Delayed pubarche

Primary adrenal insufficiency is a life-threatening condition caused by impaired secretion of adrenal glucocorticoid and mineralocorticoid hormones [16]. Impaired adrenal steroidogenesis, adrenal dysgenesis and adrenal destruction are the most common causes of primary adrenal insufficiency in children, with congenital adrenal hyperplasia (CAH) and autoimmune destruction being the most frequent [17]. Symptoms of adrenal insufficiency range from insidious to severe and include fatigue, weakness, weight loss, nausea, abdominal pain, vomiting, severe dehydration unresponsive to intravenous fluid, and coma [18]. Infants may also show poor feeding and impaired growth. Hypotension, particularly orthostatic, is usually present at the time of the diagnosis, while hyperpigmentation (due to the hyperproduction of pro-opiomelanocortin) is inconsistent. Laboratory tests show hyponatremia, hyperkalaemia, hypoglycaemia and ketonemia. Baseline levels of ACTH, cortisol, renin and aldosterone, and, more importantly, repetitive pathological values of cortisol during an ACTH stimulation test, are helpful in confirming the diagnosis. Since the appearance of pubic hair is related to the maturation of the adrenal cortex, a delayed pubarche and an adrenarche-gonadarche discrepancy can be expected in adolescents with adrenal insufficiency. In confirmation of this, Hochberg reported three clinical cases of delayed pubarche in Addison’s disease [8, 19]. Therefore, in presence of compatible clinical features (hypotension, hyponatraemic dehydration, hypoglycaemia, hyperpigmentation) or of an history of autoimmune disease (thyroiditis, diabetes, celiac disease), adrenal insufficiency should be carefully considered.

Albeit still being unclear, the contribution of ACTH in the regulation of adrenarche has been proved multiple times, so that an absent adrenarche can be indicative of an ACTH deficiency [13, 19]. Secondary adrenal insufficiency is caused by a deficit of pituitary ACTH or hypothalamic corticotropin-releasing hormone (CRH). The clinical presentation is different from the primary form because aldosterone production remains intact, therefore dehydration, hypotension, hyponatremia, and hyperkalaemia are not usually present [20]. Since ACTH is deficient, hyperpigmentation is absent as well. On the other hand, fatigue, weakness, weight loss and gastrointestinal symptoms (nausea, abdominal pain, vomiting) may appear. ACTH deficiency can be isolated or in combination with other pituitary hormones deficiency, in a context of panhypopituitarism [21]. Apart from its congenital form, panhypopituitarism can be caused by any type of damage to the hypothalamus and/or the pituitary gland, including tumours (such as craniopharyngioma), infections, autoimmune diseases, infiltrative diseases, chemotherapy and radiation exposure, and trauma [22]. Since growth hormone (GH)-producing cells are the most sensitive to damage, an isolated deficit of ACTH is very rare. However, since panhypopituitarism can be rather insidious, a growth deflection might not be identified promptly, especially in teenagers after the pubertal spurt.

Two rare variants of anterior panhypopituitarism have been associated with delayed pubarche, even with normal circulating levels of ACTH and cortisol. The first of them is PIT1/POU1F1 deficiency, a complex pathological entity that typically causes growth hormone, prolactin and thyrotropin deficiency. Taha et al. described 8 patients affected by this condition, all with spontaneous onset and progression of puberty, presenting very low levels of DHEAS and absent or delayed pubic hair appearance [10]. The second condition, called immunoglobulin super family member 1 (IGSF1) deficiency, is characterized by central hypothyroidism, delayed surge in testosterone during puberty, macroorchidism and, occasionally, also by hypoprolactinaemia and transient growth hormone deficiency. Van Hulle et al. reported the case of a 19-year-old patient with IGSF1 that presented delayed adrenarche and pubarche [11].

In both these two genetic conditions, the authors suspect that a reduction of prolactin secretion could be the cause of pubic hair’s delayed appearance, since prolactin receptors are expressed in the adrenal cortex and act synergistically with ACTH in the surge of adrenal androgens [23]. This strict correlation between prolactin and the adrenal gland has been identified also in the opposite scenario, where prolactin is excessively produced. In fact, Tabatabaei et al. described a case of pituitary macroadenoma in which premature pubarche was the first clinical manifestation of the pituitary mass [24].

Therefore, in presence of a delayed pubarche, ACTH should always be tested with a baseline blood sample, along with the remaining pituitary hormones. In presence of panhypopituitarism, genetic consultation and testing should be requested to identify the mutation responsible for the condition. As reported above, in few patients affected by genetic panhypopituitarism, normal ACTH values are not sufficient to guarantee the normal appearance of pubarche, due to the complex interactions between the various pituitary hormones.

Androgen insensitivity syndrome (AIS) is a rare condition, with a prevalence that varies from 1/20,000 to 1/100,000 people. It is characterized by a mutation of the androgen receptor (AR) gene in the region q11–12 on the X chromosome that leads to an androgen resistance in androgen-dependent tissues. Therefore, subjects with AIS, while having a 46,XY karyotype, typically present feminization of the external genitalia at birth, abnormal sexual development and infertility [25]. The clinical undermasculinization is variable, based on the severity of the androgen sensitivity defect, which can be complete (CAIS), partial (PAIS) or mild (MAIS), with CAIS being the most frequent of the three forms. A pelvic ultrasound must be performed in these patients in order to identify genital abnormalities. Typical findings include the presence of two nondysplastic testes, absent or rudimentary müllerian structures (fallopian tubes, uterus, and cervix) and the presence of a short vagina. Wolffian duct derivatives can be absent or rudimentary, as well as epididymis and vas deferens [26]. AIS subjects normally experience puberty, whose timing is closer to male rather than female standards, and present normal breast development thanks to the aromatization of testosterone to estradiol. Pubarche, on the other, is impaired by androgen resistance, leading to moderate, sparse, or even absent pubic hair, depending on the severity of the genetic defect [27]. DHEAS is typically in range, as in the case reported by Lanciotti et al. [28] Primary amenorrhea is also present, because of the absence of female internal genitalia [29]. Apart for its social and psychological aspect, to make a prompt diagnosis of AIS is critical, since this condition is characterized by an increased, although mild, risk of testicular malignancy, due to the presence of dysgenetic or abdominal testes. Therefore, in females that experience thelarche with absent or delayed adrenarche and primary amenorrhea, pelvic ultrasounds and karyotype should be performed in the suspect of an androgen insensitivity syndrome, whose confirmation is addressed by sequencing the AR gene.

Turner syndrome (TS) is a common chromosomal disorder (prevalence of 1/2,500 female live births) caused by a total or partial loss of the second X chromosome (genotype 45,X) [30, 31]. TS is characterized by short stature and gonadal dysgenesis, although many other clinical features may appear [32]. In pure gonadal dysgenesis, pubarche is expected to appear regularly, since adrenal androgens are excreted at a normal rate. In fact, in TS patients, pubarche is usually the first developmental feature to appear. In confirmation of this, Bannick et al. reported that the development of pubic hair in TS subjects was similar to that of the normal female population, except for stage 5, that was reached later than healthy girls [33]. In TS, however, the appearance of pubic hair is sometimes delayed or even absent, especially in presence of premature ovarian failure (POF), although adrenarche normally occurs and DHEAS values are within range [9]. A possible explanation of this phenomenon is that ovaries play a role in the adrenal metabolism of DHEA into other androgens during pubarche. Thus, females with POF might require higher levels of androgens than those with normal functioning ovaries [34]. Moreover, in around 20% of TS subjects, pubarche is observed only after estrogen replacement therapy [35]. Turner syndrome diagnosis is sometimes tricky, and it can be delayed even after 18 years of age [36]. Therefore, in presence of a delayed pubarche with compatible TS features (e.g. short stature, primary amenorrhea, dysmorphic features, heart murmur), a karyotype analysis must be performed to rule out this condition.

The relationship between thyroid dysregulation and pubertal development is complex and the studies that explored this matter showed controversial results, especially regarding precocious and delayed puberty [37]. On the other hand, a connection between the activity of the thyroid and the adrenal glands have been reported in various papers, but most of the evidence relies on studies conducted on animals. Huang et al., for example, demonstrated that the administration of thyroxine on immature mice induced the hypertrophy of a fetal part of the adrenal gland that later regresses in adult mice [38]. As Wondiford suggested, it could be inferred that thyroid hormone excess might increase steroid hormone levels also in humans, and especially in children or young adults. Also, by assumption, thyroid hormone deficiency per se might be able to cause a subtle adrenal insufficiency, by acting directly on the gland or by limiting the response to ACTH [39]. Unfortunately, as anticipated, very few papers have examined this topic, but the only two that described a relationship between pubarche and thyroid activity are in line with the concepts described above.

Wilken et al. reported that, in a cohort of 323 of young females, higher prepubertal concentrations of free thyroxine (FT4) were associated with an earlier onset of pubarche, without the appearance of thelarche. This result was independent from common confusing factors, especially obesity [40]. As for delayed pubarche, on the other hand, De Luca et al. reported a dissociation between adrenarche and gonadarche in two longstanding hypothyroid subjects, who presented advanced gonadal development and absent sexual hair, both axillary and pubic. After beginning a substitutive therapy with thyroxine, pubarche finally appeared [41].

Phthalates diesters are chemicals with anti-androgenic properties that are used as softeners in plastic production and can be found in various products, such as food packaging, medical devices and building materials. Some studies have showed a relationship between phthalate exposure and changes in girls pubertal timing, but this finding has not been consistently confirmed in the medical literature and the topic remains controversial [42‐44]. In a large Danish population-based study, female subjects with higher urinary phthalate concentration had a significant delay of pubic hair development, without alterations of gonadotropins and sex steroid hormone levels [12]. The authors hypothesized that delayed pubarche could be caused by a decrease androgen sensitivity or by a decrease of adrenal steroidogenesis. However, it should be specified that, despite the delayed appearance, statistical analysis showed that vast majority of the girls developed pubic hair within a normal range of age, and it is unclear whether some subjects developed pubic hair after 14 years of age. Further studies are needed to demonstrate if phthalate exposure may induce a pathological delayed pubarche or if they just postpone pubic hair appearance within a physiological, and thus acceptable, range of age.