Summary
Female puberty, driven by the hypothalamic–pituitary–ovarian axis (HPO), sees numerous alterations in the body secondary to the rise in oestradiol concentration. Whilst the onset, tempo and sequence will vary between individuals, delay in initiation of events or arrest during the process warrants medical attention. Pubertal transition requires not only an intact HPO axis but also functional reproductive organs.
8.1 Introduction
Female puberty, driven by the hypothalamic–pituitary–ovarian axis (HPO), sees numerous alterations in the body secondary to the rise in oestradiol concentration. Whilst the onset, tempo and sequence will vary between individuals, delay in initiation of events or arrest during the process warrant medical attention. Pubertal transition requires not only an intact HPO axis but also functional reproductive organs.
8.2 Puberty and Its Delay
Female puberty is a slow linear process requiring approximately 3 years for completion. There is maturation of the HPO axis and subsequent coordinated hormonal patterns associated with ovulation and menstruation (Figure 8.1). Puberty is driven primarily by high oestradiol concentrations and culminates in the development of secondary sexual characteristics. Breast maturation and changes in bodily shape with growth and presence of axillary and pubic hair are the external phenotypic changes associated with puberty, whilst the attainment of an adult uterine configuration and many more subtle changes including those affecting the cardiovascular and neurological systems are internal alterations.
Puberty will start in 95% of girls between the ages of 8.5 and 13 years. Breast budding (thelarche) is usually the first sign of puberty and will begin in most girls by 11.3 years. Ninety-five per cent of girls will have achieved breast Tanner stage 2 by 13. The occurrence of menses occurs approximately 2 years after thelarche with an average age of 13 years. By the age of 14.5, 95% of girls will have periods [Reference Conway1]. The exact timing can be affected by multiple factors including ethnicity and BMI.
Primary amenorrhoea occurs in approximately 0.3% of females. Primary amenorrhoea with no secondary sexual characteristics by the age of 13 or in the presence of secondary sexual characteristics by 15 years of age is indicative of delayed puberty [Reference Conway1,2].
Some girls may already have a diagnosis with which pubertal development problems can be predicted, but for the majority pubertal delay may be first sign of an underlying issue triggering GP assessment.
Aberrations in the pubertal transition may be secondary to a spectrum of pathologies disrupting the HPO axis. If there is lack of both thelarche and menarche, this is indicative of complete early oestrogen deficiency. However, some may present with varying degrees of incomplete secondary sexual development suggesting an interruption at some point in the pubertal process. When primary amenorrhoea occurs in isolation and other secondary sexual characteristics are present this implies oestrogenisation and therefore alternative diagnoses should be considered as the cause is likely to be anatomical rather than hormonal. Hypoestrogenaemia concurring with anatomical anomalies has been described, however this scenario is incredibly rare.
Puberty is a significant milestone in a girl’s life and its absence will have not only physical but also psychological sequela. Lack of ‘development’ and not keeping up with peers can be highly distressing and this should not be forgotten nor overlooked in the assessment and treatment plan.
8.3 Causes of Primary Amenorrhoea
The aetiology of pubertal delay and primary amenorrhoea can be based on the presence or absence of secondary sexual characteristics (Table 8.1).
Table 8.1 Aetiology of pubertal delay and primary amenorrhoea based on the presence of secondary sexual characteristics.
| Absence of secondary sexual characteristics | Presence of secondary sexual characteristics |
|---|---|
| Constitutional delay | Uterine outlet obstruction |
| Chronic illness | Mayer–Rokitansky–Küster–Hauser |
| Hypothalamic amenorrhoea | Polycystic ovary syndrome |
| Hypogonadotrophic hypogonadism | Hyperprolactinaemia and other endocrinopathies |
| Hypopituitarism | Complete androgen insensitivity syndrome |
| Premature ovarian Insufficiency | Pregnancy |
| Turner syndrome | |
| Swyer syndrome |
8.4 Absence of Secondary Sexual Characteristics
8.4.1 Constitutional Delay
Constitutional delay is a common cause of pubertal delay (14%) with overall delay in the maturation of the HPO axis. Usually other female family members will have experienced the same. There will be no other concerning features in the history and blood tests will reveal low gonadotrophins and oestradiol concentrations. All aspects of puberty will be delayed including growth velocity [3].
Although constitutional delay is considered a variant of normal, it can be clinically challenging to differentiate it from idiopathic hypogonadotrophic hypogonadism, but in the latter there may not be a familial trend and there is ongoing linear growth without the pubertal growth spurt.
Treatment usually only involves reassurance and appropriate follow-up, but in some situations oestrogen induction of puberty may be necessary.
8.4.2 Chronic Illness
The mechanisms underpinning the pathogenesis of chronic illness and pubertal delay are multifactorial. Any chronic pathology either physical or psychological may be causative. Cystic fibrosis, chronic cardiac conditions, coeliac disease, emotional and physical abuse are just a few examples.
8.4.3 Hypothalamic Amenorrhoea
Hypothalamic function and GnRH pulsatility is sensitive to physical stressors such as extreme exercise, stress and calorific restriction leading to weight loss. The pathophysiology is thought to be mediated by leptin and depending on the timing of the insult, primary or secondary amenorrhoea may ensue. There is no particular threshold for the amount of exercise that will lead to amenorrhoea. The ‘female athlete triad’ is often coined whereby there is amenorrhoea associated with decreased energy intake and low bone density [Reference Gordon, Ackerman, Berga, Kaplan, Mastorakos and Misra4]. A BMI of at least 19 kg/m2 and a fat mass of 22% is thought to be critical for the onset of menses. Anorexia and bulimia, as well as other eating disorders such as orthorexia, may lead to amenorrhoea. Ultimately loss of hypothalamic drive will lead to hypogonadotrophic hypoestrogenic state and 3% of primary amenorrhoea cases are attributed to hypothalamic amenorrhoea [Reference Gordon, Ackerman, Berga, Kaplan, Mastorakos and Misra4,Reference Meczekalski, Katulski, Czyzyk, Podfigurna-Stopa and Maciejewska-Jeske5].
Hypothalamic amenorrhoea should be a diagnosis of exclusion once all organic causes have been ruled out. Gonadotrophin levels may be normal/low with hypoestrogenic levels. Furthermore, blood tests may demonstrate hypercortisolaemia with hyperprolactinaemia and reduced IGF-1.
Although considered reversible if the underlying cause is eradicated, for example weight restoration, clinically there is often a lag between removing the trigger and resumption of GnRH pulsatility and gonadotrophin release. Indeed, in some, despite near normal gonadotrophin levels being seen, GnRH pulsatility is never repaired fully and some may remain amenorrhoeic and hypoestrogenic permanently.
Treatment is targeted at alleviating the underlying cause, but either temporary or more long-term, hormonal replacement may be required.
8.4.4 Hypogonadotrophic Hypogonadism
Hypogonadotrophic hypogonadism (HH) may be idiopathic but may be due to other acquired or congenital causes. Any physical destruction/compression of the central nervous system causes loss of GnRH/FSH and LH production. It may also be related to the production or functioning of GnRH at the genetic or molecular level. In addition to the amenorrhoea there may be related neurological symptoms including headache or visual field disturbance. Idiopathic HH may be reversible in some, but for most HH will be permanent [Reference Viswanathan and Eugster6].
Kallman syndrome is a rare (1:50,000) condition whereby there is defective GnRH neuronal migration to the arcuate nucleus. It is associated with colour-blindness and/or anosmia in combination with hypogonadism. Kallman syndrome may be sporadic in nature but may also have X-linked/autosomal dominant hereditary. One gene implicated is KAL1, which is essential for neuronal development.
Hypothalamic and/or pituitary function may be compromised or completely lost as a result of the mass effect of intracranial lesions such as craniopharyngiomas. Furthermore, the treatment of these tumours (surgical resection or adjuvant irradiation) can exacerbate the trauma to the area. Following radiotherapy, the gonadotrophic depletion may gradually develop several years after the initial insult. The hypothalamus and/or the pituitary may also be damaged secondary to head trauma or infections such as HIV or tuberculosis.
Whilst it may occur in isolation, HH can also be part of a more complex medical syndrome and primary amenorrhoea may be one feature of rare clinical spectrum syndromes including Prader–Willi syndrome, CHARGE syndrome or Dandy Walker syndrome.
Idiopathic hypogonadotrophic hypogonadism is identified when there is no underlying cause found and smell is normal. It may be very difficult to distinguish from constitutional delay of puberty. In some (10%–20%), reversal may occur, and therefore, once oestrogen therapy has achieved adequate pubertal and bone development, many advocate a trial off hormonal support to see if natural cycle resumption occurs.
8.4.5 Hypopituitarism
Global pituitary dysfunction with loss of the production and/or secretion of the pituitary hormones will lead to multiple comorbidities including hypogonadism. This may be congenital in origin in the case of septo-optic dysplasia or may be acquired secondary to tumours including pituitary adenoma, trauma, infection and inflammation. There will be other clinical and biochemical evidence of hypopituitarism.
8.4.6 Premature Ovarian Insufficiency (POI)
Premature ovarian insufficiency (POI) with hypergonadotrophic hypogonadism is defined as the loss of ovarian activity with amenorrhoea prior to the age of 40. Its incidence is quoted as 1% before the age of 40, but 0.01% prior to the age of 20. Therefore, primary amenorrhoea associated with premature ovarian insufficiency is rare, and secondary amenorrhoea is a far more frequent presentation. Often the cause of POI remains unknown, but autoimmune, genetic and infective origins have been implicated and need exclusion in the investigations. Iatrogenic POI may be secondary to gonadotoxic chemotherapy or radiotherapy [Reference Webber, Davies, Anderson, Bartlett, Braat and Cartwright7].
8.4.7 Turner Syndrome
Turner syndrome (TS), with partial or complete loss of the X chromosome renders the ovarian follicular pool vulnerable to hastened atresia with varying degrees of preservation at the time of puberty. Five to twenty per cent will enter spontaneous puberty, but only 10% will progress through puberty, and most will experience pubertal delay and primary amenorrhoea. In addition to pubertal delay other stigmata of Turner syndrome may be present and require specialist investigation and monitoring including growth optimisation and cardiac health [Reference Gravholt, Andersen, Conway, Dekkers, Geffner and Klein8].
8.5 Presence of Secondary Sexual Characteristics
8.5.1 Müllerian Duct Anomaly
In the presence of a normal hormonal milieu and development of secondary sexual characteristics, primary amenorrhoea in isolation may suggest anatomical causes.
Uterine anomalies, also known as Müllerian duct anomalies, represent a spectrum of malformations seen in the female reproductive tract due to erroneous embryogenesis. The prevalence of uterine anomalies is approximately 5.5% in the general population. Despite their embryological origin, many are not detected until later in life due to an incidental finding or with the manifestation of their clinical sequela [Reference Akhtar, Saravelos, Li and Jayaprakasan9].
The Müllerian ducts undergo a series of complex transformations at approximately the sixth to eleventh week of gestation to form the uterus and upper two-thirds of the vagina. The external genital and lower portion of the vagina develop from the urogenital sinus. Uterine/vaginal anomalies may ensue secondary to problems with vertical or lateral duct fusion or defective resorption of the septum. There may even be complete agenesis.
Gynaecological and obstetric presentations may include primary amenorrhoea, irregular menses, dysmenorrhoea, endometrioses, pelvic pain, infertility, obstetric complications or sexual problems. Due to their shared embryological origins, uterine anomalies are also associated with renal anomalies.
MRKH, which affects 1 in 4500, is complete uterine agenesis. Due to an intact functional HPO axis, the classic presentation will be with primary amenorrhoea, normal gonadotrophins, presence of secondary characteristics and typically no cyclical pain. Less commonly, a rudimentary uterine horn with functional endometrium may persist. In this scenario the associated cyclical pain may confuse and delay the diagnosis. Whilst most cases are sporadic in nature there may be more rarely an autosomal dominant pattern. Ten to fifteen per cent of cases of primary amenorrhoea are thought to be caused by MRKH.
Outlet obstruction may be as a result of different anatomical variations including imperforate hymen, transverse vaginal septum (high, medium or low) or vaginal/cervical agenesis. Imperforate hymen is the most common (1:1000), whilst transverse vaginal septum has an incidence of 1:80,000. Presentation may be with primary amenorrhoea in combination with cyclical pain due to the accumulation of blood leading to haematocolpos and hematometra. Clinical examination may reveal the visible distinctive ‘blueish’ bulge of an imperforate hymen but may not detect any abnormality if the obstruction is high. Imaging in the form of high-resolution 3D ultrasound (US) or MRI is key to aid diagnosis, to locate the level of obstruction and any associated anomalies such as renal anomaly.
Treatment may render the primary amenorrhoea completely reversible in the example of surgical management of imperforate hymen/transverse septum.
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