38 D. Keith Edmonds1,2 1 Imperial College London, London, UK 2 Queen Charlotte’s and Chelsea Hospital, London, UK The transition from childhood to adolescence and adulthood is one of the most dynamic changes that occur during the life of a woman. The changes are not only physical, but emotional, psychological, behavioural and sexual, and all these changes encompass the maturation of the female to become reproductively capable. There is enormous variation between individuals in the processes involved in puberty but the five major physical changes are growth, breast development, pubic hair development, axillary hair development and, ultimately, menstruation. Whilst these changes occur temporally at different rates, there may be changes that occur prematurely or in a delayed fashion which alter this process. Finally, some girls may undergo pubertal change without menstruation and others may fail to enter puberty entirely. The age of onset of puberty in girls ranges from 8 to 13 years and the appearance of secondary sexual characteristics before this age is known as precocious puberty; failure of appearance of any secondary sexual characteristics after 13 years in girls is considered delayed puberty. A number of factors are known to play a role in the timing of puberty. Genetics has a clear and dominant role and there is a clear correlation between age at puberty of a woman and that of her daughter. However, there are racial differences, with black females showing an earlier age of pubertal onset compared with white [1]. Furthermore, nutritional status in all ethnic groups seriously influences the age of onset of puberty. Children living in areas of malnutrition have significantly delayed onset of puberty and transfer of these girls to a socioeconomically superior environment reduces the age of onset of puberty significantly [2]. At the other extreme, evidence now exists to suggest that a high body mass index (BMI) is linked to earlier age of maturation, and the relationship between body fat and the onset of puberty is linked to the release of leptin from adipose sites [3]. Leptin and kisspeptin would seem to act as a primary signal to the hypothalamus to allow puberty to commence [4]. The hypothalamus–pituitary–gonadal axis is active during fetal life and quiescent during childhood. It is the reactivation of this axis that leads to sexual maturation, although the mechanism by which this occurs remains unclear. The arcuate nucleus in the basal hypothalamus is responsible for secretion of gonadotrophin‐releasing hormone (GnRH) into the hypothalamus–pituitary portal circulation. As puberty commences, the arcuate nucleus begins to secrete GnRH in a pulsatile manner, initially solely at night; however, as time progresses GnRH release adopts a low‐frequency low‐amplitude pulsatile pattern that starts to induce release of luteinizing hormone (LH) from the pituitary. The low‐amplitude pulsatile pattern gradually extends to include daytime secretion and gonadotrophin levels themselves start to increase, reflecting higher pulse amplitude and increasing frequency of GnRH production. As the pattern of follicle‐stimulating hormone (FSH) and LH release becomes established, so ovarian activity commences and initially this is disordered as it is uncoordinated. This means that there is follicular growth without coordinated ovulation and although estradiol levels start to rise, there is no evidence of ovulation. The ovary may have appearances that are multicystic due to this chaotic gonadotrophin stimulation and, over time (about 5–10 years), coordinated pulsatile release of GnRH leads to adult frequency of FSH release (approximately every 90 min). At this stage the ovulatory cycle is established. From age 7, most girls will begin activation of adrenal androgen production, a phenomenon known as adrenarche. As with ovarian estradiol production, androgen production is initially at extremely low levels and increases over time. An increase in vertical growth is the initial physical sign of the onset of puberty. Growth during infancy is relatively rapid until age 3–4 and then it rapidly decelerates when the childhood phase begins. Growth velocity during infancy is approximately 15 cm/year but in middle childhood, until the onset of puberty, slows to 5–6 cm/year. Interestingly, childhood growth rates are usually at their slowest in the 12–18 months immediately preceding puberty and thus if puberty is delayed this effect is exaggerated. At puberty, girls may reach a peak growth velocity of 10 cm/year and will gain approximately 25 cm of growth during puberty. Males in contrast have their growth spurt approximately 2 years later than females but eventually gain approximately 28 cm of added height. Once the final stage of growth velocity decreases, epiphyseal fusion occurs which prevents further growth. During the adolescent growth phase, bone density increases rapidly. Control of the growth spurt is primarily through growth hormone and its major secondary messenger insulin‐like growth factor (IGF)‐1. Estradiol plays an important role in the increased secretion of growth hormone during puberty, particularly in the early stages. As bone growth and height are maximally achieved, estradiol initiates epiphyseal fusion as it reaches its maximum towards the end of puberty. Thyroid hormone also plays a key role in growth and development as illustrated in severe childhood hypothyroidism, which results in a dramatic decrease in the velocity of growth. Although the growth spurt is usually the first sign of the onset of puberty, in females it is breast change that is usually used as an indicator of development. The initiation of breast development is known as thelarche and Tanner has classified this into five stages [5]. Breast growth is often unequal between the two breasts and Tanner stage 5 represents the mature end stage of breast development. This takes approximately 5 years. The adolescent development of female pubic hair occurs in conjunction with androgen release and it is the presence of androgen that determines both pubic and axillary hair growth. In approximately 20% of females, pubic hair growth may precede breast development. Early age of menarche is associated with increased risk of breast cancer, cardiovascular disease, depression, behavioural disorders, diabetes and increased early mortality [6]. This phenomenon has received increased attention over the last few years with the belief that the age of onset of puberty has been falling. However, in accepting some guidance over age, the appearance of secondary sexual characteristics prior to 8 years should be considered precocious and prompt the clinician to carry out investigations. This is due to the precocious increase in adrenal androgen secretion and is the most common cause of referral for precocious puberty. There seems to be an association between premature adrenarche and increased BMI [7], and in the overweight child referred with precocious puberty it is important not to assume that breast tissue is truly breast development and not adipose tissue. Signs of virilization such as clitoral enlargement, severe acne or increased muscle mass would lead to concerns of a virilizing ovarian or adrenal tumour or late‐onset congenital adrenal hyperplasia (CAH). Late‐onset CAH can present with pubic hair growth from the age of 1 and should be appropriately investigated. Here, breast growth tends to appear earlier than age 8 and progresses very slowly and usually occurs in isolation of the growth spurt or any other secondary sexual characteristic. The cause of this condition remains unknown and although it is appropriate to exclude an ovarian cyst, these are rarely found. This refers to progressive breast development prematurely due to early activation of the hypothalamic–pituitary–ovarian axis and is accompanied by the growth spurt; pubic hair is frequently but not always found. This therefore mimics normal onset of puberty but at a very early age. A positive family history of early onset of puberty may be discovered where an MKRN‐3 gene mutation can be found [6], but in the majority of cases the aetiology is idiopathic. Brain imaging is important, especially in girls with an onset of puberty before the age of 6, where 20% will be found to have a central nervous system (CNS) tumour. This is far less common than central precocious puberty and is usually induced by excess production of sex steroids. Causes include the following. A number of hormonal studies may be carried out in children with precocious puberty. However, they are of limited value and should be focused on specific clinical entities. LH may be used to distinguish between premature thelarche and central precocious puberty. FSH is of limited value. Estradiol is usually elevated in girls with precocious puberty and very high levels may suggest a tumour. Dehydroepiandrosterone is always elevated in children with premature adrenarche; testosterone when markedly elevated would suggest an androgen‐secreting tumour; and in those children who are considered to have late‐onset CAH, the diagnosis can be confirmed by measuring 17‐hydroxyprogesterone. Radiological studies have somewhat limited value, although pelvic ultrasound may be used if an abdominal tumour is suspected and brain MRI may be used in those children with extreme precocious puberty, where the chances of a positive finding are around 20% and MKRN‐3 gene mutation should be screened for. The majority of girls with central precocious puberty do not require hormonal treatment, because most development is extremely slow and will result in maturity at an age which would be expected even though onset has been early. It is therefore prudent to review children with precocious development of secondary sexual characteristics 6 months later to see whether there has been rapid development of secondary sexual characteristics or not. In these cases, there is a high chance that sexual maturity will be reached by age 9 and therefore suppression of the progress of puberty would be sensible. While it is possible to suppress the pituitary, growth hormone cannot be suppressed and therefore treatment will result in adult height that is significantly greater than would be expected than if the child were left untreated. Children with extremely early puberty are often tall at the time of diagnosis and they tend to finish their growth early but achieve normal adult height. It is appropriate in these young children to suppress the development of secondary sexual characteristics. The standard treatment for central precocious puberty is GnRH analogues, which may be given nasally or by intramuscular injection. Three‐monthly preparations are available and therefore four injections a year is all that is required to suppress puberty. GnRH analogues can then be administered until such time as the child reaches approximately age 11, when withdrawal will result in the normal resumption of pubertal changes. Peripheral precocious puberty, when due to an ovarian or adrenal tumour, requires surgical intervention; however, for girls with androgen excess due to CAH, suppression of the adrenal with hydrocortisone will reverse the changes. Delayed puberty is usually considered when girls have no secondary sexual characteristics by age 13.5 years. Delay in puberty occurs in only 2.5% of the population but the identification of those children who do have a significant aetiology for this may be extremely important. It is mandatory to take a detailed history as the presence of chronic medical conditions or excessive athletic participation may be an explanation for delay in the onset of puberty. In females, approximately 50% will have constitutional delay with no explanation and the vast majority will commence the onset of puberty by age 18. A further 40% have been found to have a genetic defect [6]. In the presence of secondary sexual characteristics, menstruation ought to occur within 2 years of the establishment of Tanner stage 2 breast change. However, any child presenting at any stage because of concern over failure to establish either secondary sexual characteristics or menstruation should be investigated at that time. There are often extremely good reasons why a mother will bring her daughter for investigation and this often relates to the fact that a sibling completed her pubertal development at an earlier age or she herself went through puberty at an earlier age. While investigations may not lead to a diagnosis of abnormality, proof of normality is extremely important. From a clinical point of view it is probably best to classify the aetiologies of primary amenorrhoea based on the presence or absence of secondary sexual characteristics. This is the basis of the classification system shown in Table 38.1. Finally, there is the group of patients in whom there is heterosexual development. Table 38.1 Classification of primary amenorrhoea. DSD, disorders of sexual development. The imperforate hymen may present at two stages of development. It may present in early childhood when the infant presents with a bulging hymen behind which is a mucocele, the vagina expanded by vaginal secretions of mucus. This is easily released and does not subsequently cause any problems following hymenectomy. It may also present in later life when a pubertal girl complains of intermittent abdominal pain, which is usually cyclical. The pain is due to dysmenorrhoea associated with the accumulation of menstrual blood within the vagina. The vagina is a very distensible organ and can allow quite large quantities of blood to collect in some cases. This condition is known as haematocolpos. It is very unusual for blood to accumulate within the uterus as the uterus is a muscular organ that is difficult to distend. When some blood does accumulate within the cavity it is known as haematometra. As the vaginal mass enlarges there may be associated difficulty with micturition and defecation. Examination will occasionally reveal an abdominal swelling and observation of the introitus will display a tense bulging bluish membrane, which is the hymen (see Chapter 35). In circumstances where the vagina fails to cannulate, the upper and lower parts of the vagina are separate. These girls present with cyclical abdominal pain due to the development of haematocolpos, but the thickness of the transverse vaginal septum means that the clinical appearance is very different from that of an imperforate hymen. Again, an abdominal mass may be palpable but inspection of the vagina shows that it is blind‐ending and although it may be bulging, it is pink not blue. The hymenal remnants are often seen separately. Transverse vaginal septum may occur at three levels, known as a lower, middle or upper third septum. If the space between the upper and lower vagina is considerable, no introital swelling may be visible and rectal examination may disclose a mass. The management is very different from imperforate hymen and very careful assessment must be made before embarking on any management strategy (see Chapter 35). This is a rare phenomenon when embryologically the uterine body has developed normally but there is failure of development of the cervix. This leads to failure of the development of the upper vagina. The presenting symptom is again cyclical abdominal pain, but there is no pelvic mass to be found because there is no vagina to be distended. Although a small haematometra may be present, retrograde menstruation occurs leading to the development of endometriosis and in some patients pelvic adhesions. Reconstructive surgery is possible. This is the second most common cause of primary amenorrhoea, second only to Turner’s syndrome. Secondary sexual characteristics are normal as would be expected, as ovarian function is unaffected. Examination of the genital area discloses normal female external genitalia but a blind‐ending vaginal dimple which is usually not more than 1.5 cm in depth. This is known as Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome and uterine development is usually absent. Often small uterine remnants (anlage) are found on the lateral pelvic side walls. It is important to remember that 40% of these patients have renal anomalies, 15% of which are major, for example an absent kidney, and there are also recognizable skeletal abnormalities associated with this syndrome [8] (see Chapter 35). There are a number of ways in which an individual may have an XY karyotype and a female phenotype, and these include failure of testicular development, enzymatic failure of the testis to produce androgen (particularly testosterone), and androgenic receptor absence or failure of function. In androgen insensitivity there is a structural abnormality of the androgen receptor, due to defects in the androgen receptor gene, which results in a non‐functional receptor. This means that the masculinizing effect of testosterone during normal development is prevented and patients are therefore phenotypically female with normal breast development. This occurs because of peripheral conversion of androgen to oestrogen and subsequent stimulation of breast growth. Pubic hair is very scanty in these patients as there is no androgen response in target tissues. The vulva is normal and the vagina is usually short. (see Chapter 35). This is an extremely rare cause of primary amenorrhoea, but it has been described. There are elevated levels of gonadotrophin in the presence of apparently normal ovarian tissue; patients do have some development of secondary sexual characteristics, but never produce adequate amounts of oestrogen to result in menstruation. It is believed that these women have an absence or malfunction of FSH receptors in the ovarian follicles, and are unable to respond properly to FSH. A number of girls have constitutional delay and normal secondary sexual characteristics, but there is no anatomical anomaly and endocrine investigations are all normal. If serial sampling is carried out over a 24‐hour period, these young women are found to have immature pulsatile release of GnRH. This is the sole reason for their constitutional delay. These young women will eventually menstruate spontaneously as the maturation process proceeds.
Puberty and Its Disorders
Control of the onset of puberty
Physical changes of puberty
Growth
Breast development
Pubic and axillary hair growth
Age of onset of puberty and subsequent health
Precocious puberty
Differential diagnosis of early onset of puberty
Premature adrenarche
Premature thelarche
Central precocious puberty
Peripheral precocious puberty
Investigations
Treatment
Delayed puberty
Aetiology of primary amenorrhoea
Secondary sexual characteristics normal
Secondary sexual characteristics absent
Normal stature
Short stature
Heterosexual development
Normal secondary sexual characteristics
Imperforate hymen
Transverse vaginal septum
Absent vagina and a functioning uterus
Absent vagina and a non‐functioning uterus
46 XY
Resistant ovary syndrome
Constitutional delay
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