogonadism has been reported in boys having idiopathic hypogonadotropic hypogonadism following sex steroid treatment, which highlights the importance of reassessment at the end of pubertal induction .Novel therapies having a more physiological bases like gonadotropins or kisspeptin agonists are getting investigated for the management of hypogonadotropic hypogonadism. A careful assessment and knowledge of the normal physiology remains the mainstay of managing patients with DP.

Download Full-text

Application of gonadotropin releasing hormone in hypogonadotropic hypogonadism--diagnostic and therapeutic aspects

Acta Endocrinologica ◽

10.1530/eje.0.151u089 ◽

2004 ◽

pp. U89-U94 ◽

Cited By ~ 41

Author(s):

HA Delemarre-van de Waal

Keyword(s):

Pulse Generator ◽

Pubertal Development ◽

Hypogonadotropic Hypogonadism ◽

Gonadotropin Releasing Hormone ◽

Delayed Puberty ◽

Releasing Hormone ◽

Testicular Growth ◽

Pulsatile Gnrh ◽

Portable Pump

BACKGROUND: Puberty is the result of reactivation of the gonadotropin releasing hormone (GnRH) pulse generator resulting in an increasing release of GnRH by the hypothalamus, which stimulates the gonadotropic cells of the pituitary to synthesize and secrete LH and FSH. Hypogonadotropic hypogonadism (HH) is often the result of GnRH deficiency. The clinical picture is characterized by the absence of pubertal development and infertility. It is difficult to differentiate HH from delayed puberty since low gonadotropin and low testosterone levels are found in both conditions. We hypothesized that long-term GnRH administration may differentiate between the two conditions by a difference in the increase of gonadotropins, the idea being that in normal delayed puberty the pituitary of the patient has been primed with GnRH during the fetal and early postnatal period. PATIENTS: Seventeen adolescents suspected of having hypogonadotropic hypogonadism were treated with pulsatile GnRH for 7 days. At the present time, the diagnosis of these patients is known and the results of the long-term GnRH stimulation have been evaluated according to the present diagnosis. RESULTS: The results show that the increase in gonadotropins following GnRH treatment is similar in both conditions. Therefore, at a prepubertal age a normal delayed puberty cannot be distinguished from hypogonadotropic hypogonadism using long-term GnRH stimulation. Long-term pulsatile GnRH treatment is a physiological therapy for the induction of puberty. Unlike testosterone it has the advantage of stimulation of testicular growth and fertility, as well as virilization, in males. We have treated 68 male patients with HH with pulsatile GnRH. The results show testicular growth and virilization in all the patients and spermatogenesis in 58 patients. Wearing a portable pump is cumbersome. However, the patients were very motivated and adapted very easily to this inconvenience. When spermatogenesis had developed, GnRH treatment was changed to human chorionic gonadotropin (hCG) administration 1-2 times per week intramuscularly or subcutaneously. During hCG therapy spermatogenesis was maintained or even improved. At least ten patients fathered children. CONCLUSION: Pulsatile GnRH cannot distinguish between a normal delayed puberty and a hypothalamic defect in still prepubertal patients. Pulsatile GnRH offers an appropriate way to initiate testicular growth including virilization and fertility in males with hypogonadotropic hypogonadism.

Download Full-text

TRANSITION IN ENDOCRINOLOGY: Induction of puberty

Acta Endocrinologica ◽

10.1530/eje-13-0894 ◽

2014 ◽

Vol 170 (6) ◽

pp. R229-R239 ◽

Cited By ~ 57

Author(s):

Leo Dunkel ◽

Richard Quinton

Keyword(s):

Pubertal Timing ◽

Hormone Replacement ◽

Adult Life ◽

Charge Syndrome ◽

Delayed Puberty ◽

Congenital Defects ◽

Hypogonadotrophic Hypogonadism ◽

Future Fertility ◽

Pubertal Delay ◽

Sexual Characteristics

Puberty is the period during which we attain adult secondary sexual characteristics and reproductive capability. Its onset depends upon reactivation of pulsative GNRH, secretion from its relative quiescence during childhood, on the background of intact potential for pituitary–gonadal function. This review is intended: to highlight those current practices in diagnosis and management that are evidence based and those that are not; to help clinicians deal with areas of uncertainty with reference to physiologic first principles; by sign-posting relevant data arising from other patient groups with shared issues; to illustrate how recent scientific advances are (or should be) altering clinician perceptions of pubertal delay; and finally, to emphasise that the management of men and women presenting in advanced adult life with absent puberty cannot simply be extrapolated from paediatric practice. There is a broad spectrum of pubertal timing that varies among different populations, separated in time and space. Delayed puberty usually represents an extreme of the normal, a developmental pattern referred to as constitutional delay of growth and puberty (CDGP), but organic defects of the hypothalamo–pituitary–gonadal axis predisposing to hypogonadism may not always be initially distinguishable from it. CDGP and organic, or congenital hypogonadotrophic hypogonadism are both significantly more common in boys than girls. Moreover, around 1/3 of adults with organic hypogonadotrophic hypogonadism had evidence of partial puberty at presentation and, confusingly, some 5–10% of these subsequently may exhibit recovery of endogenous gonadotrophin secretion, including men with Kallmann syndrome. However, the distinction is crucial as expectative (‘watch-and-wait’) management is inappropriate in the context of hypogonadism. The probability of pubertal delay being caused by organic hypogonadism rises exponentially both with increasing age at presentation and the presence of associated ‘red flag’ clinical features. These ‘red flags’ comprise findings indicating lack of prior ‘mini-puberty’ (such as cryptorchidism or micropenis), or the presence of non-reproductive congenital defects known to be associated with specific hypogonadal syndromes, e.g. anosmia, deafness, mirror movements, renal agenesis, dental/digital anomalies, clefting or coloboma would be compatible with Kallmann (or perhaps CHARGE) syndrome. In children, interventions (whether in the form or treatment or simple reassurance) have been historically directed at maximising height potential and minimising psychosocial morbidity, though issues of future fertility and bone density potential are now increasingly ‘in the mix’. Apubertal adults almost invariably harbour organic hypogonadism, requiring sensitive acknowledgement of underlying personal issues and the timely introduction of sex hormone replacement therapy at more physiological doses.

Download Full-text

Functional Characteristics of Novel FGFR1 Mutations in Patients with Isolated Gonadotropin-Releasing Hormone Deficiency

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-1151-4800 ◽

2020 ◽

Author(s):

Jin-Ho Choi ◽

Arum Oh ◽

Yena Lee ◽

Gu-Hwan Kim ◽

Han-Wook Yoo

Keyword(s):

Pubertal Development ◽

Hypogonadotropic Hypogonadism ◽

Gonadotropin Releasing Hormone ◽

Delayed Puberty ◽

Functional Assay ◽

Functional Characteristics ◽

Releasing Hormone ◽

Phenotypic Spectrum ◽

The Impact

Abstract Background Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) has a wide phenotypic spectrum including Kallmann syndrome (KS) and normosmic idiopathic hypogonadotropic hypogonadism (nIHH). FGFR1 mutations have been identified in 3–10% of patients with KS or nIHH. This study was performed to investigate clinical phenotypes and functional characteristics of FGFR1 mutations in patients with IGD. Methods This study included 8 patients (from 7 families) with FGFR1 mutations identified by targeted gene panel sequencing or whole exome sequencing (WES). The impact of the identified mutations on FGFR1 function was assessed using in vitro studies. Results Seven heterozygous mutations in FGFR1 were identified in 8 patients from 7 independent families. The patients exhibited a wide spectrum of pubertal development, including anosmia in a prepubertal boy (n=1), delayed puberty (n=2), nIHH (n=3), and KS (n=2). Four of the mutations were classified as likely pathogenic, and the other three were variants of uncertain significance. FGF8-FGFR1 signaling activities for the novel FGFR1 variants (p.Y339H, p.S681I, and p.N185Kfs*16) were reduced by in vitro functional assay, indicating loss-of-function mutations. Conclusions This study identified seven rare sequence variants in FGFR1 in patients with KS and nIHH. Probands with an FGFR1 mutations displayed a wide phenotypic spectrum ranging from KS to anosmia. A prepubertal male with anosmia should be followed up to assess pubertal development because they can manifest hypogonadotropic hypogonadism after puberty. These results expand the phenotypic spectrum of FGFR1 mutations and suggest a broader biologic role of FGFR1 in reproduction.

Download Full-text

Sex steroid hormones and breast cancer: is there a link with oral contraceptives and hormone replacement therapy?

The Medical Journal of Australia ◽

10.5694/j.1326-5377.1992.tb126427.x ◽

1990 ◽

Vol 156 (2) ◽

pp. 124-132 ◽

Cited By ~ 10

Author(s):

Soo Keat Khoo ◽

Pamela Chick

Keyword(s):

Breast Cancer ◽

Hormone Replacement Therapy ◽

Replacement Therapy ◽

Steroid Hormones ◽

Oral Contraceptives ◽

Hormone Replacement ◽

Sex Steroid Hormones ◽

Sex Steroid

Download Full-text

Menarche in primary ovarian insufficiency after a month of hormone replacement therapy: a case report

Journal of Medical Case Reports ◽

10.1186/s13256-020-02603-6 ◽

2021 ◽

Vol 15 (1) ◽

Author(s):

Biwen Cheng

Keyword(s):

Replacement Therapy ◽

Hormone Replacement ◽

Estrogen Therapy ◽

Primary Ovarian Insufficiency ◽

Hormonal Replacement Therapy ◽

Delayed Puberty ◽

Ovarian Insufficiency ◽

Breakthrough Bleeding ◽

Hormonal Replacement ◽

Ovarian Dysgenesis

Abstract Background Gynecologic anomalies, including uterine agenesis and ovarian dysgenesis, are some of the several differential diagnoses in adolescent females with primary amenorrhea and delayed puberty. Primary ovarian insufficiency is reported in the clinical practice of reproductive endocrinology can be determined by conducting sex hormone tests to evaluate the hypothalamic-pituitary-ovarian axis. However, confirmation of Mullerian agenesis by image modalities can be extremely challenging. Once the diagnosis is established, breakthrough bleeding usually occurs 2 to 3 years after hormonal replacement therapy. Case presentation We report a case of a seventeen year old Taiwanese female, 46 XX karyotype, with ovarian dysgenesis and an initial tentative diagnosis of uterine agenesis who experienced a breakthrough bleeding after a month of hormonal replacement therapy. Conclusions The breakthrough bleeding after a month of estrogen therapy in primary ovarian insufficiency is uncommon, and the diagnosis of the absent uterus can have an extensive psychological impact on patients and their families.

Download Full-text