I.S. Fraser

IMPACT OF NEW DIAGNOSTIC METHODS ON THE DIFFERENTIAL DIAGNOSIS AND TREATMENT OF SECONDARY AMENORRHŒA

The development of homologous prolactin assays, multiple pituitary stimulation, tomography, and computerised axial tomography permit more detailed investigation of patients with secondary amenorrhoea than was formerly possible. 39% of 90 patients with secondary amenorrhoea had hyperprolactinaemia. 10 patients (11% of total) had pituitary tumours. 8 of these women had galactorrhoea (27% of those with galactorrhoea). For patients with hyperprolactinaemia but no tumour, bromocriptine is the treatment of first choice rather than clomiphene or human gonadotrophins. The best treatment for patients with detectable tumour is controversial, particularly when the tumour is confined to the sella turcica. Whether or not these tumors are true neoplasms remains to be determined. Clinically, a history of secondary anemorrhoea with or without galactorrhoea following withdrawal of oral contraceptives remains the commonest presenting syndrome.

Hormone replacement therapy and irregular bleeding

The use of hormone replacement therapy (HRT) is increasing in many countries: an estimated 37.8% of women in the USA use HRT1 and 21.7% in the UK2. Not only are these levels projected to increase3, but it is also anticipated that more countries will expand their use of HRT. Despite the increase in overall use, some women are reticent to persist with HRT because of unpredictable vaginal bleeding, which is common to all preparations. Irregular bleeding occurs in up to 60% of users, regardless of whether sequential or continuous combined regimens are taken4, and is the reason given for discontinuation of HRT in up to one in three women5. In addition, the expectation of unscheduled vaginal bleeding is thought to deter many women from starting HRT6. Irregular bleeding is most common in the initial months of use. This is of clinical importance, since all of the established and potential health advantages of HRT, apart from the current relief of menopausal symptoms, require longer-term usage to be of benefit7–9. Bleeding patterns tend to regulate over time with sequential HRT, and amenorrhea is more common with prolonged use of the continuous combined preparations. Up to 80% of continuous combined HRT users complain of breakthrough bleeding in the first month of use. This figure has been shown to fall to fewer than 50% at 6 months and fewer than 10% at 1 year10, which is helpful information when counselling patients. However, although these numbers indicate a real reduction in breakthrough bleeding, many women who continue to be troubled by breakthrough bleeding will discontinue HRT over these initial months. There are no available preparations with which regular bleeding or amenorrhea can be guaranteed, suggesting that a common mechanism may underlie this phenomenon. Normal menstruation involves the breakdown, remodelling and repair of the functional endometrial layers, and there is some evidence that disruptions of this process at a number of stages may result in changes in the quantity and pattern of menstrual loss. Menstrual bleeding is thought to arise primarily from the spiral arterioles, with endometrial capillaries making little contribution11,12. Endometrial destruction and regeneration are largely controlled by local factors, although the initial trigger comes from falling estradiol and progesterone levels following luteolysis. Lysosomes release hydrolytic enzymes in premenstrual endometrium that appear to contribute to tissue breakdown, bleeding, remodelling and subsequent regeneration13,14. These organelles are sensitive to falling levels of progesterone, and it is unclear whether they have a primary or secondary role in the onset of endometrial menstrual breakdown. Matrix metalloproteinases (MMPs) also act to degrade most components of the extracellular matrix, and are regulated by ovarian steroid hormones15. Excessive or prolonged tissue degradation due to MMP activity could result in increased or prolonged menstrual bleeding. Certain MMPs are strongly expressed in menstrual endometrium16. There is recent evidence that MMP expression is disrupted in HRT users17. Endometrial leukocytes are known to be involved in tissue destruction and regeneration. In CLIMACTERIC 2001;4:95–101

The causes and management of endometrial breakthrough bleeding

The term breakthrough bleeding (BTB) is rather poorly defined, but essentially describes the symptom of vaginal bleeding occurring with scheduled periods of withdrawal bleeding, in the absence of pelvic pathology in women taking exogenous sex steroids, usually contraceptives or hormone-replacement therapy (HRT). It may also describe occasional bleeding in those who are predominantly experiencing amenorrhoea due to these preparations. Rather confusingly, the term is sometimes used to describe intermenstrual bleeding in women who are not taking sex steroids, when structural or other pathological causes are more likely. In the absence of such pathology intermenstrual bleeding in the normal menstrual cycle is relatively uncommon, suggesting that exogenous sex steroids can profoundly disrupt the tight regulation of endometrial vascular development, function and breakdown. Intermenstrual bleeding also occurs spontaneously in some women and it is possible that this phenomenon has similar mechanisms to that seen in sex-steroid-related breakthrough bleeding.