Secondary Amenorrhoea

Secondary Amenorrhoea

The main function of prolactin is to promote additional breast development and post-partum it stimulates the prepared mammary gland to produce milk. In excess prolactin can cause the secretion of milk from the breasts in a non-lactating woman (galactorrhoea). The most likely cause is a prolactinoma (the excess secretion is usually the result of an abnormal G- protein coupled to the pituitary receptor). This is a tumour of the prolactin secreting cells- the mammotrophs (acidophils) of the anterior pituitary, which produce large amounts of prolactin and have become refractory to normal feedback control see below

However, although a prolactinoma is the most likely cause, hyperprolactinaemia has a diverse range of possible aetiologies, including; problems with dopamine metabolism (failure of Prolactin Inhibitory Factor-PIF activity or a reduction in tuberoinfundibular neuron activity in the hypothalamus), a non-secreting pituitary tumour which obstructs the delivery of dopamine (PIF) to the mammotrophs, certain drugs e.g. haloperidol (dopamine receptor antagonists), oestrogens, opiates, chronic renal failure, cirrhosis, stress, idiopathic etc, etc (Thorner, 2000). The most likely diagnosis is secondary amenorrhoea (interruption of a normal menstrual cycle).

Investigations

There are a whole series of investigations that can be performed in order to confirm the precise nature of the pathology. The ‘gold standard’ for diagnosis of hyperprolactinaemia (>390mu/L) are two or more blood samples, taken using venepuncture between 0900-1600h (in accordance with circadian cues as prolactin secretion is increased during REM sleep), under non-stressful conditions and the levels of prolactin are then measured (Hope et al, 1998). A scan looking for changes in the pituitary fossa can also be done preferably using an MRI, but high resolution CT scanning can be used when this facility is not available (Grace and Borley, 1999; Drury, 1995). However most prolactinoma’s are incidentally picked up on a lateral X-ray.

Visual field measurements can also provide important clues as to the size of the tumour (see below). The visual field should be plotted by automated computer perimetry, Goldmann perimetry or at the bedside using a red pin as a target (Kumar and Clark, 1995), as shown below:

A bitemporal hemianopia can occur if the tumour squeezes the optic chiasma which is the point at which nerves carrying information from the bitemporal fields cross to the other side of the brain.

The control of prolactin synthesis and secretion involves the release of hypothalamic factors from the neurons in the hypothalamus into capillaries of the pituitary portal vessels. These hormones are then released by capillaries onto the mammotrophs of the anterior pituitary where they modulate the release of prolactin. Prolactin is secreted into the veins leaving the inferior surface of the pituitary and then enters the general circulation.

Dopamine acts on the mammotroph D2 receptor which inhibits adenylate cyclase, and thereby inhibits both prolactin synthesis and release (Thorner, 2000). Through a process of negative feedback prolactin inhibits the release of TRH from the hypothalamus (long feedback loop) and inhibits its own secretion from the pituitary (short feedback loop). VIP acts in an autocrine or paracrine fashion on the mammotrophs increasing the secretion of prolactin.

Consequences

The patient fails to menstruate because the high circulating prolactin levels reduce LH pulsatility at the pituitary, and there is also a reduced response to GnRH at the pituitary leading to very low levels of LH (and FSH). To a lesser extent prolactin blocks the actions of LH and FSH at the ovaries, resulting in hypogonadism (Johnson and Everitt, 2000).

LH normally promotes thecal cell production of androgens. These androgens are normally converted to oestradiol by the granulosa cells under the influence of FSH. FSH and growth factors in the follicular fluid promote granulosa cell proliferation, maturation of granulosa cell steroid synthetic capacity and the development of LH receptors on the granulosa cells. Hence if Prolactin levels are high and LH and FSH levels are lowered, follicles won’t develop and little oestradiol is produced by the ovaries- as the oestradiol producing Graafian follicles aren’t formed (Johnson and Everitt, 2000). The low oestradiol levels are insufficient to promote the growth and terminal differentiation (decidualization) of the endometrium. As a result, menstruation doesn’t occur in this patient (Drury, 1995). The oestrogen levels will not reach the critically high levels needed to produce the LH surge and hence no ovulation will occur either.

Management

The choice of treatment for the prolactinoma depends to a certain extent on the size of the tumour itself. Tumours can generally be classified into microadenomas (<10mm in diameter on MRI) and macroadenomas (>10mm). In most cases the hyperprolactinaemia is due to microadenomas, which are sometimes too small to be seen in routine imaging. A histology slide of a pituitary with an adenoma causing acromegaly is shown below:

Administering bromocriptine or cabergoline- both dopamine D2 receptor agonists, can provide good results as long as doses are steadily increased and the woman isn’t pregnant (Schlechte, 1995; Hope et al, 1998; Johnson and Everitt, 2000). A noted result of this treatment is that as prolactin levels go down, growth hormone levels increase. Hence, side effects in accordance with this change can be expected, such as soft tissue growth in the hands, feet and face. Dopamine isn’t given because it cannot cross the blood brain barrier and has a smaller half-life than these drugs.

If the tumour is a macroadenoma, where visual and pressure effects (leading to headaches) are often observed, then usually a trans-sphenoidal hypophysectomy (or a transcranial approach if the former is impractical) is perhaps a better option (Grace and Borley, 1999). This is where surgical access to the pituitary gland (which sits in the sella turcica) is obtained via the nose and sphenoidal sinus. The only way a surgeon can distinguish between normal tissue and the tumour is purely by observation of the pituitary and using his experience. Tumours often look whiter and glisten more than the surrounding normal tissue. However, there is a considerable late recurrence rate of 50% in 5 years.

A point of caution here is that a substantial part of normal tissue could also be removed along with the tumour. A critical loss of ACTH secreting cells (corticotrophs) leads to a large decrease in the level of cortisol in the blood. As a result, the patient cannot tolerate stress which can lead to vascular collapse. A cerebral angiography is occasionally required prior to surgical intervention (Thorner, 2000).

Radiotherapy can be used if surgery is impractical. An external three-beam technique is implemented, this involves focussing three beams onto the tumour, which is then ablated. Three beams are used to minimise the intensity of damaging rays to normal tissue, as the combined beam will only ever be focussed on the tumour (Drury, 1995). The location of the tumour can be determined by inserting catheters through the internal carotid arteries and into the hypophyseal arteries (which supply the pituitary), bromocriptine or dopamine should then be administered and measurements should be taken on both sides to see on which side the prolactin decreases- this is the normal side. As a last resort a 90Yttrium needle implant can be used but this rarely abolishes the tumour mass (Hope et al, 1998; Johnson and Everitt, 2000).

References

Drury PL. (1995) Endocrinology. In: Kumar P and Clark M editors. Clinical Medicine. 3rd ed. London: Baillire Tindall: 769-828.

Fuller G and Manford M. (2000) Neurology. London: Churchill Livingstone.

Grace PA, Borley NR. (1999) Surgery at a Glance. Cornwell: Blackwell Science.

Hope R A, Longmore JM, McManus SK and Wood-allum CA. (1998) Oxford Handbook of Clinical Medicine. 4th ed. New York: Oxford University Press.

Johnson MH and Everitt BJ. (2000) Essential Reproduction. 5th ed. Milan: Blackwell Science.

Schlechte JA. (1995) Clinical impact of hyperprolactinaemia. Baillieres Clinical Endocrinology and Metabolism 9: 359-366.

Stevens A and Lowe J. (1997) Human Histology. 2nd ed. Mosby: Barcelona.

Thorner MO. (1995) Chapter 4. In: Clinical Endocrinology. Besser MG and Thorner MO. 2nd ed. London: Mosby-Wolfe.

Thorner MO. (2000) Anterior Pituitary Disorders. In: Ledingham JG and Warrell DA, editors. Concise Oxford Textbook of Medicine. New York: Oxford University Press: 803-814. --Riaz 18:39, 10 September 2006 (EDT)