Investigation of secondary amenorrhoea

Unless organic disease is suspected, or the woman is desperately seeking relief from infertility, most experts would not investigate amenorrhoea until it has lasted for 6–12 months, as most women start menstruating during this time.

When investigation is indicated, a careful history is essential in which the doctor inquires about the woman’s general health, and seeks to determine whether she has an eating disorder or exercises excessively, or if any medical or psychiatric condition is present. A physical examination, including a vaginal examination, follows and in certain cases a pelvic ultrasound examination may be performed. If these examinations reveal no definite diagnosis, the following tests are ordered:

The purpose of the investigations is to exclude organic disease (for example a prolactin-secreting microadenoma or hypothyroidism) and to treat anovulation as a cause of infertility. If organic disease is not detected and infertility is not a problem, amenorrhoea does not represent a danger to the woman, but because low oestrogen levels may lead to bone loss, after 6 months of amenorrhoea hormone replacement treatment (see p. 325) should be advised.

The sequence of investigations is shown in Figure 28.2.

Fig. 28.2 The investigation and treatment of secondary amenorrhoea.

Weight loss

Women who have an eating disorder, particularly anorexia nervosa, cease to menstruate, as do some women who are compulsive exercisers. Amenorrhoea can occur in obese and overweight women who lose weight rapidly. The cause is a failure of the hypothalamus to release sufficient gonadotrophin-releasing hormone (GnRH) to initiate the release of gonadotrophins, and in consequence only a small quantity of oestrogen is secreted by the ovaries. If this persists for more than 6 months, bone loss may occur at a time when bone formation is reaching its peak. A consequence of this is a greater risk of osteoporosis in later life. Even during the recovery phase menstruation may not occur for several months, which may aggravate the problem.

Hyperprolactinaemia and prolactin-secreting tumours

Prolactin secretion by the pituitary gland is inhibited under normal conditions by dopamine released from the hypothalamus. In certain circumstances, this control is diminished. Examples are hypothyroidism and the administration of dopamine-depleting agents or dopamine receptor-blocking agents. A more common cause of hyperprolactinaemia is a microadenoma of the pituitary gland. In these cases, the increased circulating levels of prolactin act directly on the hypothalamus to reduce the secretion of GnRH, which in turn prevents the FSH and LH rises needed for follicle development and ovulation.

The woman develops oestrogen deficiency, with menstrual disturbances (usually amenorrhoea), a dry vagina and, often, a reduction of her libido. If the hyperprolactinaemia persists, osteopenia and, perhaps, osteoporosis will result. In 30% of women inappropriate milk secretion (galactorrhoea) occurs.

As hyperprolactinaemia accounts for 10–20% of cases of amenorrhoea, investigation is important. The diagnosis is made if a raised blood level of prolactin is found. If this is noted during investigation, a high-resolution CT scan of the pituitary is made to detect a prolactin-secreting tumour, although in most cases none is found. A microadenoma (<10 mm in diameter) is more common than a macroadenoma.

Treatment is needed if a macroadenoma is detected, or if the woman desires to become pregnant, but in all cases of hyperprolactinaemia careful follow-up is needed as some women with this condition, but no tumour, eventually develop one. Women who have functional hyperprolactinaemia require assessment at 1–3-year intervals, when the level of prolactin in a blood sample is measured and a CT scan made. Women who have a microadenoma need to be assessed annually, but treatment is not required unless they are infertile or have marked symptoms of low circulating levels of oestradiol. In both these groups, if amenorrhoea persists for more than 6 months, as is likely, hormone replacement treatment should be offered to prevent bone loss and the development of osteoporosis.

If a macroadenoma is detected, treatment consists of prescribing a dopamine agonist, such as bromocriptine or cabergoline, in a dose that reduces the prolactin levels to the normal range and maintains them in this range. In most women the treatment causes the tumour to shrink.

Surgery is only indicated if bromocriptine treatment fails. Both during and after treatment, regular measurements of serum prolactin and an annual CT scan are mandatory.

A patient who has a macroadenoma should avoid becoming pregnant until the tumour has shrunk to lie completely within the pituitary fossa, as shown by a CT scan, as it may grow during pregnancy.

Hypothalamopituitary insensitivity: hypothalamic amenorrhoea

In about one-third of cases of amenorrhoea, hypothalamopituitary insensitivity is postulated. Many of these cases, coincidentally, follow the use of oral contraceptives, but eating disorders may also be involved, as may psychosomatic factors (for example change of work, marital disharmony or separation). Severe depression or acute or chronic illness may be factors.

Polycystic ovarian syndrome (PCOS)

PCOS is the most common cause of anovulatory infertility, affecting around 6–10% of premenopausal women. The diagnosis of PCOS is dependent on the exclusion of other causes of androgen excess (pituitary or adrenal disorders) and with the presence of 12 or more primordial ovarian follicles (Fig. 28.3). Obesity is a common feature and its presence extenuates the physical and biochemical abnormalities. Polycystic ovaries are present in 20% of normal females many of whom have androgen levels within the normal range and have regular menses.

Fig. 28.3 Transvaginal scan showing polycystic ovaries.

The aetiology of PCOS has not been resolved but there is increasing evidence of a genetic basis with in utero androgen ‘programming’ of the fetal ovary during ovarian development and oogenesis. Insulin resistance is present in most women with PCOS. Insulin activates the biosynthesis of ovarian androgens, synergistically with LH. In addition it increases free androgen index by suppressing hepatic synthesis of sex hormone-binding globulin and by stimulation of adrenal androgen secretion.

Treatment depends on the presenting symptoms and on the wishes of the woman (Box 28.1). If there are no symptoms no treatment is indicated. Lifestyle changes should be encouraged, and obese women persuaded to seek help from an experienced dietitian. If the woman wishes to conceive then metformin, which acts by reducing hepatic glucose production and increasing peripheral tissue sensitivity, and or/clomifene (see above), can be used to induce ovulation. They should be screened for glucose intolerance preferably before conception and certainly during early pregnancy.

Women with PCOS should be followed up, as over 20% will be found to have, or will develop, impaired glucose tolerance or diabetes. They also have an increased risk of developing endometrial carcinoma if the anovulation persists for a number of years.

Uterine abnormalities

Surgical removal of the uterus, endometrial ablation or radiation result in amenorrhoea. Excessive curettage (particularly following an abortion or postpartum) may act in the same way as endometrial ablation, producing amenorrhoea by removing the basal endometrial layer and permitting synechiae to form (Asherman’s syndrome). The diagnosis is made by hysteroscopy, transvaginal ultrasound scanning, or from a hysterogram.

Primary gonadal (ovarian) failure

In most cases the cause of primary ovarian failure is unknown. In this condition the ovarian follicles disappear before the age of 40, and the woman undergoes a premature menopause. In other women the follicles persist but the woman develops autoantibodies that mask the gonadotrophin receptors in the ovaries, with the result that the gonadotrophins can no longer bind to them. These women may have a premature menopause, but inexplicably, some months or years later the woman ovulates and menstruates – the ‘resistant ovarian syndrome’. Treatment consists of providing hormone replacement to control menopausal symptoms and to prevent bone loss and cardiovascular sequelae (see p. 324). If the woman wishes to have a child, she may enter an assisted conception programme and receive a donor ovum.

Transvaginal ultrasound

This is the least invasive method of imaging the uterine cavity. The presence of submucous myomata can be detected and the width of the endometrium measured. An endometrium more than 5 mm wide in a postmenopausal woman indicates the need for curettage to exclude endometrial pathology (Fig. 28.4).

Fig. 28.4 Transvaginal scan showing thickened cystic endometrium measuring 1.41 cm, indicative of endometrial hyperplasia.

Hysteroscopy

Using a hysteroscope, the uterine cavity can be inspected and abnormalities, such as endometrial polyps (Fig. 28.5) or submucous fibroids, can be detected and often removed. In addition, an endometrial sample can be taken for histological examination. Hysteroscopy is an office procedure that can be performed either with or without a local anaesthetic.

Fig. 28.5 Transvaginal scan demonstrating a 2 cm endometrial polyp.

Hysteroscopy provides a clearer picture of the interior of the uterus and makes the diagnosis clearer than diagnostic curettage under anaesthesia, which it has replaced. In several large studies hysteroscopy has shown that about 25% of women with menorrhagia or irregular menstruation have submucous myomata, usually projecting into the uterine cavity, and of these about 10% have endometrial polyps. Previously, these cases would have been identified as dysfunctional uterine bleeding. They can be treated at the time of hysteroscopic diagnosis by hysteroscopic resection.

Endometrial sampling (biopsy)

Endometrial sampling (biopsy) is carried out by introducing a narrow biopsy curette through the uterine cervix and obtaining a representative sample of the endometrium. The procedure can take place in the doctor’s office.

There is now no place for a diagnostic curettage per se.

Patients seen during a severe bleeding episode

In this situation treatment may be required urgently. Two methods are available: to perform curettage and to administer hormones. The hormones usually chosen are combined equine oestrogens (CEE), 25 mg given intravenously and repeated 6-hourly for two to three doses. CEE in this dosage may cause marked nausea in some women. Once CEE has stopped the bleeding, a progestogen must be given for 14 days to induce secretory change and then endometrial shedding. An alternative to CEE is to give 17-hydroxyprogesterone acetate 125–250 mg intramuscularly, or oral norethisterone 20–30 mg/day, in divided doses, for 4 days. If a progestogen is used, a withdrawal bleed may be expected 3–6 days later. This can be avoided if norethisterone (5–10 mg daily) is continued for 20 days.

Patients seen between bleeding episodes

In this situation several choices are available. They should be discussed with the woman, as her wishes and concerns should be addressed before treatment is instituted. The choices fall into two main groups: hormonal treatment and surgical treatment.

Medical treatment

The treatments of choice are:

Note that the use of cyclical progesterone therapy, especially in the luteal phase, is not effective.

Surgical treatment