AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

In the vast majority of prolactin deficiency states, the deficiency occurs secondary to general anterior pituitary dysfunction. The most commonly associated condition is postpartum pituitary necrosis (Sheehan syndrome); however, prolactin deficiency can also be caused by anterior pituitary impairment secondary to pituitary (or extrapituitary) tumor or treatment of tumor, parasellar diseases, head injury, infection (eg, tuberculosis, histoplasmosis), or infiltrative diseases (eg, sarcoidosis, hemochromatosis, lymphocytic hypophysitis).^{1, 2, 3}

Partial isolated prolactin deficiency is rare, and case reports of total isolated prolactin deficiency are rarer still and may have a genetic component (ie, familial puerperal alactogenesis).^{4, 5, 6} Although the endocrine and metabolic function of prolactin is not fully understood, the clinical manifestation of prolactin deficiency is probably limited to puerperal alactogenesis.⁴

Related eMedicine topics:
Hyperprolactinemia
Pituitary Disease and Pregnancy

Related Medscape topic:
Resource Center Pregnancy

Pathophysiology

Prolactin deficiency is characterized by the inability of pituitary lactotrophs to secrete prolactin and by the resulting lack of puerperal lactogenesis. Other pathophysiologic mechanisms have not been fully established. Prolactin is principally regulated by tonic inhibition rather than by intermittent stimulation. Its principal inhibitory regulator is dopamine. Prolactin enhances dopamine secretion and thus exhibits feedback inhibition of its own secretion. The only other known physiologic inhibitors include triiodothyronine (T3) and somatostatin.⁷

Menstrual disorders, delayed puberty, infertility, and subfertility have been associated with hypoprolactinemia, through mechanisms that are not entirely clear. Prolactin concentration in follicular fluid during in vitro fertilization (IVF) correlates with the oocyte maturation level and fertilization rate. Further, in a randomized human trial, bromocriptine-induced hypoprolactinemia during IVF resulted in decreased fertilization and cleavage rate compared with a hyperprolactinemic cycle group. A partial prolactin deficiency may result in inadequate lactation. Further, a possibility exists that male factor infertility may be associated with hypoprolactinemia. Serum prolactin levels that were suppressed by bromocriptine resulted in decreased spermatogenesis and decreased testosterone production in healthy male volunteers.⁸

Some data support the idea that prolactin is also an immunoregulating hormone. Prolactin receptors have been found on human T lymphocytes and B lymphocytes, and some data support T-lymphocyte dependence on prolactin for maintenance of immune competence.⁹ In research using a mouse model, inhibition of prolactin release impaired lymphocyte function and depressed macrophage activation.¹⁰ Further, the study's mice had a decreased tolerance for bacterial exposure; this reduced tolerance was manifested by death from a normally nonlethal dose of bacteria.

Part of the immunosuppressive effects of cyclosporine may be mediated through a competitive antagonistic action at the prolactin receptor site. Further evidence is found in the observation of the immunosuppressant effects of bromocriptine, which has been shown to be an effective adjuvant (immunosuppressant) in patients after transplantation and in patients with autoimmune disease.^{11, 12}

Because prolactin release is inversely related to dopamine levels in the anterior pituitary, critically ill patients on prolonged dopamine infusion have resultant prolactin deficiency. It has been hypothesized that this causes impairment of the T-lymphocyte proliferation response; this impairment occurs in patients in intensive care units (ICUs) and may be an important cause of infection susceptibility in this group. However, no data support the hypothesis that lack of prolactin in otherwise healthy patients results in immunodeficiency.

Several studies have found a correlation in preterm infants between hypoprolactinemia and increased mortality.¹³ The precise pathophysiologic mechanism is unknown, but it is speculated to be associated with the effects of prolactin on surfactant synthesis, whole-body water regulation, or gastrointestinal maturation.¹⁴

Related eMedicine topic:
Human Milk and Lactation

Frequency

United States

In association with other anterior pituitary dysfunction, prolactin deficiency is uncommon except with pituitary infarction (Sheehan syndrome). In isolation, partial prolactin deficiency occurs rarely, and total isolated prolactin deficiency is limited to case reports.^{5, 6}

Related eMedicine topic:
Hypopituitarism (Panhypopituitarism)

Mortality/Morbidity

No fatalities resulting from prolactin deficiency in adults have been documented. In preterm infants, however, increased mortality may be associated with hypoprolactinemia.¹³

Race

No race predilection exists for prolactin deficiency.

Sex

Clinical manifestations occur only in females (puerperal alactogenesis). Excluding women with Sheehan syndrome, incidence in males and females is probably equal.

Age

The prevalence of hypoprolactinemia parallels the prevalence of all causes of hypopituitarism. Obviously, Sheehan syndrome is possible only in women of reproductive age.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The most important historical finding in prolactin deficiency is puerperal alactogenesis. A history of anterior pituitary dysfunction is also important.

• Menstrual disorders, delayed puberty, infertility, and subfertility are important historically, secondary to their association with hypoprolactinemia.
• Inadequate lactation is speculated to be secondary to a partial prolactin deficiency and can be considered a historical marker.

Physical

No specific physical findings are associated with hypoprolactinemia other than puerperal alactogenesis. The most common symptom complex of anterior pituitary dysfunction in men and women is secondary hypogonadism caused by deficiencies of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

Causes

The most common causes of prolactin deficiency include postpartum pituitary necrosis (Sheehan syndrome) and all other causes of anterior pituitary dysfunction.

• Classically, the typical sequence in loss of pituitary hormones is the following:
• • Gonadotropins (LH, FSH)
  • Growth hormone
  • Thyrotropin-releasing hormone
  • Corticotropin
  • Prolactin (deficiency uncommon except with pituitary infarction [Sheehan syndrome])
• Another cause can be medication (ie, dopamine infusion, ergot preparation, pyridoxine, diuretics). Nicotine also diminishes the amount of prolactin released in response to the suckling stimulus. This may explain the decreased milk yield in mothers who smoke; they have been found to lactate for a shorter time than do comparable groups of mothers who do not smoke. Although plasma prolactin levels are usually within the reference range in anorexia, bulimic patients have been reported to have either reference-range or low prolactin levels.
• Retained placental fragments in the peripartum interval can also suppress prolactin.
• Prolactin deficiency is associated with G-protein mutations, such as Albright hereditary osteodystrophy. In this case, it may be found with olfactory dysfunction in type I pseudohypoparathyroidism.
• Prolactin deficiency is found in a rare hereditary disorder called multiple pituitary hormone deficiency (MPHD). This familial occurrence has been associated with mutation of the PROP1 gene or Pit1 gene (also called POU1F1).^{15, 16, 17} These genes encode transcription factors that are necessary for the differentiation of lactotrophs, as well as of somatotrophs and thyrotrophs. MPHD is associated not only with prolactin deficiency, but usually with somatotropin (growth hormone [GH], thyrotropin [also known as thyroid-stimulating hormone, or TSH]) deficiencies as well.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to Be Considered

Postpartum pituitary necrosis (Sheehan syndrome)
Pituitary (or extrapituitary) tumor or treatment of tumor
Parasellar diseases
Head injury
Pituitary infection
Pituitary infiltrative diseases (lymphocytic hypophysitis)^{1, 2}
Idiopathic hypogonadotropic hypogonadism
Familial puerperal alactogenesis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The prolactin level following administration of thyrotropin may be the best screening test for Sheehan syndrome.
• Usually, no workup is necessary, because supplemental prolactin is not yet available for treatment; however, suspicion of the disease can be confirmed by administering thyrotropin-releasing hormone or an antidopaminergic agent (eg, metoclopramide) and measuring prolactin levels. Failure to respond (rise in the level of prolactin) in the setting of the challenge is diagnostic.
• The following tests can also be performed: prolactin assay in the third trimester or in peripartum women; LH, FSH, thyrotropin, and free thyroxine; and other tests as necessary to diagnose anterior hypopituitarism.
• The author recommends that female patients who are interested in lactation and have suspected anterior pituitary dysfunction have prolactin measured in the third trimester of pregnancy or peripartum. This test can then be used to ascertain the possibility of puerperal alactogenesis. In this way, the patient can be forewarned of her inability to support lactation, and a recommendation for formula and bottle-feeding can be made. This enables the patient to avoid the often traumatic experience of waiting for her milk to come in, with this event instead being predicted by a simple laboratory test. Third trimester prolactin levels in normal pregnancies are often 150-250 mcg/L.
• Normal baseline serum prolactin levels are less than 20 mcg/L in nongravid women and are usually less than 10 mcg/L in men. During pregnancy, serum levels may reach 200-500 mcg/L.
• • Prolactin is secreted in a pulsatile manner, with a distinct circadian pattern.^{18, 19, 20} Circulating prolactin levels are lowest at midday (noon), with a modest increase occurring during the afternoon.
  • Prolactin levels increase shortly (60-90 min) after onset of sleep, peaking in the early morning.
  • Prolactin levels also rise in response to stress, food, serotonin, acetylcholine, opiates, estrogens, thyrotropin-releasing hormone, and angiotensin II.

Imaging Studies

• Consider pituitary imaging if anterior pituitary dysfunction is suspected. Magnetic resonance imaging (MRI) is the usual imaging procedure.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Generally, formula and/or bottle-feeding of infants are recommended for women with puerperal hypoprolactinemia and insufficient milk supply. Drugs to increase milk output generally are not effective.

Consultations

Consult an endocrinologist.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Currently, no medication exists to treat prolactin deficiency; however, experimental recombinant human prolactin has been formulated and has been shown to be effective in correcting lactational performance in rats treated with bromocriptine.

Inadequate lactation may respond to antidopaminergic agents that block the dopamine-induced hypothalamic inhibitory control of prolactin. Metoclopramide has been shown in prospective, placebo-controlled studies to significantly increase milk yield in patients with inadequate lactation.^{21, 22, 23, 24, 25, 26} Subfertility caused by hypoprolactinemia may be treated with clomiphene citrate (50 mg/d for 5 d) or with gonadotropins (LH, FSH; dose varies).

Related eMedicine article:
Infertility

Drug Category: Antidopaminergic agents

These block dopamine-induced inhibitory control of prolactin at the hypothalamic level.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Typically, prolactin deficiency is not managed in the hospital setting.

Patient Education

• If hypoprolactinemia is established, educate the patient about the reality of not being able to breast-feed her baby.
• For excellent patient education resources, visit eMedicine's Women's Health Center. Also, see eMedicine's patient education article Breastfeeding.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to diagnose prolactin deficiency

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Aug 5, 2008