Hormonal Control of the Menstrual Cycle and Hormonal Disorders PDF

3 CHAPTER Hormonal control of the menstrual cycle and hormonal disorders HELEN BICKERSTAFF Introduction Physiology of the menstrual cycle Puberty and secondary sexu...

3 CHAPTER Hormonal control of the menstrual cycle and hormonal disorders HELEN BICKERSTAFF Introduction Physiology of the menstrual cycle Puberty and secondary sexual development Disorders of sexual development Disorders of menstrual regularity Further reading Self assessment LEARNING OBJECTIVES Describe the features of the normal menstrual cycle and the ovarian and endometrial changes that accompany them. Describe the normal changes of puberty and the secondary sexual differentiation that accompanies it. Understand the classification and causes of abnormal puberty and disorders of sexual development (DSD). Describe the causes and investigation of primary and secondary amenorrhoea and oligomenorrhoea.  Understand the epidemiology and effects of polycystic ovary syndrome (PCOS), its diagnosis and management. Describe the common effects and management of premenstrual syndrome (PMS). Describe premature cessation of periods. Introduction This chapter considers hormonal control of the menstrual cycle and the abnormalities that may affect the physiological initiation, regulation and cessation of the cycle. Abnormalities of uterine bleeding are the subject of the next chapter. Physiology of the menstrual cycle The external manifestation of a normal menstrual cycle is the presence of regular vaginal bleeding. This occurs as a result of the shedding of the endometrial lining following failure of fertilization of the oocyte or failure of implantation. The cycle depends on changes occurring after puberty within the ovaries and fluctuation in ovarian hormone levels, which are themselves controlled by the pituitary and hypothalamus within the hypothalamo–pituitary–ovarian axis (HPO). In situations of DSD or hormonal abnormalities, menstruation may not begin. The hypothalamus The hypothalamus in the forebrain secretes the peptide hormone gonadotrophin-releasing hormone (GnRH), which in turn controls pituitary hormone secretion. GnRH must be released in a pulsatile fashion to stimulate pituitary secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The pituitary gland GnRH stimulation of the basophil cells in the anterior pituitary gland causes synthesis and release of the gonadotrophic hormones FSH and LH. This process is modulated by the ovarian sex steroid hormones oestrogen and progesterone. Low levels of oestrogen have an inhibitory effect on LH production (negative feedback), whereas high levels of oestrogen will increase LH production (positive feedback). The mechanism of action for the positive feedback effect of oestrogen involves an increase in GnRH receptor concentrations, while the mechanism of the negative feedback effect is uncertain. The high levels of circulating oestrogen in the late follicular phase of the ovary act via the positive-feedback mechanism to generate a periovulatory LH surge from the pituitary. The clinical relevance of these mechanisms is seen in the use of the combined oral contraceptive pill, which artificially creates a constant serum oestrogen level in the negative-feedback range, inducing a correspondingly low level of gonadotrophin hormone release. Unlike oestrogen, low levels of progesterone have a positive-feedback effect on pituitary LH and FSH secretion (as seen immediately prior to ovulation) and contribute to the LH and FSH surge. High levels of progesterone, as seen in the luteal phase, inhibit pituitary LH and FSH production. Positive-feedback effects of progesterone occur via increasing sensitivity to GnRH in the pituitary. Negative-feedback effects are generated through both decreased GnRH production from the hypothalamus and decreased sensitivity to GnRH in the pituitary. It is known that progesterone can only have these effects on gonadotropic hormone release after priming by oestrogen (Figure 3.1). The ovary Starting at menarche, the primordial follicles containing oocytes, arrested at the first prophase step in meiotic division, will start to activate and grow in a cyclical fashion, causing ovulation and subsequent menstruation in the event of non-fertilization. In the course of a normal menstrual cycle, the ovary will go through three phases: follicular, ovulatory and luteal. Figure 3.1 Hypothalamus–pituitary axis. (E2, oestrogen; FSH, follicle-stimulating hormone; GnRH, gonadotrophin-releasing hormone; LH, luteinizing hormone; P4, progesterone.) Follicular phase The initial stages of follicular development are independent of hormone stimulation. However, follicular development will fail at the preantral stage, and follicular atresia will ensue if pituitary hormones LH and FSH are absent. FSH levels rise in the first days of the menstrual cycle, when oestrogen, progesterone and inhibin levels are low. This stimulates a cohort of small antral follicles on the ovaries to grow. Within the follicles, there are two cell types that are involved in the processing of steroids, including oestrogen and progesterone. These are the theca and the granulosa cells, which respond to LH and FSH stimulation, respectively. LH stimulates production of androgens from cholesterol within theca cells. These androgens are converted into oestrogens by the process of aromatization in granulosa cells, under the influence of FSH. As the follicles grow and oestrogen secretion increases, there is negative feedback on the pituitary to decrease FSH secretion. This assists in the selection of one follicle to continue in its development towards ovulation – the dominant follicle. In the ovary, the follicle that has the most efficient aromatase activity and highest concentration of FSH-induced LH receptors will be the most likely to survive as FSH levels drop, while smaller follicles will undergo atresia. There are other autocrine and paracrine mediators playing a role in the follicular phase of the menstrual cycle. These include inhibin and activin. Inhibin is secreted by the granulosa cells within the ovaries. It participates in feedback to the pituitary to down-regulate FSH release, and also appears to enhance ongoing androgen synthesis. Activin is structurally similar to inhibin, but has an opposite action. It is produced in granulosa cells and in the pituitary, and acts to increase FSH binding on the follicles. Insulin-like growth factors (IGF-I, IGF-II) act as paracrine regulators. Circulating levels do not change during the menstrual cycle, but follicular fluid levels increase towards ovulation, with the highest level found in the dominant follicle. Kisspeptins are proteins that have more recently been found to play a role in regulation of the HPO axis, via the mediation of the metabolic hormone leptin’s effect on the hypothalamus. Leptin is thought to be key in the relationship between energy production, weight and reproductive health. Mutations in the kisspeptin receptor, gpr-54, are associated with delayed or absent puberty, probably due to a reduction in leptin-linked triggers for gonadotrophin release. Ovulation By the end of the follicular phase, which lasts an average of 14 days, the dominant follicle has grown to approximately 20 mm in diameter. As the follicle matures, FSH induces LH receptors on the granulosa cells to compensate for lower FSH levels and prepare for the signal for ovulation. Production of oestrogen increases until it reaches the necessary threshold to exert a positive feedback effort on the hypothalamus and pituitary to cause the LH surge. This occurs over 24–36 hours, during which time the LH-induced luteinization of granulosa cells in the dominant follicle causes progesterone to be produced, adding further to the positive feedback for LH secretion and causing a small periovulatory rise in FSH. Androgens, synthesized in the theca cells, also rise around the time of ovulation, and this is thought to have an important role in stimulating libido, ensuring that sexual activity is likely to occur at the time of greatest fertility. The LH surge is one of the best predictors of imminent ovulation, and this is the hormone detected in urine by most over-the-counter ‘ovulation predictor’ tests. The LH surge has another function in stimulating the resumption of meiosis in the oocyte just prior to its release. The physical ovulation of the oocyte occurs after breakdown of the follicular wall takes place under the influence of LH, FSH and proteolytic enzymes, such as plasminogen activators and prostaglandins (PGs). Studies have shown that inhibition of PG production may result in failure of ovulation. Thus, women wishing to become pregnant should be advised to avoid taking PG synthetase inhibitors, such as aspirin and ibuprofen, which may inhibit oocyte release. Luteal phase After the release of the oocyte, the remaining granulosa and theca cells on the ovary form the corpus luteum (CL). The granulosa cells have a vacuolated appearance with accumulated yellow pigment, hence the name CL (‘yellow body’). The CL undergoes extensive vascularization in order to supply granulosa cells with a rich blood supply for continued steroidogenesis. This is aided by local production of vascular endothelial growth factor (VEGF). Ongoing pituitary LH secretion and granulosa cell activity ensure a supply of progesterone, which stabilizes the endometrium in preparation for pregnancy. Progesterone levels are at their highest in the cycle during the luteal phase. This also has the effect of suppressing FSH and LH secretion to a level that will not produce further follicular growth in the ovary during that cycle. The luteal phase lasts 14 days in most women, without great variation. In the absence of beta- human chorionic gonadotrophin (βhCG) being produced from an implanting embryo, the CL will regress in a process known as luteolysis. The mature CL is less sensitive to LH, produces less progesterone and will gradually disappear from the ovary. The withdrawal of progesterone has the effect on the uterus of causing shedding of the endometrium and thus menstruation. Reduction in levels of progesterone, oestrogen and inhibin feeding back to the pituitary cause increased secretion of gonadotrophic hormones, particularly FSH. New preantral follicles begin to be stimulated and the cycle begins anew. The endometrium The hormone changes effected by the HPO axis during the menstrual cycle will occur whether the uterus is present or not. However, the specific secondary changes in the uterine endometrium give the most obvious external sign of regular cycles (Figure 3.2). The proliferative phase The endometrium enters the proliferative phase after menstruation, when glandular and stromal growth begin. The epithelium lining the endometrial glands changes from a single layer of columnar cells to a pseudostratified epithelium with frequent mitoses. Endometrial thickness increases rapidly, from 0.5 mm at menstruation to 3.5–5 mm at the end of the proliferative phase. The secretory phase After ovulation (generally around day 14), there is a period of endometrial glandular secretory activity. Following the LH surge, the oestrogen-induced cellular proliferation is inhibited and the endometrial thickness does not increase any further. However, the endometrial glands will become more tortuous, spiral arteries will grow and fluid is secreted into glandular cells and into the uterine lumen. Later in the secretory phase, progesterone induces the formation of a temporary layer, known as the decidua, in the endometrial stroma. Histologically, this is seen as occurring around blood vessels. Stromal cells show increased mitotic activity, nuclear enlargement and generation of a basement membrane (Figure 3.3).  Apical membrane projections of the endometrial epithelial cells, known as pinopodes, appear after day 21–22 and appear to be a progesterone-dependent stage in making the endometrium receptive for embryo implantation (Figure 3.4). Figure 3.2 Changes in hormone levels, endometrium and follicle development during the menstrual cycle. Figure 3.3 Tissue sections of normal endometrium during proliferative (A) and secretory (B) phases of the menstrual cycle. Figure 3.4 Photomicrograph of endometrial pinopods from the implantation window. Menstruation Menstruation (day 1) is the shedding of the ‘dead’ endometrium and ceases as the endometrium regenerates (which normally happens by day 5–6 of the cycle). Immediately prior to menstruation, three distinct layers of endometrium can be seen. The basalis is the lower 25% of the endometrium, which will remain throughout menstruation and shows few changes during the menstrual cycle. The midportion is the stratum spongiosum with oedematous stroma and exhausted glands. The superficial portion (upper 25%) is the stratum compactum with prominent decidualized stromal cells. A fall in circulating levels of oestrogen and progesterone approximately 14 days after ovulation leads to loss of tissue fluid, vasoconstriction of spiral arterioles and distal ischaemia. This results in tissue breakdown and loss of the upper layers, along with bleeding from fragments of the remaining arterioles, seen as menstrual bleeding. Enhanced fibrinolysis reduces clotting. The effects of oestrogen and progesterone on the endometrium can be reproduced artificially, for example in patients taking the combined oral contraceptive pill or hormone replacement therapy (HRT), who experience a withdrawal bleed during their pill-free week each month. Vaginal bleeding will cease after 5–10 days as arterioles vasoconstrict and the endometrium begins to regenerate. Haemostasis in the uterine endometrium is different from haemostasis elsewhere in the body as it does not involve the processes of clot formation and fibrosis. The endocrine influences in menstruation are clear. However, the paracrine mediators are less so. PG F2α, endothelin-1 and platelet activating factor (PAF) are vasoconstrictors that are produced within the endometrium and are thought likely to be involved in vessel constriction, both initiating and controlling menstruation. They may be balanced by the effect of vasodilator agents, such as PG E2, prostacyclin (PGI) and nitric oxide, which are also produced by the endometrium. Recent research has shown that progesterone withdrawal increases endometrial PG synthesis and decreases PG metabolism. The cyclooxygenase (COX)-2 enzyme and chemokines are involved in PG synthesis and this is likely to be the target of non-steroidal anti-inflammatory drugs (NSAIDs) used for the treatment of heavy and painful periods. Endometrial repair involves both glandular and stromal regeneration and angiogenesis to reconstitute the endometrial vasculature. VEGF and fibroblast growth factor (FGF) are found within the endometrium and both are powerful angiogenic agents. Epidermal growth factor (EGF) appears to be responsible for mediation of oestrogen-induced glandular and stromal regeneration. Other growth factors, such as transforming growth factors (TGFs) and IGFs, and the interleukins may also be important.  Puberty and secondary sexual development Normal puberty Puberty is the process of reproductive and sexual development and maturation that changes a child into an adult. During childhood, the HPO axis is suppressed and levels of GnRH, FSH and LH are very low. From the age of 8–9 years GnRH is secreted in pulsations of increasing amplitude and frequency. These are initially sleep-related, but as puberty progresses, these extend throughout the day. This stimulates secretion of FSH and LH by the pituitary glands, which in turn triggers follicular growth and steroidogenesis in the ovary. The oestrogen produced by the ovary then initiates the physical changes of puberty. The exact mechanism determining the onset of puberty is still unknown, but it is influenced by many factors including race, heredity, body weight and exercise. Leptin plays a permissive role in the onset of puberty. The physical changes occurring in puberty are breast development (thelarche), pubic and axillary hair growth (adrenarche), growth spurt and onset of menstruation (menarche). The first physical signs of puberty are breast budding and this occurs 2–3 years before menarche. The appearance of pubic hair is dependent on the secretion of adrenal androgens and is usually after thelarche. In addition to increasing levels of adrenal and gonadal hormones, growth hormone secretion also increases, leading to a pubertal growth spurt. The mean age of menarche is 12.8 years and it may take over 3 years before the menstrual cycle establishes a regular pattern. Initial cycles are usually anovulatory and can be unpredictable and irregular. The absence of menstruation is called amenorrhoea and may be primary or secondary (see Box 3.2, page 41). Pubertal development was described by Tanner and the stages of breast and pubic hair development are often referred to as Tanner stages 1–5 (Figure 3.5). Precocious puberty This is defined as the onset of puberty before the age of 8 in a girl or 9 in a boy. It is classified as either central or peripheral. Central precocious puberty is gonadotrophin dependent. The aetiology is often unknown, although up to 25% are due to central nervous system (CNS) malformations or brain tumours. Peripheral precocious puberty, which is gonadotrophin independent, is always pathological and can be caused by oestrogen secretion, such as exogenous ingestion or a hormone-producing tumour. Delayed puberty When there are no signs of secondary sexual characteristics by the age of 14 years this is termed delayed puberty. It is due to either a central defect (hypogonadotrophic hypogonadism) or a failure of gonadal function (hypergonadotrophic hypogonadism), which are described below. Figure 3.5 Tanner staging. Box 3.1 Hypo- and hypergonadotrophic hypogonadism Hypogonadotrophic hypogonadism This is central and may be constitutional, but other causes must be excluded: these include anorexia nervosa, excessive exercise and chronic illness, such as diabetes or renal failure. Rarer causes include a pituitary tumour and Kalmans syndrome. Associated with delayed puberty and primary amenorrhoea. Hypergonadotrophic hypogonadism This is caused by gonadal failure. The gonad does not function despite high gonadotrophins. Associated with Turner syndrome and XX gonadal dysgenesis. Premature ovarian failure can occur at any age, including prior to pubertal age, and may be idiopathic, but can also be part of an autoimmune or metabolic disorder or following chemo- or radiotherapy for childhood cancer. Associated with delayed puberty and primary amenorrhoea. Hypergonadotrophic hypogonadism can also occur later in life and will cause secondary amenorrhoea after normal sexual development.  Disorders of sexual development DSD are conditions where the sequence of events described above does not happen. The clinical consequences of this depend upon where within the sequence the variation occurs. DSD may be diagnosed at birth with ambiguous or abnormal genitalia, but may also be seen at puberty in girls who present with primary amenorrhoea or increasing virilization. Table 3.1 Summary of terminology for disorders of sex development (DSD) There has been change in the terminology used to refer to these conditions over the last 10 years. Older terms, such as ‘hermaphrodite’ and ‘intersex’, are confusing to both the clinician and patients, and in addition can be hurtful. The accepted terminology is summarized in Table 3.1. Non-structural causes of DSD Turner syndrome The total complement of chromosomes is 45 in Turner syndrome, which results from a complete or partial absence of one X chromosome (45XO). Turner syndrome is the most common chromosomal anomaly in females, occurring in 1 in 2,500 live female births. A mosaic karyotype is not uncommon, leading to a variable presentation. Although there can be variation, the most typical clinical features include short stature, webbing of the neck and a wide carrying angle. Associated medical conditions include coarctation of the aorta, inflammatory bowel disease, sensorineural and conduction deafness, renal anomalies and endocrine dysfunction, such as autoimmune thyroid disease. In this condition, the ovary does not complete its normal development and only the stroma is present at birth. The gonads are called ‘streak gonads’ and do not function to produce oestrogen or oocytes. Diagnosis is usually made at birth or in early childhood from the clinical appearance of the baby or due to short stature during childhood. However, in about 10% of women, the diagnosis is not made until adolescence with delayed puberty. The ovaries do not produce oestrogen, so the normal physical changes of puberty cannot happen. In childhood, treatment is focused on growth, but in adolescence it focuses on induction of puberty. Pregnancy is only possible with ovum donation. Psychological input and support is important. In girls with mosaicism the clinical picture can vary and normal puberty and menstruation can occur, with early cessation of periods. 46XY gonadal dysgenesis In this situation, the gonads do not develop into a testis, despite the presence of an XY karyotype. In about 15% of cases, this is due to a mutation in the SRY gene on the Y chromosome, but in most cases the cause is unknown. In complete gonadal dysgenesis (Swyer syndrome), the gonad remains as a streak gonad and does not produce any hormones. In the absence of anti-Müllerian hormone (AMH), the Müllerian structures do not regress and the uterus, vagina and Fallopian tubes develop normally. The absence of testosterone means the fetus does not virilize. The baby is phenotypically female, although has an XY chromosome. The gonads do not function and presentation is usually at adolescence with delayed puberty. The dysgenetic gonad has a high malignancy risk and should be removed when the diagnosis is made. This is usually performed laparoscopically. Puberty must be induced with oestrogen and pregnancies have been reported with a donor oocyte. Full disclosure of the diagnosis including the XY karytoype is essential, although this can be devastating and specialized psychological input is crucial. Mixed gonadal dysgenesis is a more complex condition. The karyotype may be 46XX, but XX/XY mosaicism is present in up to 20%. In this situation, both functioning ovarian and testicular tissue can be present and if so, this condition is known as ovotesticular DSD. The anatomical findings vary depending on the function of the gonads. For example, if the testis is functional, then the baby will virilize and have ambiguous or normal male genitalia. The Müllerian structures are usually absent on the side of the functioning testis, but a unicornuate uterus may be present if there is an ovary or streak gonad. 46XY DSD The most common cause of 46XY DSD, complete androgen insensitivity syndrome (CAIS), occurs in individuals where virilization of the external genitalia does not occur, due to a partial or complete inability of the androgen receptor to respond to androgen stimulation. In the fetus with CAIS, testes form normally due to the action of the SRY gene. At the appropriate time, these testes secrete AMH, leading to the regression of the Müllerian ducts. Hence, CAIS women do not have a uterus. Testosterone is also produced at the appropriate time; however, due to the inability of the androgen receptor to respond, the external genitalia do not virilize and instead undergo female development. The baby is born with normal female external genitalia, an absent uterus and testes that are found somewhere in their line of descent through the abdomen from the pelvis to the inguinal canal. Presentation is usually at puberty with primary amenorrhoea, although if the testes are in the inguinal canal they can cause a hernia in a younger girl. Once the diagnosis is made, initial management is psychological with full disclosure of the XY karyotype and the information that the patient will be infertile. Gonadectomy is recommended because of the small long-term risk of testicular malignancy, although this can be deferred until after puberty. Once the gonads are removed, long-term HRT will be required. The vagina is usually shortened and treatment will be required to create a vagina suitable for penetrative intercourse. Vaginal dilation is the most effective method of improving vaginal length and entails the insertion of vaginal moulds of gradually increasing length and width for at least 30 minutes a day. Surgical vaginal reconstruction operations are reserved for those women that have not responded to a dilation treatment programme. In cases of partial androgen insensitivity, the androgen receptor can respond to some extent with limited virilization. The child is usually diagnosed at birth with ambiguous genitalia. 5-Alpha-reductase deficiency In this condition, the fetus has an XY karytype and normal functioning testes that produce both testosterone and AMH. However, the fetus is unable to convert testosterone to dihydrotestosterone in the peripheral tissues and so cannot virilize normally. Presentation is usually with ambiguous genitalia at birth, but can also be with increasing virilization at puberty of a female child, due to the large increase in circulating testosterone with the onset of puberty. In the Western world, the child is usually assigned to a female sex of rearing, but there have been descriptions of a few communities where transition from a female to male gender at puberty is accepted. 46XX DSD The most common cause of 46XX DSD, congenital adrenal hyperplasia (CAH), leads to virilization of a female fetus. It is due to an enzyme deficiency in the corticosteroid production pathway in the adrenal gland, with over 90% being a deficiency in 21-hydroxylase, which converts progesterone to deoxycorticosterone and 17-hydroxyprogesterone (17-OHP) to deoxycortisol. The reduced levels of cortisol being produced drive the negative-feedback loop, resulting in hyperplasia of the adrenal glands. This leads to an excess of androgen precursors and then to elevated testosterone production. Raised androgen levels in a female fetus will lead to virilization of the external genitalia. The clitoris is enlarged and the labia are fused and scrotal in appearance. The upper vagina joins the urethra and opens as one common channel onto the perineum. In addition, two-thirds of children with 21-hydroxylase CAH will have a ‘salt-losing’ variety, which also affects the ability to produce aldosterone. This represents a life- threatening situation, and those children who are salt-losing often become dangerously unwell within a few days of birth. Affected individuals require life-long steroid replacement, such as hydrocortisone, along with fludrocortisone for salt losers. Once the infant is well and stabilized on their steroid regime, surgical treatment of the genitalia is considered. Traditionally, all female infants with CAH underwent feminizing genital surgery within the first year of life. This management is now controversial as adult patients with CAH are very dissatisfied with the outcome of their surgery and argue that surgery should have been deferred until they were old enough to have a choice. Surgery certainly leaves scarring and may reduce sexual sensitivity, but the alternative of leaving the genitalia virilized throughout childhood can be difficult for parents to consider. At present, cases are managed individually by a multidisciplinary team (MDT) involving surgeons, endocrinologists and psychologists. Disorders of menstrual regularity Amenorrhoea and oligomenorrhoea Amenorrhoea is defined as the absence of menstruation for more than 6 months in the absence of pregnancy in a woman of fertile age, and oligomenorrhoea is defined as irregular periods at intervals of more than 35 days, with only 4–9 periods a year. The causes may be hypothalamic, pituitary, ovarian or endometrial, and both amenorrhoea and oligomenorrhoea may be primary or secondary. Box 3.2 Amenorrhoea Primary amenorrhoea is when girls fail to menstruate by 16 years of age.  Secondary amenorrhoea is absence of menstruation for more than 6 months in a normal female of reproductive age that is not due to pregnancy, lactation or the menopause. Hypothalamic disorders Hypothalamic disorders will give rise to hypogonadotrophic hypogonadism, with the following causes: Excessive exercise, weight loss and stress. Hypothalamic lesions (craniopharyngioma, glioma), which can compress hypothalamic tissue or block dopamine. Head injuries. Kallman’s syndrome (X-linked recessive condition resulting in deficiency in GnRH causing underdeveloped genitalia). Systemic disorders including sarcoidosis, tuberculosis resulting in an infiltrative process in the hypothalamo-hypophyseal region. Drugs: progestogens, HRT or dopamine antagonists. Pituitary disorders Pituitary disorders will also give rise to hypogonadotrophic hypogonadism, with the following causes: Adenomas, of which prolactinoma is most common. Pituitary necrosis (e.g. Sheehan’s syndrome, due to prolonged hypotension following major obstetric haemorrhage). Iatrogenic damage (surgery or radiotherapy). Congenital failure of pituitary development. Ovarian disorders Anovulation is often due to polycystic ovary syndrome (PCOS), described below. Ovarian failure is the cause of hypergonadotrophic hypogonadism. Premature ovarian failure (POF) is defined as cessation of periods before 40 years of age and is described in Chapter 8, The menopause and postreproductive health. Endometrial disorders Primary amenorrhoea may result from Müllerian defects in the genital tract including an absent uterus, or outflow tract abnormalities, leading to a haematocolpos. Secondary amenorrhoea may result from scarring of the endometrium called Asherman syndrome and is described further in Chapter 4, Disorders of menstrual bleeding. Findings from the history should guide the examination (Table 3.2). A general inspection of the patient should be carried out to assess body mass index (BMI), secondary sexual characteristics (hair growth, breast development using Tanner scores) and signs of endocrine abnormalities (hirsutism, acne, abdominal striae, moon face, skin changes). If the history is suggestive of a pituitary lesion, an assessment of visual fields is indicated. External genitalia and a vaginal examination should be performed to detect structural outflow abnormalities or demonstrate atrophic changes consistent with hypo-oestrogenism. Investigation of amenorrhoea/oligomenorrhoea Findings from the history and examination should guide the choice and order of investigations. A pregnancy test should be carried out if the patient is sexually active. Blood can be taken for LH, FSH and testosterone; raised LH or raised testosterone could be suggestive of PCOS; raised FSH may be suggestive of POF. A raised prolactin level may indicate a prolactinoma. Thyroid function should be checked if clinically indicated. An ultrasound scan can be useful in detecting the classical appearances of polycystic ovaries (Figure 3.6) and magnetic resonance imaging (MRI) of the brain should be carried out if symptoms are consistent with a pituitary adenoma. Hysteroscopy is not routine, but is a suitable investigation where Asherman or cervical stenosis is suspected. Karyotyping is diagnostic of Turner’s and other sex chromosome abnormalities. Table 3.2 History and examination of patient with amenorrhoea/oligomenorrhoea Table 3.3 Management of amenorrhoea/oligomenorrhoea  The management of amenorrhoea/oligomenorrhoea is outlined in Table 3.3. More specific descriptions of management are detailed in the chapters indicated. Polycystic ovary syndrome PCOS is a syndrome of ovarian dysfunction along with the cardinal features of hyperandrogenism and polycystic ovary morphology (Figure 3.6). The prevalence of polycystic ovaries seen on ultrasound is around 25% of all women but is not always associated with the full syndrome. Clinical manifestations include menstrual irregularities, signs of androgen excess (e.g. hirsutism and acne) and obesity. Elevated serum LH levels, biochemical evidence of hyperandrogenism and raised insulin resistance are also common features. PCOS is associated with an increased risk of type 2 diabetes and cardiovascular events. It affects around 5–10% of women of reproductive age. The aetiology of PCOS is not completely clear, although the frequent familial trend points to a genetic cause. Clinical features Oligomenorrhoea/amenorrhoea in up to 75% of patients, predominantly related to chronic anovulation. Hirsutism. Subfertility in up to 75% of women. eResource 3.1  Polycystic ovary syndrome (PCOS) http://www.routledgetextbooks.com/textbooks/tenteachers/gynaecologyv3.1.php Figure 3.6 Gross appearance of a polycystic ovary (A) and transvaginal ultrasound scan image (B). Obesity in at least 40% of patients. Acanthosis nigricans (areas of increased velvety skin pigmentation occur in the axillae and other flexures). May be asymptomatic. Diagnosis Patients must have two out of the three features below: Amenorrhoea/oligomenorrhoea. Clinical or biochemical hyperandrogenism. Polycystic ovaries on ultrasound. The ultrasound criteria for the diagnosis of a polycystic ovary are eight or more subcapsular follicular cysts