Hyperprolactinemia, Prolactin and Pituitary Adenomas

PROLACTIN (PRL) AND ITS PHYSIOLOGICAL ROLE

PRL is a  low molecular weight peptide hormone secreted by Hypophysis, a small gland located

hyperprolactinemia and pituitary adenomas

Magnetic Resonance Imaging (RMN) of the Hypothalamic-Pituitary region. Hyperprolactinemia is often linked to Pituitary Adenomas secreting Prolactin.

at the base of the Central Nervous System in a tiny bony enclosure called the Sella Turcica. The HYPOPHYSIS is directly related to the most central areas of the BRAIN that, through chemical mediators, nervous and vascular structures, control its whole complex function.

Prolactin is an hormone widely distributed in vertebrates, with very different actions in the different species: among these effects are reported in women the control of growth, on behavior and metabolism. In particular, for what concerns effects on behavior are described induction of maternal behavior (parental behavior), binding to the domestic structure (homing), contentment and decreased post-orgasmic libido.

But the most important physiological role of Prolactin in women is to prepare the mammary gland at lactation and to maintain it after childbirth. In fact, its levels increase progressively during gestation and high concentrations were also found in the amniotic fluid and fetus where it could have an important role in lung maturation and fluid and electrolyte balance. During the postnatal period newborn will stimulate the production through the sucking of the nipple (breastfeeding). Prolactin, during puerperium, contrasts the reactivation of the ovary and determines a sophisticated nervous arc that starts from the nipple and reaches diencephalic regions hence the typical absence of menstruation (Amenorrhea) following the birth for a period depending on personal breastfeeding.

Out of pregnancy and puerperium Prolactin does not have a particular function and normally its level in  blood is quite low while maintaining a circadian cycle with lower concentrations in the morning and higher at night. A circa-annual rhythm (variations of concentrations during the year) has been verified in some female populations (Japanese) and not in others (American). In women with Fibrocystic Mastopathy this rhythm seems to be less pronounced.

Prolactin may increase also in others physiological conditions (physiological hyperprolactinemia) such as :

  • intense physical exertion
  • sexual activity
  • eating, stress
  • excessive stimulation of the nipple.

Outside of pregnancy and of physiological conditions that we have listed, when Prolactin  blood levels increase determines the clinical condition of HYPERPROLACTINEMIA.

IATROGENIC HYPERPROLACTINEMIA.

A Prolactin increase is sometimes found in some pharmacological treatments such as certain hormonal therapies based on Estrogen and Progesterone (eg contraception); some therapies for depression, gastro-intestinal disorders, high blood pressure.  Probably for an action of some of these drugs on diencephalic chemical mediators that control Pituitary Gland function.

Temporary increases can also occur during surgery and general anesthesia. It can also moderately increase over the course of some diseases (secondary Hyperprolactinemia) such as Hypothyroidism, Chronic Renal Failure, Hepatic Cirrhosis, the Polycystic Ovarian Syndrome.

PATHOLOGICAL HYPERPROLACTINEMIA

There are conditions of chronic and pathological increase of Prolactin. The most frequent cause of Hyperprolactinemia is a small benign Hypophyseal Adenoma (Hypophyseal Microadenoma) with a diameter of usually a few millimeters consisting of Prolactin-secreting cells. Sometimes, larger Adenomas may also be found (> 10 mm) and they are called Macroadenomas; despite their benignity, however, can cause disorders by compression of nerve structures near the Sella Turcica (optic nerve).

Cases in which the Pituary Gland produces a greater amount of Prolactin without a detectable Adenoma (the best technique to revail it is the Magnetic Resonance Imaging) are not rare. Other times there is a Hyperprolactinemia because it lacks of inhibitory control of Hypothalamic regions due to inflammatory, vascular or tumoral diseases involving the Skull base. In clinical practice, so it is important to make a careful differential diagnosis to come to understand the true origin of the cause of Hyperprolactinemia and then determine a possible therapeutic strategy.

SYMPTOMS AND MOST RELEVANT CLINICAL CONDITIONS OF HYPERPROLACTINEMIA

In many cases Hyperprolactinemia is asymptomatic, particularly when blood levels are slightly increased; in other cases the most frequent symptoms are menstrual irregularities, galactorrhea and infertility. These same symptoms can also occur in case of persistent PRL increases linked to iatrogenic causes (see above) or when the Hyperprolactinemia is secondary to other disease (i.e. Hypothyroidism).

Menstrual irregularities can be very different, ranging from cycle shortening (Polymenorrhea) and small persistent bleeding (Spotting) to decrease (Oligomenorrhea) of them, or more frequently to menstruation absence (Amenorrhea).

Another important symptom related to Hyperprolactinemia is the Galactorrhea, i.e. the production of milk outside a reproductive event. The amount of breasts milk produced in these cases is generally poor and bilateral and may be accompanied by swelling and soreness of the glands.

Consequence of Prolactin anti-gonadal and particularly anti-ovulatory is the infertility, the difficulty or inability to give birth because of ovulatory failure or severe luteal insufficiency.

Alterations of sexuality were also described, in particular reduction of desire and Anorgasmia.

Eye disorders and Headache are much more rare and occur in case of Hypophyseal Adenomas of considerable size that tend to expand and compress nearby structures.

THERAPY: WHAT ARE THE THERAPEUTIC OPTIONS?

When Hyperprolactinemia cause is identifiable in a pharmacological treatment, it will be enough to stop the medication to solve the problem. In cases linked with other diseases, the argument is certainly more complex, but the treatment is crucial for prognostic purposes.

In hyperprolactinemia without Pituitary Adenoma or where there is a Microadenoma, using medications (Dopamine agonist) that, through an action on Hypothalamic-Pituitary chemical mediators, not only reduce Prolactin production but sometimes also induce a volumetric regression  of Adenoma. These medications (Bromocriptine, Cabergoline) are generally used for long periods and always under specialist control. Their therapeutic success is witnessed by a fairly rapid (a few months) disorders resolution.

When a Macroadenoma is found, often there is only a surgical choice. In situations where it is found (Magnetic Resonance) a macroadenoma, the therapy of choice is undoubtedly surgical. The transsphenoidal (through the nose) surgery guarantees good success rates. Even in these cases, however, medical therapies are used in patterns and methods of administration dependent on the clinical presentation and the overall therapeutic strategy undertaken. Radiotherapy is another therapeutic option. It is normally used when surgery is not indicated, or it is in a complementary manner.

THE PERSISTEN LACTATION

Sometimes, especially after a long period of lactation, breasts continue to secrete a fair amount of milk. This secretion is generally bilateral and follows a reproductive event. Although, a matter of considerable concern in mothers, in most cases it is linked to an increased sensitivity of mammary glands at normal levels of prolactin. The use of anti-prolattinemic even in these cases it is very useful.

PREGNANCY AND PROLACTIN-SECRETING PITUITARY ADENOMAS

The Pituitary Gland increases its volume by about 50-70% during pregnancy because of an effect of Estrogens on Prolactin-secreting cells. It is not uncommon that a pregnancy will arise even in patients with Prolactin-secreting Pituitary Adenoma, especially during an undergoing treatment. In these cases, if it is a Microadenoma, the risks of its rapid growth are very low (1.6%). If ongoing therapy is withheld and you keep a careful monitoring of the clinical situation, controlling the visual field (a possible Adenoma expansion compressing the optic nerve), measuring the PRL (keeping in mind that physiologically increases already during pregnancy) and possibly carrying out a Head MRI.

The attitude is different in patients with clinical Macroprolactinoma, certainly a more complex clinical situation. In these cases, medical therapy is continued or undertaken. Clinical controls are tighter and, in some cases, may be necessary a surgery.

PLEASE NOTE …

Prolactin has a very important role in women. Its evaluation is therefore recommended under the following conditions: persistent disorders of menstruation, breast milky secretions, abnormal persistence of lactation after childbirth, headaches and visual field defects, infertility, disorders of sexual behavior.

Detection of hormone elevated levels requires a careful clinical evaluation and a particularly accurate differential diagnosis must take into account any other concomitant diseases, physiological situations, pharmacological interference.

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Filiberto Di Prospero
Medical Doctor, Consultant in Gynecology and Obstetrics, Endocrinology and Metabolism. Director of Gynecologic Endocrinology Unit at Civitanova Marche General Hospital (Italy). Private clinics in Civitanova Marche, Rome and Milan.

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