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Primary amenorrhoea
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Primary amenorrhoea
Puberty Puberty is the transition to sexual maturity, with the most visible changes being the growth spurt and development of secondary sexual characteristics. It proceeds in a predictable fashion and is staged using the Tanner system (Table 1). The average age at onset of puberty is 11 years but this is influenced by many factors including genetics, general health and BMI. In most girls the earliest sign of puberty is breast development, although 15% may have pubic hair as the initial sign. Menarche occurs around 2 years after the onset of puberty. The primary driver for puberty is the onset of pulsatile gonadotrophins-releasing hormone (GnRH) secretion from the hypothalamus (see Figure 1). The increasing frequency and amplitude of these pulses stimulate the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland. These hormones then stimulate the production of estradiol by the ovaries. In the beginning stages of puberty, estradiol stimulates breast development (thelarche) and the skeletal growth spurt. In the later stages, the specific combination of FSH, LH and estradiol leads to ovulation and the menstrual cycle begins (menarche). Around the time of the onset of this increase in GnRH pulsatile secretion, Adrenarche, a physiologically distinct event, begins. Dehydroepiandrosterone (DHEA) and androstenedione are released from the adrenal gland, leading to growth of pubic and axillary hair, maturation of apocrine sweat glands and acne. Thus, an individual with a defect in the hypothalamic-pituitary-ovarian axis can still develop pubic and axillary hair.
Claire M Austin Tahir Mahmood
Abstract Primary amenorrhoea is defined as the absence of menstruation by age 14 years in the absence of secondary sexual characteristics, or by age 16 years if secondary sexual characteristics are present. Regular menstruation is regarded as a sign of reproductive health thus absent menstruation causes a significant degree of stress and anxiety to the individuals involved. Puberty is governed by a complex neuro-hormonal system with input from multiple endogenous and exogenous factors, and pathology at various levels in this system can result in amenorrhoea. The causes range from genetic, anatomical, and endocrine to constitutional delay. A stepwise diagnostic approach is key to guiding appropriate investigations whilst minimising the physical and psychological impact on young adolescent women.
Keywords adolescent; adrenarche; amenorrhoea; gonadotrophinsreleasing hormone; menarche; menstruation; menstruation disturbances; puberty; reproductive health; sexual maturation
Introduction Amenorrhoea, the absence of menses, can be transient or permanent and is a symptom that reflects potential dysfunction in the hypothalamic-pituitary-ovarian axis or anatomical anomalies in the uterus or outflow tract. Amenorrhoea can be classified as either primary or secondary depending on the presence (secondary) or absence (primary) of previous menses. Primary amenorrhoea, the focus of this article, is defined as: the absence of menses by age 14 years in the absence of secondary sexual characteristics or the absence of menses by age 16 years in the presence of normal secondary sexual characteristics. Primary amenorrhoea is rare with <5% of adolescent girls presenting to gynaecological services. Whilst the average gynaecologist will see only a few cases, the importance of sensitively managing the initial presentation and diagnostic work up during the vulnerable adolescent years requires all gynaecologists to have a good understanding of the subject. (This article should be read in conjunction with the previous review published in this journal: Basak S, Prakash A. Investigation and treatment of primary amenorrhoea. Obstet Gynaecol Reprod Med 2013; 23: 364 e369.)
Causes of primary amenorrhoea Disruption at any level of the pathway will result in primary amenorrhoea. The causes can be classified by the presence or absence of secondary sexual characteristics and the level at which the pathology exists. Constitutional delay of puberty accounted for 14% of attendances in one large case series; it is more common in boys than girls. A thorough history and examination will help to guide the most appropriate investigations. Almost all causes of secondary amenorrhoea can also cause primary amenorrhoea but they are not discussed in this article. A suggested diagnostic flow chart (Figure 2) and table of differential diagnoses (Table 2) provides guidance for day to day management of such cases.
Tanner stages of breast and pubic hair development
Claire M Austin MBChB MRCOG is a Specialty Trainee in Obstetrics and Gynaecology at Victoria Hospital, Kirkcaldy, Scotland, UK. Conflict of interest: none declared.
Breast development
Pubic hair development
Stage 1 Stage 2 Stage 3
Prepubertal Breast bud Further enlargement of breast and areola Areola and papilla form a secondary mound Mature stage
Prepubertal Sparse growth along labia Darker, coarser hair. Spreads to mons. Hair adult type
Stage 4 Stage 5
Tahir Mahmood MD FRCPI MD FACO FRCPE FRCOG is a Consultant Obstetrician and Gynaecologist at Victoria Hospital, Kirkcaldy, Scotland, UK. Conflict of interest: none declared.
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Tanner stage
Hair spreads to thighs
Table 1
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Hormonal control of the hypothalamic-pituitary-ovarian axis Leptin Ghrelin Kisspeptin + other factors Modulate
Hypothalamus GnRH
Pituitary Estradiol
LH FSH Estradiol Ovary
Breast development Endometrial growth Menstrual cycle
Abbreviations: GnRH (Gonadotropin Releasing Hormone). FSH (Follicle Stimulating Hormone). LH (Luteinising Hormone). Figure 1
A suggested approach to the initial diagnostic work-up for patients with primary amenorrhoea History and examination • Breast development • BMI • Exclude pregnancy FSH + prolactin FSH
Hypothalamic
Prolactin
Pituitary • Cranial imaging • Drug history
FSH
FSH
Ovarian • Karyotype • Fragile X genetics
Uterus present?
Yes
No
Karyotype • Vaginal examination Please refer to the table of differential diagnoses for the next steps in management of these patients. Figure 2
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Differential diagnosis of primary amenorrhoea Condition
Brief Description
Hypothalamic causes Functional Reduced amplitude or frequency of GnRH Hypothalamic release from hypothalamus Amenorrhoea Secondary to weight loss, stress, excessive exercise
Clinical Features
Key Investigations
Management
Low body weight May have any degree of breast development
FSH/LH low Estradiol low 46 XX Ovaries, uterus and vagina present Consider DEXA scan for bone mineral density As above
Aim 30 kcal/kg lean body mass (diet/exercise modification) Manage stress
Kallmann Syndrome
Failure of migration of GnRH neurones from olfactory bulb to hypothalamus during embryonic development. Incidence 1:120,000 females
Absent breast development Normal pubic hair Anosmia
Other rare causes of primary hypothalamic hypogonadism
Causes include tumours, irradiation, infiltrative disorders such as haemochromatosis
Absent breast development Normal pubic hair Signs of underlying condition
As above
Headache Visual field defects Galactorrhoea Breast development incomplete Normal pubic hair
FSH/LH low Estradiol low Prolactin elevated 46 XX MRI Brain e space occupying lesion in suprasellar space
Pituitary causes: hyperprolactinaemia Tumours Microadenoma (<10 mm) and Macroadenomas (>10 mm) can be functioning (prolactinoma) or non-functioning (craniopharyngioma) Compression of pituitary stalk /reduced dopamine levels/no inhibition of prolactin /prolactinaemia/suppression of hypothalamic GnRH
Drugs
Due to blocking effect on dopamine. Examples Breast development include antipsychotics and SSRIs incomplete Galactorrhoea Medication history Ovarian and chromosomal causes Turner Syndrome Partial or complete absence of second X Short stature chromosome. Karyotype 45 X. Associated with Wide spaced nipples premature ovarian insufficiency. Webbed neck Absent secondary sexual characteristics (usually)
FSH/LH low Estradiol Low Prolactin High 46 XX
46 XX Gonadal Dysgenesis
FSH/LH High Estradiol Low 46 XX Uterus present Streak/undetectable ovaries
Group of conditions with normal 46 XX karyotype but undetectable/streak ovaries. Several mutations identified, including in FSH receptor
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No breast development Normal pubic hair Female external genitalia, vagina present
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FSH/LH High Estradiol Low Hypothyroid 45 X
Puberty induction with gradually increasing doses of oestrogen Cyclical progestin after 2 years of oestrogen Long term oestrogen replacement As above Management of underlying condition
Medical (bromocriptine or cabergoline) effective in 80e90% cases. Trans-sphenoidal surgery if medical treatment fails. Puberty should then resume (unless damage to hypothalamus during surgical treatment) Seek alternative medication
Screen for other complications (particularly cardiac) Puberty induction Long term estrogen replacement Consider Growth Hormone Puberty induction Removal of gonads due to risk of malignancy
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Table 2 (continued ) Condition
Brief Description
46 XY Gonadal Dysgenesis
1:100,000 births. Mutations in several genes As above identified including SRY gene (Swyer Syndrome). Streak gonads, no AMH secretion so phenotypic female
Fragile X Syndrome (carrier)
Primary Ovarian Insufficiency
Androgen Insensitivity Syndrome
Outflow tract causes Mullerian Agenesis
Transverse Vaginal Septum
Imperforate Hymen
Clinical Features
Key Investigations
Management
FSH/LH high Estradiol Low 46 XY Uterus present Streak gonads X-linked cause of intellectual disability. Variable degree of breast FSH/LH high Affected individuals have >200 CGG repeats in development Estradiol Low the FMR1 gene. Females can be carriers of (depending on when 46 XX premutations (55e200 repeats). Associated ovaries failed). Mutation in FMR1 with premature ovarian insufficiency Normal pubic hair gene Defined as ovarian failure combined with high As above. FSH/LH high FSH levels. Many causes including Turners and History of autoimmune Estradiol Low Fragile X mutations. Other causes include disease or 46 XX chemotherapy or radiotherapy. Associated previous cancer Possible Steroid Cell with autoimmune adrenal insufficiency and treatment autoantibodies other autoimmune disorders. Defect in the androgen receptor leading to Tall FSH/LH high partial or complete insensitivity to androgens. Normal breast Estradiol normal The individual has an XY karyotype but is development Testosterone e phenotypically female. Peripheral conversion Blind ending vagina normal of androgen to estrogen leads to breast No pubic/axillary hair male range development. 46XY Intra-abdominal testes Absent uterus and vagina
As above Sensitive discussion about gender
Congenital absence of vagina, and usually the Normal secondary sexual uterus. Normal ovarian function. Incidence characteristics 1:5000 females. Associated with renal Blind ending vagina anomalies in 30% cases
Creation of a vagina (see text)
FSH normal Estradiol normal 46 XX Imaging (USS or MRI): absent vagina and uterus Rare, exact incidence unknown. Possibly due Normal secondary sexual FSH normal to failure of canalisation of the vaginal plate at characteristics. Estradiol normal the point the Mullerian duct meets the Cyclical abdominal pain Clinical examination urogenital sinus. and MRI reveal vaginal septum More common than transverse vaginal Normal secondary sexual FSH normal septum. Incidence w1:2000. Cause unknown characteristics Estradiol normal Cyclical abdominal pain Abdominal mass Bluish bulging hymen
Puberty induction Long term estrogen replacement Referral to clinical genetics Puberty induction Long term estrogen replacement Screen for thyroid and adrenal disease Removal of gonads Estrogen replacement
Surgical resection and anastomosis of proximal and distal portions of the vagina
Cruciate incision in the hymen (aseptic technique)
Table 2
The most efficient approach to establishing the cause of primary amenorrhoea involves answering three questions: 1. What is the stage of breast development? - This reflects estradiol action and therefore likely ovarian function 2. What is the FSH level? 3. Is there a uterus present? - As determined by ultrasound or MRI
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Case 1 A 17-year-old presents with primary amenorrhoea. She reports onset of puberty at age 12, with normal breast development. She has no significant medical or surgical history and takes no medications. What are your first steps? It is essential to take a thorough history, particularly focusing on any red flag symptoms (see Table 3) or family history of
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Mullerian Agenesis will not be able to get pregnant or carry a child but she would be able to have her eggs harvested and have a child that is genetically her own through IVF and surrogacy. There is currently research into uterine transplants but this is many years away from introduction into clinical practice. Women with Mullerian Agenesis can have a fulfilling sex life and there are several methods to create a functional vagina. The first line approach is to use dilators to stretch the vagina. This nonsurgical approach has a success rate of about 95% and avoids the complications of surgery. It does require commitment from the woman and can take up to 1 year for adequate vaginal length to be achieved. Surgical techniques include the McIndoe procedure (using a skin graft to create a neovagina), a sigmoid vaginoplasty (using a segment of the sigmoid to create neovagina; patients report chronic discharge and there is a risk of adenocarcinoma in the graft) or the Vecchietti procedure (an acrylic “olive” is placed against the vaginal dimple and attached to a traction device placed laparoscpically which uses constant traction to create a neovagina). There are several support groups which can help provide extra support for the young woman and her family.
Red flag symptoms. (few of the symptoms that should trigger further investigation of primary amenorrhoea.) Symptom/sign
Possible pathology
Headache Galactorrhoea Cyclical abdominal pain Underweight Raised BMI/Acne/Hirsuite Short stature, wide spaced nipples Anosmia
Intracranial lesion Hyperprolactinaemia Outflow obstruction Eating disorder Polycystic ovarian syndrome Turner syndrome Kallmann syndrome
Table 3
delayed puberty. An examination should always include height, weight and an assessment of secondary sexual characteristics (breast development, pubic and axillary hair growth). External genitalia should be inspected only, especially in young girls. Your examination reveals Tanner Stage V breast and pubic hair development. Her height is 170 cm, weight 65 kg and BMI 22. Abdominal palpation is normal. Patient declined internal genital examination. Rest of her examination is unremarkable. What initial investigations will you perform? Pregnancy test (essential if secondary sexual characteristics present, regardless of reported sexual activity or not) Negative Serum FSH e 8IU/L (normal) Hormone Profile: Estradiol normal; Prolactin normal; Total Testosterone normal; TSH normal What is your differential diagnosis? This patient has normal secondary sexual characteristics which suggests normal estradiol levels (confirmed with serum estradiol) and her FSH is normal which indicates an intact HPO axis. This is highly suggestive of an outflow tract issue. A pelvic ultrasound is performed which shows normal ovaries but no evidence of a uterus. An MRI confirms absence of the uterus and vagina. A karyotype is 46 XX.
Case 2 A 14-year-old girl presents with no periods or breast development. There is no medical or surgical history of note. Her mother had an early menopause at age 38. On examination she has Stage IV pubic hair development but no breast development. External genitalia are normal. Investigations: Pregnancy Test negative (not strictly necessary if no secondary sexual characteristics) FSH 30 IU/l (high) Hormone Profile: Estradiol very low; LH high; Prolactin normal; TSH normal What other investigations would be useful in this case? The high FSH and LH along with a low estradiol suggests ovarian insufficiency. There are many causes for this but gonadal dysgenesis is the most common in this age group. You therefore organise: Karyotype: 46 XX Ultrasound Scan: Both ovaries present but small. Prepubertal uterus with thin endometrial echo present What is your diagnosis and what is the likely cause?
€ ster-Hauser Diagnosis: Mullerian Agenesis (Mayer-Rokitansky-Ku Syndrome) This congenital syndrome refers to congenital absence of the vagina, and usually absence of the uterus (although this varies from a small uterine remnant to complete absence of the uterus). The ovaries are present and functional. This affects 1:5000 women and the exact underlying mechanism that causes agenesis of the Mullerian ducts is not known. These women have a normal 46XX karyotype. There is an association with other developmental anomalies; up to 50% have renal tract anomalies, 10e15% has skeletal anomalies, and other associations include deafness and congenital heart defects. How will you counsel the patient? This diagnosis will be a shock to the young woman. It is extremely important to give information in a sensitive manner and not to force any decisions about treatment or management without appropriate time and counselling. The absence of a vagina and uterus needs to be sensitively discussed, particularly regarding future fertility and sexual function. A woman with
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Diagnosis: Primary Ovarian Insufficiency This is defined as primary hypogonadism in women <40 years. Turner Syndrome is the most common genetic cause but has been excluded here with a normal karyotype (see case 3). There is a strong association between young age at menopause, including premature ovarian insufficiency, with carriers of premutations for the Fragile X syndrome. This is an X-linked form of intellectual disability caused by an expansion of an unstable CGG sequence in the FMR1 gene. The full mutation form consists of >200 repeats but premutations of fewer repeats can cause some clinical phenotypes including ovarian failure. The premutations can also expand between generations. The mechanism by which premutations causes ovarian failure is not known. The prevalence of these premutations ranges from 2 to 5% in women with POI, but increases to 12e14% if at least one family member had
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menopause <40 years (as in this case). The diagnosis is important as it may influence the decision to use her own oocytes for IVF in the future given the genetic inheritance of the condition. It may also prompt screening amongst other relatives. This patient underwent genetic testing which identified a premutation of 102 repeats and was referred to clinical genetics to enable full counselling of all these issues. Other causes of primary ovarian insufficiency include autoimmune where the presence of ovarian auto antibodies is detected and is more commonly seen in association with autoimmune adrenal failure. Childhood chemotherapy and radiotherapy is likely to become a more common cause of premature ovarian insufficiency as more children with cancer are surviving to adulthood. These causes can also present as both primary and secondary amenorrhoea. How will you induce puberty? In this case, the patient has not entered puberty so she will need hormonal support to induce breast development. This is achieved by using either oral or transdermal estradiol. Initial doses are much lower than that used for adult replacement. The dose of estradiol is slowly increased over 2 years. Cyclical progestins are commenced after 2 years of therapy, if progestins are introduced too early they will limit breast development. Progestins are then used for endometrial protection. Estrogens and progestin therapy is required long term (until age 50 years) to maintain bone and cardiovascular health. The patient should be counselled that contraception is required as unpredictable, spontaneous ovulation can occur. Once breast development is established and menses have begun, the combined oral contraceptive can be used as this has the added benefit of contraception. However, one study suggested that physiologic oestrogen doses (which are lower than in the combined contraceptive pill) may be more beneficial for bone health.
diagnosed until adolescence or early adulthood. The clinical phenotype can vary, especially in women with mosaicism. The degree of mosaicism can vary in different tissues thus many of the classical features may not be present. Primary ovarian insufficiency is an indication for karyotyping which can detect 10% mosaicism with 95% confidence (<5% mosaicism is unlikely to be of clinical significance). Spontaneous puberty is uncommon in women with the karyotype 45XO, but is seen more frequently in women with mosaicism. The majority of girls require puberty induction, as described in the previous case. In this case, the patient has achieved normal breast development but will require long term oestrogen for her bone and cardiovascular health and cyclical progestin to induce menstruation. Ovulation induction with IVF may be a possibility in the future if this patient wishes, depending on her ovarian reserve at the time. However surrogacy with a donor egg or adoption are likely to be her only realistic fertility options. What other (non-reproductive) investigations and management is required? Almost all patients with Turner Syndrome have a short stature due to deficiency of the SHOX gene which is located on both X and Y chromosomes (thus there are usually two copies in each cell but only one copy in the Turner Syndrome) and is essential for growth and development of the skeleton. If Turner Syndrome is diagnosed in infancy or childhood then Growth Hormone can be used to improve adult height; the efficacy is dependent on age at commencing treatment, as well as other factors. This patient does not require growth hormone treatment as she is of normal height. Turner Syndrome is particularly associated with cardiovascular problems including congenital heart defects, aortic dilatation and an increased risk of ischaemic heart disease. This is an important cause of mortality in these patients. An echo, ECG, BP and lipid profile should be performed alongside a cardiology review. Endocrine problems such as hypothyroidism are common and should be screened for and treated. This patient has subclinical hypothyroidism which should be monitored with yearly Thyroid function tests. Other associated conditions include diabetes, renal developmental anomalies, coeliac disease and sensorineural deafness.
Case 3 A young woman presents with normal breast development but no periods at the age of 16. She denies any medical or surgical history. Examination and investigations are below: Height 168 cm, Weight 60 kg, BMI 21 Tanner Stage V breasts and pubic hair Normal external genitalia Pregnancy test negative FSH 55IU/l (very high) Hormone profile: Estradiol low; LH high; Prolactin normal; TSH 4.5 mU/l (mildly elevated) T4 normal; Testosterone normal As with the previous case, this hormone profile is suggestive of ovarian insufficiency. Karyotype 45X,46XX Ultrasound: Uterus containing thin endometrial echo. Right ovary identified with a volume of 1.5 ml. Left ovary not seen
Case 4 A 14-year-old presents with her very anxious mother concerned that puberty has not started. The patient is in 3rd year at high school and is about to sit her end of year exams. She is a high achiever and is on her school hockey team. You perform a full examination which reveals: Tanner Stage II Breasts, Tanner Stage IV pubic and axillary hair Weight 163 cm, Weight 47 kg, BMI 17.7 Rest of examination is unremarkable What is your differential diagnosis? This appears to be a classic case of hypothalamic hypogonadism with exam stressors, an anxious mother and an athletic hobby. However, it is important to consider other causes of delayed puberty. You proceed with your usual investigations:
Diagnosis: Turner Syndrome Mosaicism Turner syndrome results from partial or complete loss of the second X chromosome with a prevalence of 1 in 2500 live female births. Up to a third of women with Turner syndrome are not
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Pregnancy Test negative FSH 2 IU/l (Low) Hormone Profile: Estradiol (low); LH (low); Prolactin (normal); TSH (normal) Imaging: Ultrasound confirms presence of uterus, with thin endometrial echo
What is your differential diagnosis? The presence of normal breast development suggests the presence of estradiol. The differential diagnoses include Mullerian Agenesis (normal breast development and a blind ending vagina), Gonadal dysgenesis or Complete Androgen Insensitivity (lack of pubic hair and palpable inguinal masses). In order to differentiate further investigations are required. Pregnancy Test negative FSH 6IU/l (normal) Hormone Profile: Estradiol normal; LH high; Prolactin normal; Testosterone (normal male range); TSH normal Ultrasound: Absent uterus. Inguinal testes noted. Karyotype: 46 XY
Diagnosis: Hypothalamic Amenorrhoea Hypothalamic amenorrhoea can cause both primary and secondary amenorrhoea. It is characterised by reduced pulses of Gonadotrophins, secondary to a decrease in GnRH release from the hypothalamus. The control of GnRH pulsatility is complex and not fully understood. It has been shown to be influenced by several hormones and signalling molecules including leptin, ghrelin and cortisol. It has been proposed that there is a critical body fat level required for the onset of puberty. Leptin, produced by fat cells, appears to play an important in role in the timing and progression of puberty, but it does not seem to be the only factor. Decreased calorie intake or excessive exercise is common causes of hypothalamic amenorrhoea, potentially mediated through leptin. As weight increases, leptin levels also increase and the hypothalamic-pituitary-ovarian axis resumes. Stress has been shown to increase cortisol levels which have a negative impact on GnRH secretion. Due to the low levels of GnRH and subsequent low FSH and LH levels, follicle development, estradiol secretion and ovulation are inhibited. The low estradiol levels leads to reduced breast development and can have a significant impact on bone mineral density, particularly at this critical period of bone development. How will you counsel the patient and her mother? An understanding of the reasons for the delay in pubertal development may be enough to encourage increased weight gain, reduction in exercise and behavioural changes to reduce stress. It may be helpful to give her a weight target to work towards (giving a BMI of >18.5). Family therapy and CBT can be helpful in the context of eating disorders or coping with stress. Conservative measures should be pursued in the first instance. It is also important to assess the bone health and so a dual energy X-ray absorptiometry (DEXA) scan should be considered. Consideration should also be given to disorders of malabsorption or chronic medical conditions including coeliac or inflammatory bowel disease. A careful history should guide you toward further investigation if required. If after 6e12 months, puberty has not resumed (as measured by breast development or menses beginning) oestrogen therapy can be commenced to improve bone mineral density, breast development and eventually to lead to menstruation.
Diagnosis: Complete Androgen Insensitivity Syndrome The incidence of complete androgen insensitivity syndrome (CAIS) is 1:20,000 and results from a mutation in the Androgen Receptor gene, thus despite normal male androgen levels, there is an inability to respond. In CAIS, the woman is phenotypically female with normal female external genitalia but absent ovaries, uterus and vagina. Testes are present and can be intraabdominal or inguinal. If inguinal masses are palpable, the condition may be diagnosed in childhood during investigation of presumed inguinal hernias. The testes are at risk of malignancy so gonadectomy is recommended by age 20. Breast development occurs due to oestrogen that is produced by the testes and aromatisation of androgens to oestrogen in the breast tissue. As with Mullerian Agenesis, the vagina is short and blind ended so the creation of a vagina with dilators is usually required. How will you counsel the patient? This is a difficult diagnosis to explain to adolescents and their families. Gender identity is a topical and sensitive issue. Whilst most people with CAIS identify as female, it is important not to emphasise this so strongly that they are unable to voice any concerns they may have. Whilst the person will be phenotypically female, the presence of testes and absence of ovaries, uterus and vagina will be difficult to come to terms with. Referral to clinical psychologists and patient/family support groups is very important. Management is generally supportive is the first instance, followed by the creation of a vagina if the patient wishes this. Following removal of the testes (which should be performed by age 20), HRT will be required to ensure long term bone and cardiovascular health. Adoption or surrogacy (with donor eggs) is the only options for fertility.
Conclusion We have discussed the common and some of the rarer causes of primary amenorrhoea. This area of medicine is multifaceted, encompassing physical and psychological issues, alongside the very topical issue of gender identity. The complex neurohormonal mechanisms underpinning puberty have yet to be fully elucidated and thus our understanding of this topic is likely to change in the future. Utilising a structured approach to the diagnostic work-up will ensure a rational and efficient pathway to diagnosis and appropriate management for the individual patients and their families. A
Case 5 A 17-year-old presents with no periods. She reports onset of breast development age 12 but her periods never started. Examination reveals: Tanner Stage V Breasts with pale areolae Sparse pubic hair Abdominal examination: palpable inguinal masses External genitalia: no evidence of virilisation. Internal examination: blind ending vagina
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FURTHER READING Basak S, Prakash A. Investigation and treatment of primary amenorrhoea. Obstet Gynaecol Reprod Med 2013; 23: 364e9. DiVall SA, Radovick S. Endocrinology of female puberty. Curr Opin Endocrinol Diabetes Obes 2009; 16: 1e4. Solnik MJ. Assessment of primary amenorrhoea. BMJ Best Pract 2014 [cited 01.06.18]. Available from https://bestpractice.bmj.com/ topics/en-gb/1101. The Practice Committee of the American Society for Reproductive Medicine. Current evaluation of amenorrhea. Fertil Steril 2008; 90: S219e25.
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Practice points C C
C
C
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Assess secondary sexual characteristics using the Tanner System Pregnancy test is essential if secondary sexual development is present FSH, Prolactin and estradiol will direct you to the most likely cause Sensitive discussion of gender, sexuality and fertility requires multi-disciplinary involvement
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Primary amenorrhoea
Puberty Puberty is the transition to sexual maturity, with the most visible changes being the growth spurt and development of secondary sexual characteristics. It proceeds in a predictable fashion and is staged using the Tanner system (Table 1). The average age at onset of puberty is 11 years but this is influenced by many factors including genetics, general health and BMI. In most girls the earliest sign of puberty is breast development, although 15% may have pubic hair as the initial sign. Menarche occurs around 2 years after the onset of puberty. The primary driver for puberty is the onset of pulsatile gonadotrophins-releasing hormone (GnRH) secretion from the hypothalamus (see Figure 1). The increasing frequency and amplitude of these pulses stimulate the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland. These hormones then stimulate the production of estradiol by the ovaries. In the beginning stages of puberty, estradiol stimulates breast development (thelarche) and the skeletal growth spurt. In the later stages, the specific combination of FSH, LH and estradiol leads to ovulation and the menstrual cycle begins (menarche). Around the time of the onset of this increase in GnRH pulsatile secretion, Adrenarche, a physiologically distinct event, begins. Dehydroepiandrosterone (DHEA) and androstenedione are released from the adrenal gland, leading to growth of pubic and axillary hair, maturation of apocrine sweat glands and acne. Thus, an individual with a defect in the hypothalamic-pituitary-ovarian axis can still develop pubic and axillary hair.
Claire M Austin Tahir Mahmood
Abstract Primary amenorrhoea is defined as the absence of menstruation by age 14 years in the absence of secondary sexual characteristics, or by age 16 years if secondary sexual characteristics are present. Regular menstruation is regarded as a sign of reproductive health thus absent menstruation causes a significant degree of stress and anxiety to the individuals involved. Puberty is governed by a complex neuro-hormonal system with input from multiple endogenous and exogenous factors, and pathology at various levels in this system can result in amenorrhoea. The causes range from genetic, anatomical, and endocrine to constitutional delay. A stepwise diagnostic approach is key to guiding appropriate investigations whilst minimising the physical and psychological impact on young adolescent women.
Keywords adolescent; adrenarche; amenorrhoea; gonadotrophinsreleasing hormone; menarche; menstruation; menstruation disturbances; puberty; reproductive health; sexual maturation
Introduction Amenorrhoea, the absence of menses, can be transient or permanent and is a symptom that reflects potential dysfunction in the hypothalamic-pituitary-ovarian axis or anatomical anomalies in the uterus or outflow tract. Amenorrhoea can be classified as either primary or secondary depending on the presence (secondary) or absence (primary) of previous menses. Primary amenorrhoea, the focus of this article, is defined as: the absence of menses by age 14 years in the absence of secondary sexual characteristics or the absence of menses by age 16 years in the presence of normal secondary sexual characteristics. Primary amenorrhoea is rare with <5% of adolescent girls presenting to gynaecological services. Whilst the average gynaecologist will see only a few cases, the importance of sensitively managing the initial presentation and diagnostic work up during the vulnerable adolescent years requires all gynaecologists to have a good understanding of the subject. (This article should be read in conjunction with the previous review published in this journal: Basak S, Prakash A. Investigation and treatment of primary amenorrhoea. Obstet Gynaecol Reprod Med 2013; 23: 364 e369.)
Causes of primary amenorrhoea Disruption at any level of the pathway will result in primary amenorrhoea. The causes can be classified by the presence or absence of secondary sexual characteristics and the level at which the pathology exists. Constitutional delay of puberty accounted for 14% of attendances in one large case series; it is more common in boys than girls. A thorough history and examination will help to guide the most appropriate investigations. Almost all causes of secondary amenorrhoea can also cause primary amenorrhoea but they are not discussed in this article. A suggested diagnostic flow chart (Figure 2) and table of differential diagnoses (Table 2) provides guidance for day to day management of such cases.
Tanner stages of breast and pubic hair development
Claire M Austin MBChB MRCOG is a Specialty Trainee in Obstetrics and Gynaecology at Victoria Hospital, Kirkcaldy, Scotland, UK. Conflict of interest: none declared.
Breast development
Pubic hair development
Stage 1 Stage 2 Stage 3
Prepubertal Breast bud Further enlargement of breast and areola Areola and papilla form a secondary mound Mature stage
Prepubertal Sparse growth along labia Darker, coarser hair. Spreads to mons. Hair adult type
Stage 4 Stage 5
Tahir Mahmood MD FRCPI MD FACO FRCPE FRCOG is a Consultant Obstetrician and Gynaecologist at Victoria Hospital, Kirkcaldy, Scotland, UK. Conflict of interest: none declared.
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Tanner stage
Hair spreads to thighs
Table 1
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Hormonal control of the hypothalamic-pituitary-ovarian axis Leptin Ghrelin Kisspeptin + other factors Modulate
Hypothalamus GnRH
Pituitary Estradiol
LH FSH Estradiol Ovary
Breast development Endometrial growth Menstrual cycle
Abbreviations: GnRH (Gonadotropin Releasing Hormone). FSH (Follicle Stimulating Hormone). LH (Luteinising Hormone). Figure 1
A suggested approach to the initial diagnostic work-up for patients with primary amenorrhoea History and examination • Breast development • BMI • Exclude pregnancy FSH + prolactin FSH
Hypothalamic
Prolactin
Pituitary • Cranial imaging • Drug history
FSH
FSH
Ovarian • Karyotype • Fragile X genetics
Uterus present?
Yes
No
Karyotype • Vaginal examination Please refer to the table of differential diagnoses for the next steps in management of these patients. Figure 2
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Differential diagnosis of primary amenorrhoea Condition
Brief Description
Hypothalamic causes Functional Reduced amplitude or frequency of GnRH Hypothalamic release from hypothalamus Amenorrhoea Secondary to weight loss, stress, excessive exercise
Clinical Features
Key Investigations
Management
Low body weight May have any degree of breast development
FSH/LH low Estradiol low 46 XX Ovaries, uterus and vagina present Consider DEXA scan for bone mineral density As above
Aim 30 kcal/kg lean body mass (diet/exercise modification) Manage stress
Kallmann Syndrome
Failure of migration of GnRH neurones from olfactory bulb to hypothalamus during embryonic development. Incidence 1:120,000 females
Absent breast development Normal pubic hair Anosmia
Other rare causes of primary hypothalamic hypogonadism
Causes include tumours, irradiation, infiltrative disorders such as haemochromatosis
Absent breast development Normal pubic hair Signs of underlying condition
As above
Headache Visual field defects Galactorrhoea Breast development incomplete Normal pubic hair
FSH/LH low Estradiol low Prolactin elevated 46 XX MRI Brain e space occupying lesion in suprasellar space
Pituitary causes: hyperprolactinaemia Tumours Microadenoma (<10 mm) and Macroadenomas (>10 mm) can be functioning (prolactinoma) or non-functioning (craniopharyngioma) Compression of pituitary stalk /reduced dopamine levels/no inhibition of prolactin /prolactinaemia/suppression of hypothalamic GnRH
Drugs
Due to blocking effect on dopamine. Examples Breast development include antipsychotics and SSRIs incomplete Galactorrhoea Medication history Ovarian and chromosomal causes Turner Syndrome Partial or complete absence of second X Short stature chromosome. Karyotype 45 X. Associated with Wide spaced nipples premature ovarian insufficiency. Webbed neck Absent secondary sexual characteristics (usually)
FSH/LH low Estradiol Low Prolactin High 46 XX
46 XX Gonadal Dysgenesis
FSH/LH High Estradiol Low 46 XX Uterus present Streak/undetectable ovaries
Group of conditions with normal 46 XX karyotype but undetectable/streak ovaries. Several mutations identified, including in FSH receptor
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No breast development Normal pubic hair Female external genitalia, vagina present
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FSH/LH High Estradiol Low Hypothyroid 45 X
Puberty induction with gradually increasing doses of oestrogen Cyclical progestin after 2 years of oestrogen Long term oestrogen replacement As above Management of underlying condition
Medical (bromocriptine or cabergoline) effective in 80e90% cases. Trans-sphenoidal surgery if medical treatment fails. Puberty should then resume (unless damage to hypothalamus during surgical treatment) Seek alternative medication
Screen for other complications (particularly cardiac) Puberty induction Long term estrogen replacement Consider Growth Hormone Puberty induction Removal of gonads due to risk of malignancy
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Table 2 (continued ) Condition
Brief Description
46 XY Gonadal Dysgenesis
1:100,000 births. Mutations in several genes As above identified including SRY gene (Swyer Syndrome). Streak gonads, no AMH secretion so phenotypic female
Fragile X Syndrome (carrier)
Primary Ovarian Insufficiency
Androgen Insensitivity Syndrome
Outflow tract causes Mullerian Agenesis
Transverse Vaginal Septum
Imperforate Hymen
Clinical Features
Key Investigations
Management
FSH/LH high Estradiol Low 46 XY Uterus present Streak gonads X-linked cause of intellectual disability. Variable degree of breast FSH/LH high Affected individuals have >200 CGG repeats in development Estradiol Low the FMR1 gene. Females can be carriers of (depending on when 46 XX premutations (55e200 repeats). Associated ovaries failed). Mutation in FMR1 with premature ovarian insufficiency Normal pubic hair gene Defined as ovarian failure combined with high As above. FSH/LH high FSH levels. Many causes including Turners and History of autoimmune Estradiol Low Fragile X mutations. Other causes include disease or 46 XX chemotherapy or radiotherapy. Associated previous cancer Possible Steroid Cell with autoimmune adrenal insufficiency and treatment autoantibodies other autoimmune disorders. Defect in the androgen receptor leading to Tall FSH/LH high partial or complete insensitivity to androgens. Normal breast Estradiol normal The individual has an XY karyotype but is development Testosterone e phenotypically female. Peripheral conversion Blind ending vagina normal of androgen to estrogen leads to breast No pubic/axillary hair male range development. 46XY Intra-abdominal testes Absent uterus and vagina
As above Sensitive discussion about gender
Congenital absence of vagina, and usually the Normal secondary sexual uterus. Normal ovarian function. Incidence characteristics 1:5000 females. Associated with renal Blind ending vagina anomalies in 30% cases
Creation of a vagina (see text)
FSH normal Estradiol normal 46 XX Imaging (USS or MRI): absent vagina and uterus Rare, exact incidence unknown. Possibly due Normal secondary sexual FSH normal to failure of canalisation of the vaginal plate at characteristics. Estradiol normal the point the Mullerian duct meets the Cyclical abdominal pain Clinical examination urogenital sinus. and MRI reveal vaginal septum More common than transverse vaginal Normal secondary sexual FSH normal septum. Incidence w1:2000. Cause unknown characteristics Estradiol normal Cyclical abdominal pain Abdominal mass Bluish bulging hymen
Puberty induction Long term estrogen replacement Referral to clinical genetics Puberty induction Long term estrogen replacement Screen for thyroid and adrenal disease Removal of gonads Estrogen replacement
Surgical resection and anastomosis of proximal and distal portions of the vagina
Cruciate incision in the hymen (aseptic technique)
Table 2
The most efficient approach to establishing the cause of primary amenorrhoea involves answering three questions: 1. What is the stage of breast development? - This reflects estradiol action and therefore likely ovarian function 2. What is the FSH level? 3. Is there a uterus present? - As determined by ultrasound or MRI
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Case 1 A 17-year-old presents with primary amenorrhoea. She reports onset of puberty at age 12, with normal breast development. She has no significant medical or surgical history and takes no medications. What are your first steps? It is essential to take a thorough history, particularly focusing on any red flag symptoms (see Table 3) or family history of
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Mullerian Agenesis will not be able to get pregnant or carry a child but she would be able to have her eggs harvested and have a child that is genetically her own through IVF and surrogacy. There is currently research into uterine transplants but this is many years away from introduction into clinical practice. Women with Mullerian Agenesis can have a fulfilling sex life and there are several methods to create a functional vagina. The first line approach is to use dilators to stretch the vagina. This nonsurgical approach has a success rate of about 95% and avoids the complications of surgery. It does require commitment from the woman and can take up to 1 year for adequate vaginal length to be achieved. Surgical techniques include the McIndoe procedure (using a skin graft to create a neovagina), a sigmoid vaginoplasty (using a segment of the sigmoid to create neovagina; patients report chronic discharge and there is a risk of adenocarcinoma in the graft) or the Vecchietti procedure (an acrylic “olive” is placed against the vaginal dimple and attached to a traction device placed laparoscpically which uses constant traction to create a neovagina). There are several support groups which can help provide extra support for the young woman and her family.
Red flag symptoms. (few of the symptoms that should trigger further investigation of primary amenorrhoea.) Symptom/sign
Possible pathology
Headache Galactorrhoea Cyclical abdominal pain Underweight Raised BMI/Acne/Hirsuite Short stature, wide spaced nipples Anosmia
Intracranial lesion Hyperprolactinaemia Outflow obstruction Eating disorder Polycystic ovarian syndrome Turner syndrome Kallmann syndrome
Table 3
delayed puberty. An examination should always include height, weight and an assessment of secondary sexual characteristics (breast development, pubic and axillary hair growth). External genitalia should be inspected only, especially in young girls. Your examination reveals Tanner Stage V breast and pubic hair development. Her height is 170 cm, weight 65 kg and BMI 22. Abdominal palpation is normal. Patient declined internal genital examination. Rest of her examination is unremarkable. What initial investigations will you perform? Pregnancy test (essential if secondary sexual characteristics present, regardless of reported sexual activity or not) Negative Serum FSH e 8IU/L (normal) Hormone Profile: Estradiol normal; Prolactin normal; Total Testosterone normal; TSH normal What is your differential diagnosis? This patient has normal secondary sexual characteristics which suggests normal estradiol levels (confirmed with serum estradiol) and her FSH is normal which indicates an intact HPO axis. This is highly suggestive of an outflow tract issue. A pelvic ultrasound is performed which shows normal ovaries but no evidence of a uterus. An MRI confirms absence of the uterus and vagina. A karyotype is 46 XX.
Case 2 A 14-year-old girl presents with no periods or breast development. There is no medical or surgical history of note. Her mother had an early menopause at age 38. On examination she has Stage IV pubic hair development but no breast development. External genitalia are normal. Investigations: Pregnancy Test negative (not strictly necessary if no secondary sexual characteristics) FSH 30 IU/l (high) Hormone Profile: Estradiol very low; LH high; Prolactin normal; TSH normal What other investigations would be useful in this case? The high FSH and LH along with a low estradiol suggests ovarian insufficiency. There are many causes for this but gonadal dysgenesis is the most common in this age group. You therefore organise: Karyotype: 46 XX Ultrasound Scan: Both ovaries present but small. Prepubertal uterus with thin endometrial echo present What is your diagnosis and what is the likely cause?
€ ster-Hauser Diagnosis: Mullerian Agenesis (Mayer-Rokitansky-Ku Syndrome) This congenital syndrome refers to congenital absence of the vagina, and usually absence of the uterus (although this varies from a small uterine remnant to complete absence of the uterus). The ovaries are present and functional. This affects 1:5000 women and the exact underlying mechanism that causes agenesis of the Mullerian ducts is not known. These women have a normal 46XX karyotype. There is an association with other developmental anomalies; up to 50% have renal tract anomalies, 10e15% has skeletal anomalies, and other associations include deafness and congenital heart defects. How will you counsel the patient? This diagnosis will be a shock to the young woman. It is extremely important to give information in a sensitive manner and not to force any decisions about treatment or management without appropriate time and counselling. The absence of a vagina and uterus needs to be sensitively discussed, particularly regarding future fertility and sexual function. A woman with
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Diagnosis: Primary Ovarian Insufficiency This is defined as primary hypogonadism in women <40 years. Turner Syndrome is the most common genetic cause but has been excluded here with a normal karyotype (see case 3). There is a strong association between young age at menopause, including premature ovarian insufficiency, with carriers of premutations for the Fragile X syndrome. This is an X-linked form of intellectual disability caused by an expansion of an unstable CGG sequence in the FMR1 gene. The full mutation form consists of >200 repeats but premutations of fewer repeats can cause some clinical phenotypes including ovarian failure. The premutations can also expand between generations. The mechanism by which premutations causes ovarian failure is not known. The prevalence of these premutations ranges from 2 to 5% in women with POI, but increases to 12e14% if at least one family member had
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menopause <40 years (as in this case). The diagnosis is important as it may influence the decision to use her own oocytes for IVF in the future given the genetic inheritance of the condition. It may also prompt screening amongst other relatives. This patient underwent genetic testing which identified a premutation of 102 repeats and was referred to clinical genetics to enable full counselling of all these issues. Other causes of primary ovarian insufficiency include autoimmune where the presence of ovarian auto antibodies is detected and is more commonly seen in association with autoimmune adrenal failure. Childhood chemotherapy and radiotherapy is likely to become a more common cause of premature ovarian insufficiency as more children with cancer are surviving to adulthood. These causes can also present as both primary and secondary amenorrhoea. How will you induce puberty? In this case, the patient has not entered puberty so she will need hormonal support to induce breast development. This is achieved by using either oral or transdermal estradiol. Initial doses are much lower than that used for adult replacement. The dose of estradiol is slowly increased over 2 years. Cyclical progestins are commenced after 2 years of therapy, if progestins are introduced too early they will limit breast development. Progestins are then used for endometrial protection. Estrogens and progestin therapy is required long term (until age 50 years) to maintain bone and cardiovascular health. The patient should be counselled that contraception is required as unpredictable, spontaneous ovulation can occur. Once breast development is established and menses have begun, the combined oral contraceptive can be used as this has the added benefit of contraception. However, one study suggested that physiologic oestrogen doses (which are lower than in the combined contraceptive pill) may be more beneficial for bone health.
diagnosed until adolescence or early adulthood. The clinical phenotype can vary, especially in women with mosaicism. The degree of mosaicism can vary in different tissues thus many of the classical features may not be present. Primary ovarian insufficiency is an indication for karyotyping which can detect 10% mosaicism with 95% confidence (<5% mosaicism is unlikely to be of clinical significance). Spontaneous puberty is uncommon in women with the karyotype 45XO, but is seen more frequently in women with mosaicism. The majority of girls require puberty induction, as described in the previous case. In this case, the patient has achieved normal breast development but will require long term oestrogen for her bone and cardiovascular health and cyclical progestin to induce menstruation. Ovulation induction with IVF may be a possibility in the future if this patient wishes, depending on her ovarian reserve at the time. However surrogacy with a donor egg or adoption are likely to be her only realistic fertility options. What other (non-reproductive) investigations and management is required? Almost all patients with Turner Syndrome have a short stature due to deficiency of the SHOX gene which is located on both X and Y chromosomes (thus there are usually two copies in each cell but only one copy in the Turner Syndrome) and is essential for growth and development of the skeleton. If Turner Syndrome is diagnosed in infancy or childhood then Growth Hormone can be used to improve adult height; the efficacy is dependent on age at commencing treatment, as well as other factors. This patient does not require growth hormone treatment as she is of normal height. Turner Syndrome is particularly associated with cardiovascular problems including congenital heart defects, aortic dilatation and an increased risk of ischaemic heart disease. This is an important cause of mortality in these patients. An echo, ECG, BP and lipid profile should be performed alongside a cardiology review. Endocrine problems such as hypothyroidism are common and should be screened for and treated. This patient has subclinical hypothyroidism which should be monitored with yearly Thyroid function tests. Other associated conditions include diabetes, renal developmental anomalies, coeliac disease and sensorineural deafness.
Case 3 A young woman presents with normal breast development but no periods at the age of 16. She denies any medical or surgical history. Examination and investigations are below: Height 168 cm, Weight 60 kg, BMI 21 Tanner Stage V breasts and pubic hair Normal external genitalia Pregnancy test negative FSH 55IU/l (very high) Hormone profile: Estradiol low; LH high; Prolactin normal; TSH 4.5 mU/l (mildly elevated) T4 normal; Testosterone normal As with the previous case, this hormone profile is suggestive of ovarian insufficiency. Karyotype 45X,46XX Ultrasound: Uterus containing thin endometrial echo. Right ovary identified with a volume of 1.5 ml. Left ovary not seen
Case 4 A 14-year-old presents with her very anxious mother concerned that puberty has not started. The patient is in 3rd year at high school and is about to sit her end of year exams. She is a high achiever and is on her school hockey team. You perform a full examination which reveals: Tanner Stage II Breasts, Tanner Stage IV pubic and axillary hair Weight 163 cm, Weight 47 kg, BMI 17.7 Rest of examination is unremarkable What is your differential diagnosis? This appears to be a classic case of hypothalamic hypogonadism with exam stressors, an anxious mother and an athletic hobby. However, it is important to consider other causes of delayed puberty. You proceed with your usual investigations:
Diagnosis: Turner Syndrome Mosaicism Turner syndrome results from partial or complete loss of the second X chromosome with a prevalence of 1 in 2500 live female births. Up to a third of women with Turner syndrome are not
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Pregnancy Test negative FSH 2 IU/l (Low) Hormone Profile: Estradiol (low); LH (low); Prolactin (normal); TSH (normal) Imaging: Ultrasound confirms presence of uterus, with thin endometrial echo
What is your differential diagnosis? The presence of normal breast development suggests the presence of estradiol. The differential diagnoses include Mullerian Agenesis (normal breast development and a blind ending vagina), Gonadal dysgenesis or Complete Androgen Insensitivity (lack of pubic hair and palpable inguinal masses). In order to differentiate further investigations are required. Pregnancy Test negative FSH 6IU/l (normal) Hormone Profile: Estradiol normal; LH high; Prolactin normal; Testosterone (normal male range); TSH normal Ultrasound: Absent uterus. Inguinal testes noted. Karyotype: 46 XY
Diagnosis: Hypothalamic Amenorrhoea Hypothalamic amenorrhoea can cause both primary and secondary amenorrhoea. It is characterised by reduced pulses of Gonadotrophins, secondary to a decrease in GnRH release from the hypothalamus. The control of GnRH pulsatility is complex and not fully understood. It has been shown to be influenced by several hormones and signalling molecules including leptin, ghrelin and cortisol. It has been proposed that there is a critical body fat level required for the onset of puberty. Leptin, produced by fat cells, appears to play an important in role in the timing and progression of puberty, but it does not seem to be the only factor. Decreased calorie intake or excessive exercise is common causes of hypothalamic amenorrhoea, potentially mediated through leptin. As weight increases, leptin levels also increase and the hypothalamic-pituitary-ovarian axis resumes. Stress has been shown to increase cortisol levels which have a negative impact on GnRH secretion. Due to the low levels of GnRH and subsequent low FSH and LH levels, follicle development, estradiol secretion and ovulation are inhibited. The low estradiol levels leads to reduced breast development and can have a significant impact on bone mineral density, particularly at this critical period of bone development. How will you counsel the patient and her mother? An understanding of the reasons for the delay in pubertal development may be enough to encourage increased weight gain, reduction in exercise and behavioural changes to reduce stress. It may be helpful to give her a weight target to work towards (giving a BMI of >18.5). Family therapy and CBT can be helpful in the context of eating disorders or coping with stress. Conservative measures should be pursued in the first instance. It is also important to assess the bone health and so a dual energy X-ray absorptiometry (DEXA) scan should be considered. Consideration should also be given to disorders of malabsorption or chronic medical conditions including coeliac or inflammatory bowel disease. A careful history should guide you toward further investigation if required. If after 6e12 months, puberty has not resumed (as measured by breast development or menses beginning) oestrogen therapy can be commenced to improve bone mineral density, breast development and eventually to lead to menstruation.
Diagnosis: Complete Androgen Insensitivity Syndrome The incidence of complete androgen insensitivity syndrome (CAIS) is 1:20,000 and results from a mutation in the Androgen Receptor gene, thus despite normal male androgen levels, there is an inability to respond. In CAIS, the woman is phenotypically female with normal female external genitalia but absent ovaries, uterus and vagina. Testes are present and can be intraabdominal or inguinal. If inguinal masses are palpable, the condition may be diagnosed in childhood during investigation of presumed inguinal hernias. The testes are at risk of malignancy so gonadectomy is recommended by age 20. Breast development occurs due to oestrogen that is produced by the testes and aromatisation of androgens to oestrogen in the breast tissue. As with Mullerian Agenesis, the vagina is short and blind ended so the creation of a vagina with dilators is usually required. How will you counsel the patient? This is a difficult diagnosis to explain to adolescents and their families. Gender identity is a topical and sensitive issue. Whilst most people with CAIS identify as female, it is important not to emphasise this so strongly that they are unable to voice any concerns they may have. Whilst the person will be phenotypically female, the presence of testes and absence of ovaries, uterus and vagina will be difficult to come to terms with. Referral to clinical psychologists and patient/family support groups is very important. Management is generally supportive is the first instance, followed by the creation of a vagina if the patient wishes this. Following removal of the testes (which should be performed by age 20), HRT will be required to ensure long term bone and cardiovascular health. Adoption or surrogacy (with donor eggs) is the only options for fertility.
Conclusion We have discussed the common and some of the rarer causes of primary amenorrhoea. This area of medicine is multifaceted, encompassing physical and psychological issues, alongside the very topical issue of gender identity. The complex neurohormonal mechanisms underpinning puberty have yet to be fully elucidated and thus our understanding of this topic is likely to change in the future. Utilising a structured approach to the diagnostic work-up will ensure a rational and efficient pathway to diagnosis and appropriate management for the individual patients and their families. A
Case 5 A 17-year-old presents with no periods. She reports onset of breast development age 12 but her periods never started. Examination reveals: Tanner Stage V Breasts with pale areolae Sparse pubic hair Abdominal examination: palpable inguinal masses External genitalia: no evidence of virilisation. Internal examination: blind ending vagina
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FURTHER READING Basak S, Prakash A. Investigation and treatment of primary amenorrhoea. Obstet Gynaecol Reprod Med 2013; 23: 364e9. DiVall SA, Radovick S. Endocrinology of female puberty. Curr Opin Endocrinol Diabetes Obes 2009; 16: 1e4. Solnik MJ. Assessment of primary amenorrhoea. BMJ Best Pract 2014 [cited 01.06.18]. Available from https://bestpractice.bmj.com/ topics/en-gb/1101. The Practice Committee of the American Society for Reproductive Medicine. Current evaluation of amenorrhea. Fertil Steril 2008; 90: S219e25.
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Assess secondary sexual characteristics using the Tanner System Pregnancy test is essential if secondary sexual development is present FSH, Prolactin and estradiol will direct you to the most likely cause Sensitive discussion of gender, sexuality and fertility requires multi-disciplinary involvement
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