Ovulation Induction and Controlled Ovarian Stimulation, 2st ed.

12. Management of Hyperprolactinaemia

Roy Homburg1

(1)

Homerton Fertility Centre, Homerton University Hospital, London, UK

Abstract

Excessive prolactin secretion is a not infrequent cause of anovulation and consequent infertility, often associated with amenorrhea or oligomenorrhea. Only hyperprolactinaemia causing ovulatory disturbance deserves treatment. Clinically, galactorrhea may be a sign of hyperprolactinaemia but galactorrhea may often occur without associated hyperprolactinaemia and vice-versa. Oligo/amenorrhea is a more important symptom which demands a serum prolactin estimation. Any disruption in the hypothalamic-pituitary pathway, (e.g. dopamine reducing medications, space occupying lesions) will raise prolactin concentrations and if these reach a certain level, ovulatory dysfunction will result. A further cause of hyperprolactinaemia is a prolactin-secreting tumour (prolactinoma) of the anterior pituitary which is autonomous in nature and may be a micro or a macroadenoma. Hypothyroidism is a further possible cause of hyperprolactinaemia as thyroid releasing hormone, secreted by the hypothalamus as a compensatory mechanism, has the property of prolactin release from the pituitary. The work-up following the finding of hyperprolactinaemia associated with oligo- or anovulation should include neuro-radiological visualization of the hypothalamic pituitary region by MRI or CT to look for a micro- or macroadenoma, empty sella syndrome or a para-sellar tumour. Serum TSH, FSH and LH should also be estimated. Visual disturbances associated with a visualized tumour should also prompt an examination of visual fields. A pituitary tumour impinging on the optic chiasma characteristically causes a bitemporal hemianopia. When hyperprolactinaemia and anovulatory infertility are associated with medication, the benefits and disadvantages of reducing dosage or withdrawing medication must be carefully weighed up. Hypothyroidism as a cause should be treated with the appropriate medication for correction of thyroid function rather than with specific prolactin-lowering agents. Many dopamine agonists are in use for the treatment of infertility associated with hyperprolactinaemia: bromocriptine carbergoline, quinagolide

Keywords

HyperprolactinaemiaAnovulationHypogonadismAmenorrheaOligomenorrheaOvulationInfertilityProlactinHypothyroidismGalactorrheaPsychiatric drugs neurolepticsChlorpromazinesHypotensive agentsPregnancyOral contraceptivesPCOSHeadachesThyroid disordersProlactinomasMacroprolactinomaNeuro-radiological visualizationMRICTTSHFSHLHTumourStressNon-secreting pituitary adenomasPara-sellar tumoursPan-hypopituitarismDopamineBromocriptineCarbergolineQuinagolide

Excessive prolactin secretion is a not infrequent cause of anovulation and consequent infertility. It is often associated with hypogonadism and amenorrhea or oligomenorrhea. However, mild or moderate hyperprolactinaemia is a fairly common finding which is not necessarily associated with oligo- or anovulation. Only hyperprolactinaemia causing ovulatory disturbance deserves treatment. If associated with normal ovulation it can safely be ignored as a cause of infertility.

12.1 Aetiology

Unlike other pituitary hormones whose release is controlled by hypothalamic stimulatory hormones, prolactin has an inhibitory signal (dopamine) controlling its release from the pituitary. Any interference with this pathway, (e.g. dopamine reducing medications, space occupying lesions) will thus raise prolactin concentrations and if these reach a certain level, ovulatory dysfunction will result.

A further, and probably commonest, cause of hyperprolactinaemia is a prolactin-secreting tumour (prolactinoma) of the anterior pituitary which is autonomous in nature and may be a microadenoma (up to 10 mm in diameter) or a macroadenoma (>10 mm diameter).

Hypothyroidism is a further possible cause of hyperprolactinaemia as thyroid releasing hormone, secreted by the hypothalamus as a compensatory mechanism, has the property of prolactin release from the pituitary.

Finally, physiologically, prolactin is secreted in higher concentrations during pregnancy and lactation. Idiopathic hyperprolactinaemia demanding treatment is not unusual (30 % of all cases). Also physiologically, prolactin is high during sleep. For this reason, blood samples for prolactin estimation should be drawn at least 2 h after awakening.

12.2 Diagnosis

Clinically, galactorrhea may be a sign of hyperprolactinaemia. However, galactorrhea may often occur without associated hyperprolactinaemia and hyperprolactinaemia may often occur without associated galactorrhea. Oligo- or amenorrhea is a more important symptom which demands a serum prolactin estimation.

Either of the above symptoms, when associated with hyperprolactinaemia, should prompt the use of the following check list:

·               Medications – particularly the use of psychiatric drugs, neuroleptics, chlorpromazines and hypotensive agents.

·               Pregnancy or use of oral contraceptives.

·               PCOS – frequently associated with a mild hyperprolactinaemia.

·               Headaches, visual field disturbaces.

·               Thyroid disorders.

The upper limit of normal for serum prolactin depends somewhat on the individual laboratory and in our laboratory is 600 mIU/ml (30 ng/ml). Prolactin concentrations exceeding 2,000 mIU/ml (100 ng/ml) are almost always due to prolactinomas and >10,000 mIU/ml (500 ng/ml) almost certainly indicates a macroprolactinoma.

The work-up following the finding of hyperprolactinaemia associated with oligo- or anovulation should therefore include neuro-radiological visualization of the hypothalamic pituitary region by MRI or CT to look for a micro- or macroadenoma, empty sella syndrome or a para-sellar tumour. Serum TSH, FSH and LH should also be estimated. Visual disturbances associated with a visualized tumour should also prompt an examination of visual fields. A pituitary tumour impinging on the optic chiasma characteristically causes a bitemporal hemianopia.

12.3 Indications for Treatment

Hyperprolactinaemia not associated with ovulatory dysfunction does not require treatment for infertility. Similarly, the mild hyperprolactinaemia often associated with PCOS requires no treatment. Stress can cause a mild hyperprolactinaemia. Expectant rather than medical treatment is usually recommended for infertility. When hyperprolactinaemia and anovulatory or oligo-ovulatory infertility are associated with medication, the benefits and disadvantages of reducing dosage or withdrawing medication must be carefully weighed up.

Hypothyroidism as a cause should be treated with the appropriate medication for correction of thyroid function rather than with specific prolactin-lowering agents.

All other cases of hyperprolactinaemia associated with ovulatory dysfunction and infertility, whether idiopathic or from a pituitary tumour, require treating.

12.4 Treatment

Neuro-surgical treatment for the treatment of hyperprolactinaemia, is today, thankfully, very rarely required. For both micro- and macroprolactinomas prolactin-lowering drugs are safer, more efficient and often capable of causing tumour shrinkage without recourse to surgery. Surgery often results in pan-hypopituitarism, high recurrence rates and general morbidity. It should be reserved only for the very rare case completely resistant to medication, for non-secreting pituitary adenomas or para-sellar tumours and in those who have severe visual disturbances which fail to improve with medication. For all the rest, prolactin lowering medication will serve the purpose adequately.

Many dopamine agonists are in use for the treatment of infertility associated with hyperprolactinaemia. The original and probably still most widely used drug is bromocriptine. It is provided in tablets of 2.5 mg but I usually start with half a tablet, at bedtime, taken with toast or dry biscuit, for the first week to 10 days of treatment. This tends to help avoid the rather unpleasant, not infrequent side effects of this drug, nausea, vomiting, diarrhoea and postural hypotension. Following this initial dosage regime, 2.5 mg nightly can be given. This may need to be titrated up to a maximum dose of even 20 mg/day but this is rarely needed for restoration of ovulation. The best way of gauging the dose is restoration of ovulation and regular menstruation. This is, after all, the aim of the treatment and is a better indication than the serum prolactin concentration itself that the correct dose is being administered. Follow-up of tumour size by MRI or CT is only really needed when a response of either the return of regular ovulation or at least by a reduction in serum prolactin concentrations is not forthcoming. If pregnancy does not ensue within a reasonable period, the addition of clomiphene citrate therapy may be helpful. The dose of bromocriptine which produces a positive response should be continued until pregnancy is achieved.

A further dopamine agonist, carbergoline, is at the least, equally as effective as bromocriptine and has the added advantage that it is long-acting. A single oral dose can lower prolactin concentrations for 1–2 weeks. For the resumption of ovulatory cycles, the recommended dose is 0.5–2.0 mg/week, usually divided into a twice- weekly dosage.

In contrast to the others, quinagolide is a non-ergot deriverative and seems, for that reason, to have less side effects than the ergot derivatives referred to above. The starting dose is 25 μg for the first 3 days followed by 50 μg for 3 days and then 75 μg daily.

12.5 Results of Treatment

Pregnancy rates using bromocriptine alone, in an average required dose of 5.0–7.5 mg/day should be around 70–80 % once ovulation is resumed. Ovulation is achieved in about 85 % of cases, even including those with a macroprolactinoma. This is a remarkably successful and simple treatment and has the additional advantage that it is capable of reducing the size of prolactinomas and, often, with continued treatment, microprolactinomas will disappear altogether. Both carbergoline and quinagolide produce similar results. Outcome of pregnancy following induction of ovulation with prolactin lowering drugs is similar to that in the normal population.