Chapter 6 Abnormalities of Menstruation
Normal and physiological changes in the menstrual cycle
Normal menstrual cycles have a length of 21–35 days (mean 28 days). A normal period lasts for 3–7 days. Menstrual blood loss of 30–50 ml/month is normal. Menstrual blood loss is considered as excessive when it is greater than 80 ml/month. It is, however, rarely measured in clinical trials, and heavy menstrual loss should be defined clinically.
Amenorrhoea
Amenorrhoea is the absence of menstruation for 6 months in a woman who had previously menstruated normally (sometimes called 2° amenorrhoea)
amenorrhoea is the term given when a girl has failed to menstruate by the age of 16 (sometimes called 1° amenorrhoea).
In practice, the distinction between 1° and 2° amenorrhoea is not generally helpful in making a diagnosis. A similar process of investigation should be carried out whether or not the patient had previously menstruated. Amenorrhoea occurs in a number of physiological conditions, and these should be borne in mind when initiating investigation.
Menarche
Menarche is the onset of menstruation at puberty. The median age at which menarche occurs (13 y) is relatively late in the events occurring around puberty. For most young women, the growth spurt and secondary sexual characteristics, such as breast development (thelarche) and the growth of pubic and axillary hair, usually precede the onset of menstruation by about 2 years.
Absent or late puberty may present with amenorrhoea. If a girl over the age of 14 presents with amenorrhoea, investigations should depend on whether or not other signs of puberty are present.
Physiological amenorrhoea
Pregnancy
During pregnancy, the levels of oestrogen and progesterone remain high, thus ensuring the integrity of the endometrium, and causing amenorrhoea. Initially, the corpus luteum is the source of oestrogen and progesterone. Later in pregnancy, the production of oestrogen and progesterone is taken over by the placenta. Pregnancy should be considered in the differential diagnosis of all women who present with amenorrhoea.
Lactation
Soon after delivery, prolactin is secreted in large quantities by the anterior pituitary. There is partial suppression of luteinising hormone (LH) production so that ovarian follicles may grow, but ovulation does not occur, and amenorrhoea is the result. If the mother does not breast feed, menstruation will return in 2–3 months, but if she does breast feed, the period of amenorrhoea will be prolonged.
Menopause
The menopause is the cessation of menstruation (mean age 51 y) due to exhaustion of the supply of ovarian follicles. Oestrogen production therefore falls. This fall in oestrogen production is accompanied by a rise in follicle stimulating hormone (FSH) levels, which continues for a considerable time. In a proportion of women, menstruation ceases abruptly, but in many, the menstrual cycles alter. Frequently, they become shorter initially, but later they lengthen and tend to be irregular, before ceasing entirely. This phase is known as the menopause transition, and the final period is recognised only in retrospect, after 1 year of amenorrhoea. See Chapter 18.
Uterine and lower genital tract disorders
Imperforate hymen or transverse vaginal septum
This condition usually presents with primary amenorrhoea. There is no visible bleeding although the usual cyclical symptoms are present. In that there is no flow of blood, the term amenorrhoea can be used, but the cause is an obstruction by a vaginal septum or an imperforate hymen rather than a functional abnormality.
Clinical Features
The patient is usually a girl of 17 or so, complaining of primary amenorrhoea and pelvic pain of increasing severity. In long-standing cases, the pressure of the distended vagina may cause urinary retention. Pregnancy must be excluded.
Examination
A pelvic mass is palpated and may even be visible. The vaginal membrane or hymen is bulging.
Asherman’s syndrome
In Asherman’s syndrome, the uterine cavity is obliterated by adhesions. The condition is usually caused by uterine surgery: most commonly curettage, for example during termination of pregnancy. In developing countries, infections such as tuberculosis and schistosomiasis are commoner causes of Asherman’s syndrome.
The adhesions should be broken down hysteroscopically. High dose oestrogens are used to stimulate endometrial proliferation following the procedure. Some authorities advocate the use of a Foley catheter placed in the uterus for a short time after adhesiolysis to prevent recurrence. Pregnancy rates following treatment are in the order of 80%. Such pregnancies may be complicated by abnormal placentation, for example by placenta accreta.
Müllerian agenesis
The diagnosis of Müllerian agenesis is made in women with primary amenorrhoea and an absent vagina, but normal female chromosomes. Ovarian function is normal.
Ovarian disorders
Gonadal dysgenesis
Women with gonadal dysgenesis have abnormal ovarian development, leading to absent or streak ovaries. The number of germ cells that migrate to the ovary during intrauterine life is reduced. These woman present with primary or secondary amenorrhoea, and have persistently elevated gonadotrophins on testing.
In women under 30 years of age at the time of presentation, a karyotype should be performed. Turner’s syndrome (p. 60) is the classic form of gonadal dysgenesis, but other karyotypes, including 46XX are also found. If a Y chromosome is present, consideration should be given to gonadectomy because of the risk of neoplasia.
Premature ovarian failure
In this condition, ovarian follicles are depleted from the ovary before the normal age of the menopause, and a premature menopause ensues. In addition to amenorrhoea, the patient may complain of menopausal symptoms such as hot flushes, loss of libido, etc. This condition is not uncommon: 1% of women will have ovarian failure by the age of 40. Premature ovarian failure is found in around 10% of women with amenorrhoea.
Cause
The majority of women with premature ovarian failure have no obvious cause for their condition. It is associated with chromosomal abnormalities such as Turner’s syndrome (XO). It may occur in association with autoimmune disease, following infections such as mumps, or following chemotherapy or pelvic radiotherapy.
Diagnosis
The diagnosis is made by finding elevated serum FSH levels (>20 IU/L). As FSH levels are elevated physiologically mid-cycle, at least two FSH levels should be obtained at six weekly intervals. If a high FSH level is followed 2 weeks later by menstruation, the cause of the elevated FSH may be more likely to represent ovulation rather than menopause.
Treatment
Women with premature ovarian failure should be advised that they are likely to be infertile, although spontaneous pregnancies have been reported. Pregnancy can be achieved by IVF (in vitro fertilisation) with donor oocytes.
Oestrogen replacement should be considered to reduce the risk of osteoporosis and cardiovascular disease. A progestogen is also required to protect the endometrium from the stimulatory effects of oestrogen. This can be in the form of hormone replacement therapy, but, alternatively, the combined oral contraceptive pill would be a suitable option and may be more acceptable to young women.
Resistant ovary syndrome
In this condition, the ovarian follicles fail to develop, despite high circulating levels of gonadotrophins. The clinical and biochemical features are that of premature ovarian failure. An ovarian biopsy will reveal ovarian follicles, and thus distinguish the condition from premature ovarian failure. In practice, this is not helpful; it may stimulate adhesion formation and the absence of follicles can be reliably determined only after the entire ovary has been examined. The treatment is the same as for premature ovarian failure.
Polycystic ovarian syndrome
Polycystic ovarian syndrome (PCOS) is a functional derangement of the hypothalamo–pituitary ovarian axis associated with anovulation. The pathophysiology of PCOS remains poorly understood. Insulin resistance is a feature, and a genetic element to the disorder has been proposed. Women with PCOS are more at risk of developing Type II diabetes.
In women with PCOS, LH levels are relatively high and FSH levels are relatively low, leading to an elevated LH:FSH ratio. Oestradiol levels tend to be within the normal range. Production of androgens is stimulated by the elevated levels of LH; increased levels of testosterone, androstendione and DHA are secreted by the ovary. Some of these androgens are converted to oestrogen in peripheral tissues. In response to high androgen levels, sex hormone binding globulin (SHBG) is reduced by about 50%, leading to an increase in the proportion of unbound, active, androgens. Hence, androgenic side effects are common, despite only a modest rise or even normal levels of total serum testosterone levels.
Clinical Features
The clinical features of PCOS are variable. In the classic ‘Stein Leventhal’ syndrome, described in 1935, the presenting features are oligomenorrhoea, hirsutism and obesity. Other manifestations are common, however, and include menstrual disorders ranging from amenorrhoea to menorrhagia and signs of androgen excess, such as hirsutism, acne and infertility.
Diagnosis
No specific features of polycystic ovarian syndrome are diagnostic of the condition. According to the Rotterdam criteria, the diagnosis can be made if two out of three of the following criteria are present:
Ultrasound will show multiple follicular cysts up to 6–8 mm diameter within the ovary. This is described as a necklace of pearls appearance. The volume of the ovarian subcortical stroma is increased. Such findings on ultrasound support rather than confirm a diagnosis of PCOS, as 25% of normal women will demonstrate these features on ultrasound.
A modest increase in total testosterone is accompanied by a decrease in SHBG resulting in an increase in free testosterone levels.
An elevated LH:FSH ratio may occur but is no longer a diagnostic criteria. A physiological raised LH level occurs during the LH surge.
Long-term Effects of PCOS
Treatment of PCOS
The treatment for PCOS is aimed at relieving symptoms and preventing adverse long-term effects. For women who are overweight, weight loss should be strongly supported as it reduces the clinical features of the condition and provides long-term health benefits.
Anovulatory women with infertility should be treated with clomiphene in the first instance. Women who fail to respond may require gonadotrophins ± gonadotrophin releasing hormone (GnRH) analogues.
Women with amenorrhoea may be treated with the combined oral contraceptive pill if contraception is required, or cyclical gestogens (e.g. medroxyprogesterone acetate 10 mg daily from day 15 to 25) if contraception is not required. The prevention of amenorrhea is important in PCOS to reduce the risk of endometrial carcinoma. The Mirena IUS is also useful to reduce the long-term risk of endometrial hyperplasia.
Pituitary disorders
Pituitary tumours are normally benign. However, as they grow in a confined space, they may cause symptoms by compressing surrounding tissue and structures. Functioning pituitary tumours may exert effects because of the hormones they release. The commonest of these are prolactin secreting pituitary tumours, accounting for 50% of all pituitary adenomas.
Hyperprolactinaemia
Prolactin is secreted from the anterior pituitary, and the normal blood level is between 150 and 600 mU/L depending on the laboratory. During pregnancy, there is a 10-fold increase in serum prolactin levels. Non-physiological hyperprolactinaemia, which occurs when the woman is non-pregnant, can cause amenorrhoea or galactorrhoea (inappropriate lactation) or both. Hyperprolactinaemia is the principal cause of amenorrhoea in around 20% of women with this condition.
Aetiology
Diagnosis of Hyperprolactinaemia
The diagnosis of hyperprolactinaemia can be made on a single serum measurement. In the presence of oligo- or amenorrhoea, a serum prolactin of 800 mU/L or greater is likely to be of pathological significance. In the absence of an obvious alternative cause, radiological examination such as computerised tomography (CT) scanning or magnetic resonance imaging (MRI) should be performed to exclude a pituitary tumour.
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