Treatment of late puberty

The induction of puberty is physically and emotionally disturbing. For that reason, low doses of medication need to be introduced and increased slowly, regardless of the age at which treatment is started. In boys with growth delay, the growth spurt may be induced earlier in the sequence of pubertal developmental by using oxandrolone, but puberty itself is induced by slowly increasing doses of testosterone. For girls with ovarian failure, oestradiol should be introduced from the age of 8 or 9 years, but doses should be very cautiously increased in order to allow time for cosmetic development of breasts and growth of the uterus.     

Diagnosis of late puberty

Late puberty is defined as the lack of pubertal development at two standard deviations above the mean age for the general population of the geographical area. In practical terms, this is a chronological age of 14 years for males (testicular volume <4 ml) and 13 years for girls (lack of thelarche). The goal of the assessment is to determine whether the delay or lack of development is due to a lag in normal pubertal maturation or represents an abnormality that must be investigated. Etiologies of pubertal delay and pubertal failure include: a) Constitutional delay of puberty (healthy patients with a clinical history of delayed growth and development; b) Hypogonadotropic states (congenital abnormalities, tumours, endocrinopathies); c) Hypergonadotropic states (chromosomal alterations, syndromes, genetic disorders, radiotherapy/chemotherapy); d) Secondary to chronic illness (organic abnormalities, oncological diseases, malnutrition, eating disorders and endocrinopathies). Diagnostic evaluation must include: a detailed physical examination, including auxological parameters (height and bone maturation), personal and familial antecedents, measurements of general hematological and biochemical parameters, gonadotropins, prolactin, thyroid hormones, sex steroids, growth hormone and growth factors. When necessary, an MRI must be performed. A karyotype is indicated in girls with delayed puberty and short stature and in boys who have small testes and hypergonadotropism.     

Etiologies of late puberty.

An expected lack of pubertal development can be due to an already diagnosed disease. The diagnosis of an unexpected lack of puberty is a difficult task. We have analyzed the etiologies of late puberty in 106 adolescents: 68 boys aged over 15 years and 38 phenotypic girls aged over 13 years. According to their clinical and biological (gonadotropin) data, they were classified in 3 groups. In the first group, hypergonadotropism was observed only in 19 females; pure gonadal dysgenesis was found in 2 cases with 46,XY, in 2 with 46,Xdel(Xq) karyotypes and 9 cases were 46,XX constitutions; 2 sisters had also blepharophimosis; in 3 cases the ovarian failure was due to autoimmune disease, and 1 case, genetically male, had 17 alpha-hydroxylase deficiency. The second group had gonadotropin insufficiency and consisted of 68 adolescents, 57 males and 11 females, with low gonadotropin levels: 33 were anosmic; in the boys, cryptorchism was present in 68% and micropenis in 31%; 38 had a familial history of hypogonadism, the transmission of which was matrilineal in 16, patrilineal in 13 and recessive autosomal in 7. The third group had low or low-normal gonadotropin levels: 22 cases of constitutional delay of puberty (11 cases in both sexes), demonstrated by further normal puberty during the follow-up. No clinical marker and familial history in 50% were noted.     

Factors affecting onset of puberty

In humans, foetal and early postnatal growth failure may have persistent consequences for growth and pubertal development in later life. During this period, the developing organs are still plastic to change their function, which may have long-lasting effects. At the time of onset of puberty, acute factors may also interfere with pubertal development. Malnutrition, as seen in anorexic patients, and chronic diseases with malabsorption or diseases with systemic effects result in a delayed onset of puberty. We have observed an earlier onset of puberty in girls with low birth weight; menarcheal age also tended to be earlier. In boys, a low birth weight tended to be associated with a later development. Two rat models with growth failure based on perinatal malnutrition have been examined, one with intrauterine growth retardation (IUGR) by ligation of the uterine arteries and one with postnatal food restriction (FR) by increasing the litter size postnatally. In both models, the rats had a persistent postnatal growth failure. The onset of puberty in female rats, defined by vaginal opening, was delayed only in the IUGR group. Despite a significantly lower weight, there was no difference in the timing of puberty onset in the FR group. In IUGR rats, the ovaries had fewer follicles, while FR rats had a normal number of follicles but an abnormal maturation pattern. In male rats, both models showed a delayed onset of puberty, defined by the balano-preputial separation, as well as impaired testicular function, shown by decreased testosterone levels. These data indicate that early malnutrition during a critical developmental time window may have long-lasting effects on pubertal development, including gonadal maturation in both humans and rats.     

The neurobiology of female puberty

In this review, studies are described indicating that the increase in pulsatile release of gonadotropin releasing hormone that signals the initiation of puberty requires both changes in transsynaptic communication and the activation of glia-to-neuron signaling pathways. The major players in the transsynaptic control of puberty are neurons that utilize excitatory and inhibitory amino acids as transmitters. Glial cells employ a combination of trophic factors and small cell-cell signaling molecules to regulate neuronal function and thus promote sexual development. A neuron-to-glia signaling pathway mediated by excitatory amino acids serves to coordinate the simultaneous activation of transsynaptic and glia-to-neuron communication required for the advent of sexual maturity.     

The troubled puberty of malaria parasites

Sexual differentiation of malaria parasites is essential for transmission, yet the underlying mechanisms are poorly understood. Russell et al. elegantly combined a loss-of-function screen with single-cell RNA-sequencing to identify key factors in this process. Gomes et al. further characterized one of them, MD1, as a regulator contributing to male fate determination.     

Urinary metabolite markers of precocious puberty

The incidence of precocious puberty (PP, the appearance of signs of pubertal development at an abnormally early age), is rapidly rising, concurrent with changes of diet, lifestyles, and social environment. The current diagnostic methods are based on a hormone (gonadotropin-releasing hormone) stimulation test, which is costly, time-consuming, and uncomfortable for patients. The lack of molecular biomarkers to support simple laboratory tests, such as a blood or urine test, has been a long standing bottleneck in the clinical diagnosis and evaluation of PP. Here we report a metabolomic study using an ultra performance liquid chromatography-quadrupole time of flight mass spectrometry and gas chromatography-time of flight mass spectrometry. Urine metabolites from 163 individuals were profiled, and the metabolic alterations were analyzed after treatment of central precocious puberty (CPP) with triptorelin depot. A panel of biomarkers selected from >70 differentially expressed urinary metabolites by receiver operating characteristic and logistic regression analysis provided excellent predictive power with high sensitivity and specificity for PP. The altered metabolic profile of the PP patients was characterized by three major perturbed metabolic pathways: catecholamine, serotonin metabolism, and tricarboxylic acid cycle, presumably resulting from activation of the sympathetic nervous system and the hypothalamic-pituitary-gonadal axis. Treatment with triptorelin depot was able to normalize these three altered pathways. Additionally, significant changes in the urine levels of 4-hydroxyphenylacetic acid, 5-hydroxyindoleacetic acid, indoleacetic acid, 5-hydroxytryptophan, and 5-hydroxykynurenamine in the CPP group suggest that the development of CPP condition may involve an alteration in symbiotic gut microbial composition.     

The neuroendocrinology of human puberty revisited

The fundamental aspects of the hypothalamic luteinizing hormone-releasing hormone (LHRH)(1) [1]pulse generator-pituitary gonadotrophin-gonadal apparatus in mammals have striking commonalities. There are, however, critical, substantive differences in the neuroendocrinology of puberty among species. The onset of puberty in the human is marked by an increase in the amplitude of LH pulses, an indirect indicator of the increase in amplitude of LHRH pulses. The hypothalamic LHRH-pituitary gonadotrophin complex is functional by at least 0.3 gestation in the human foetus; the sex difference in the fetal and neonatal pattern of LH and FSH secretion is an apparent consequence of imprinting of the fetal hypothalamus-pituitary-gonadotropin apparatus by fetal testosterone. Until about 6 months of age in boys and 12-24 months in girls, the testes and ovaries respond to the increased LH in boys and follicle-stimulating hormone (FSH) in girls by secreting testosterone and oestradiol, respectively, reaching levels that are not again achieved before the onset of puberty. Striking features of the ontogeny of the human hypothalamic pulse generator are: (1) its development and function in the foetus; (2) the continued function of the hypothalamic LHRH pulse generator-pituitary gonadotrophin-gonadal axis in infancy; (3) the gradual damping of hypothalamic LHRH oscillator activity during late infancy; (4) its quiescence during childhood - the so-called juvenile pause; (5) during late childhood the gradual disinhibition and reactivation of the LHRH pulse generator, mainly at night; (6) the increasing amplitude of the LHRH pulses, which are reflected in the progressively increased and changing pattern of circulating LH pulses, with the approach of and during puberty. The intrinsic central nervous system (CNS) mechanisms responsible for the inhibition of the LHRH pulse generator during childhood (the juvenile phase) involve the major role of an inhibitory neuronal system - the CNS inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and GABAergic neurons, as revealed by studies in the rhesus monkey by Terasawa and her associates. With the onset of puberty, the disinhibition and reactivation of the LHRH pulse generator is associated with a fall in GABAergic neurotransmission and a concomitant increase in the input of excitatory amino acid neurotransmitters (including glutamate) and possibly astroglial-derived growth factors. Despite remarkable progress over the past three decades, large gaps remain in our understanding of the neurobiological, genetic and environmental mechanisms involved in the control of the onset of puberty. The role of leptin in the control of the onset of puberty is reviewed. Severe leptin deficiency is associated with hypogonadotrophic hypogonadism; it appears that a critical level of leptin and a leptin signal is required to achieve puberty. The weight of evidence supports the hypothesis that leptin acts as one of several permissive factors and not a trigger in the onset of human puberty. The application of these advances provides a framework for the described classification of sexual precocity and delayed puberty.1 GnRH is synonymous with LHRH.     

Ascertainment and treatment of delayed puberty

The majority of patients with pubertal delay, can be classified as having primary pubertal delay (constitutional delay of growth and puberty, CDGP), although any child with a chronic disease could present with delayed puberty. In contrast, children with hypogonadism, either hyper- or hypogonadotropic, exhibit a total absence of pubertal development. Hence, early evaluation of these patients should be performed. Delay of puberty leads to psychological problems, secondary to short stature and/or delay in the acquisition of secondary sex characteristics and the reduction of bone mass. Although the final height in patients with CDGP is usually normal, some of these patients do not reach the third percentile or remain in the lowest part of the growth chart according to familial height. The most common reason for treating CDGP patients, usually with sex steroids, is for psychological difficulties and for loss of bone mineralization. Treatment must be individualized. Therapeutic options and new drugs will be discussed. Appropriate treatment and adequate nutritional intake are indicated in patients with delayed puberty due to chronic illness. In patients with hypo- or hypergonadotropic hypogonadism, puberty must be induced or completed. Different treatments (GnRH analogues, gonadotropins and sex steroids), and the main objectives are discussed.     

Precocious puberty with congenital hypothyroidism

Precocious puberty associated with profound hypothyroidism is a rare condition. It is usually characterized by breast development, vaginal bleeding, lack of pubic hair and delayed bone age. Multicystic ovaries in profound hypothyroid patients with precocious puberty have been rarely described. Vaginal bleeding in adolescent girls should be considered as a clinical significance particularly when it is prolonged or heavy, whereas vaginal bleeding in younger girls, regardless of its duration and quantity is always of clinical importance. Bleeding in such patients could be caused by local causes such as vulvar or vaginal lesions, or it could be from the endometrium, which is usually a sign of systemic hormonal disturbance [1]. In this report a rare case of vaginal bleeding, large, multicystic ovaries, precocious puberty and delayed bone age in a 7 years old girl with profound hypothyroidism is described.