Introduction – Menstrual cycle in adolescence

According to the World Health Organization, adolescence is defined as the age between 10 and 19 years and is a transitional stage between childhood and adulthood, during which significant physical and mental changes occur. The term ‘puberty’ refers to the sum of all the corporal physiological changes taking place in adolescence, which lead to sexual maturation. In females, menarche is the major landmark of puberty, and despite international variations, usually occurs between 12 and 13 years of age in well-nourished populations in developed countries. From the early 1800s to the mid 1950s, menarche occurred at increasingly younger ages, but there has not been any further decline during the past 40–50 years. Menarche typically occurs within 2–3 years after thelarche (breast budding) at Tanner stage IV of breast development and is rare before stage III. In 98% of adolescents, menstruation will have started by the age of 15, with the median age being 12.43 years. Only 10% of the females are menstruating at 11.11 years of age, while 90% are menstruating by 13.75 years of age.

There appears to be a relationship between body weight and onset of menarche, as earlier menarche has been observed in obese girls. In contrast, malnutrition, chronic disease, eating disorders and high levels of physical activity are associated with delayed menarche. It has been suggested that insulin can modulate the tempo of pubertal development, through regulation of Insulin-like growth factor binding protein-1 (IGFBP-1) and Sex Hormone Binding Globulin (SHBG) production. High levels of serum insulin, which are related with childhood obesity, result in decreased IGFBP-1 and SHBG concentrations, thus enhancing IGF-I and sex steroid bioavailability. It remains still unclear, though, if hyperinsulinaemia in childhood is the result, or the cause, of obesity. Childhood obesity is also associated with elevated serum concentrations of leptin, which acts to the hypothalamus, regulating calorie intake, GnRH pulsatility and serum insulin levels, hence regulating onset of puberty. Moreover, it has been demonstrated that homozygous mutation of the leptin receptor gene results in early-onset morbid obesity and absence of pubertal development in association with reduced growth hormone (GH) secretion. The role of genetic factors, which may determine insulin production and obesity risk in childhood, has also yet to be clearly explained.

During the first gynaecologic year (first year after menarche) mean cycle interval is 32.2 days, varying typically from 21 to 45 days. Normal menstrual flow length rarely exceeds 7 days and monthly average blood loss is estimated to be 35 ml, ranging from 10 to 80 ml. According to the World Health Organization’s international and multicentre study of 3073 girls, the median length of the first cycle after menarche was 34 days, with 38% of cycle lengths exceeding 40 days. Variability was wide with 10% of females having more than 60 days between their first and second menses, and 7% having a first cycle length of 20 days. Early menstrual life is characterised by anovulatory cycles. The frequency of ovulation is related to both time since menarche and age at menarche. Early menarche is associated with early onset of ovulatory cycles. When the age at menarche is younger than 12 years, 50% of cycles are ovulatory in the first gynaecologic year. In contrast, it may take 8–12 years after menarche until females with later-onset menarche become fully ovulatory. Long cycles most often occur in the first 3 years post-menarche, the overall trend is towards shorter and more regular cycles with increasing age. By the third year after menarche, 60–80% of menstrual cycles are 21–34 days long, as is typical of adults. An individual’s normal cycle length is established around the sixth gynaecologic year, at a chronological age of approximately 19 or 20 years.

Two large studies, one cataloguing 275.947 cycles in 2702 females and another reporting on 31.645 cycles in 656 females, support the observation that menstrual cycles typically range from 21 to approximately 45 days, even in the first gynaecologic year. In the first gynaecologic year, the 5th percentile for cycle length is 23 days and the 95th percentile is 90 days. By the fourth gynaecologic year, fewer females are having cycles that exceed 45 days, but anovulation is still significant for some, with the 95th percentile for cycle length at 50 days. By the seventh gynaecologic year, cycles are shorter and less variable, with the 5th percentile for cycle length at 27 days and the 95th percentile at only 38 days. During the early years after menarche, cycles may be somewhat long because of anovulation, but 90% of cycles will be within the range of 21–45 days.

Precocious puberty

Precocious puberty in girls has been defined by Marshal and Tanner in 1969, as “the presence of any secondary sex characteristic in a girl before the age of 8, or the onset of menstruation prior to 10 years of age.” In a US study of over 17 000 girls it was suggested that early pubertal development is reported in 15% of white girls and in 48% of black girls, despite the fact that the average age of menarche did not differ among the two groups.

In most of the cases (90%), precocious puberty is idiopathic and is related to premature release of gonadotrophins. Causes of precocious puberty can be divided in gonadotrophin dependent (‘true’ or ‘central’ precocious puberty) and gonadotrophin independent, as listed in Table 1 . Variations of precocious puberty include isolated premature thelarche and adrenarche, with the latter being associated with an increased risk of subsequent insulin resistance and the onset of polycystic ovarian syndrome. Anomalous puberty may arise when there is inappropriate hormonal secretion with virilisation. Causes include gonadal dysgenesis with a functioning tumour, congenital adrenal hyperplasia and adrenal tumours.

With regard to managing patients with precocious puberty, the following points must be taken into consideration: firstly, bone maturation is accelerated in precocious puberty, leading to premature epiphyseal closure and curtailed stature. In addition, pituitary suppression with GnRH antagonists is indicated to delay pubertal development, but it does not substantially affect adult height in girls who enter puberty between 6 and 8 years.

Precocious puberty

Precocious puberty in girls has been defined by Marshal and Tanner in 1969, as “the presence of any secondary sex characteristic in a girl before the age of 8, or the onset of menstruation prior to 10 years of age.” In a US study of over 17 000 girls it was suggested that early pubertal development is reported in 15% of white girls and in 48% of black girls, despite the fact that the average age of menarche did not differ among the two groups.

In most of the cases (90%), precocious puberty is idiopathic and is related to premature release of gonadotrophins. Causes of precocious puberty can be divided in gonadotrophin dependent (‘true’ or ‘central’ precocious puberty) and gonadotrophin independent, as listed in Table 1 . Variations of precocious puberty include isolated premature thelarche and adrenarche, with the latter being associated with an increased risk of subsequent insulin resistance and the onset of polycystic ovarian syndrome. Anomalous puberty may arise when there is inappropriate hormonal secretion with virilisation. Causes include gonadal dysgenesis with a functioning tumour, congenital adrenal hyperplasia and adrenal tumours.

With regard to managing patients with precocious puberty, the following points must be taken into consideration: firstly, bone maturation is accelerated in precocious puberty, leading to premature epiphyseal closure and curtailed stature. In addition, pituitary suppression with GnRH antagonists is indicated to delay pubertal development, but it does not substantially affect adult height in girls who enter puberty between 6 and 8 years.

Delayed puberty

According to Hickey and Balen, delayed puberty is defined as absence of onset of puberty by >2 standard deviation (SD) later than the average age, that is, >14 years in females. It is preferable though to define delayed puberty as the absence of menstruation by the age of 14 in girls with undeveloped secondary sexual characteristics. In many cases, it is idiopathic but can also occur due to general conditions resulting in malnutrition. Other causes include gonadal failure (in these cases, there are significantly elevated levels of gonadotrophins) or gonadotrophin secretion impairment. Cases that may lead to delayed onset of puberty are shown in Table 2 .

In most of the cases, delayed puberty is constitutional and, initially, patients only need to be reassured and no further intervention is necessary. It is mandatory though to review and investigate the patient in the next 6 months. Investigation of the patient should include full hormonal scan, bone age estimation and karyotyping. If a systemic disease or malnutrition is the cause of puberty delay, therapeutic intervention should focus on proper management of the underlying condition.

Amenorrhoea

Primary amenorrhoea is the absence of menstruation, either in girls aged 16 years who have already developed secondary sexual characteristics or in 14-year-olds who have no development of secondary sexual characteristics. Especially for the 14-year-olds (with the absence of the secondary sexual characteristics), we prefer and suggest the term ‘late puberty’ rather than primary amenorrhoea. Secondary amenorrhoea is the absence of menstruation for 6 months, for these adolescents who had previously irregular cycles or for these who are within the first years after menarche. For adolescents with formerly regular cycles of 21–45 days, secondary amenorrhoea is defined as the absence of three or more subsequent menstrual periods. In summary, secondary amenorrhoea is defined as the cessation of menses once they have begun.

According to the Practice Committee of ASRM (American Society for Reproductive Medicine), the timing of the evaluation of primary amenorrhea recognises the trend to earlier age at menarche and is therefore indicated when either there has been a failure to menstruate by the age of 15 in the presence of normal secondary sexual development (2SD above the mean of 13 years) or within 5 years after breast development if that occurs before the age of 10 or in case of failure of breast development initiation by the age of 13 (2SD above the mean of 10 years).

Hypothalamic amenorrhoea

Hypothalamic amenorrhoea can be classified either into dysfunctional (e.g., due to stress, excessive exercising, eating disorders or weight loss) or into organic. According to ASRM, the causes of hypothalamic amenorrhoea are demonstrated in Table 3 . Functional disorders of the hypothalamus or higher centres are the most common reason for chronic anovulation. In the majority of the cases, weight loss is the main cause of amenorrhoea. Competitive sports have a threefold higher risk of amenorrhoea, with the highest prevalence being among long-distance running.

Table 3

Causes of Hypogonadism.

Causes of hypogonadotrophic hypogonadism

Causes of hypergonadotrophic hypogonadism

• CNS disorders • Tumors ○ Craniopharyngioma ○ Germinoma ○ Pituitary tumor ○ Astrocytoma ○ Other germ cell tumors ○ Hypothalamic and optic glioma • Miscellaneous causes ○ Head trauma ○ Langerhans histiocytosis ○ Postinfectious lesions of the CNS ○ Vascular abnormalities of the CNS ○ Radiation therapy ○ Congenital malformations • Genetic causes ○ Kallmann syndrome (mutation in the KAL [anosmin] gene), with hyposmia or anosmia or without anosmia ○ Congenital adrenal hypoplasia (mutation in the DAX1 gene) ○ Mutations in the gene coding for the GnRH (LHRH) receptor ○ Isolated LH or isolated FSH deficiency • Idiopathic and genetic forms of multiple hormone deficiencies ○ Chronic systemic disease and malnutrition ○ Exercise-induced amenorrhea ○ Miscellaneous disorders, including Bardet-Biedl syndrome, Prader-Willi syndrome, Laurence-Moon syndrome, functional gonadotropin deficiency (psychogenic amenorrhea, hypothyroidism, diabetes mellitus, Cushing syndrome), hyperprolactinemia, drug use and Gaucher disease

• Gonadal dysgenesis ○ Abnormal karyotype ▪ Turner syndrome 45,X ▪ Mosaicism ○ Normal karyotype ▪ Pure gonadal dysgenesis ▪ 46,XX ▪ 46,XY (Swyer syndrome) • Gonadal agenesis • Enzymatic deficiency ○ 17-Hydroxylase deficiency ○ 17,20-Lyase deficiency ○ Aromatase deficiency • D. Premature ovarian failure ○ Idiopathic ○ Injury ▪ Chemotherapy ▪ Radiation ▪ Mumps or autoimmune oophoritis ○ 3. Resistant ovary ▪ FSH-receptor gene mutations ▪ LH/human chorionic gonadotrophin (hCG) resistance ○ Galactosemia ○ Glycoprotein syndrome type 1

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