By Jeremy P.W. Heaton, MD
Prolactin's close relationship to other hormones and neurotransmitters vital to sex, life, and aging merits review. Although prolactin hypersecretion occurs infrequently, its recognition provides an opportunity to treat a fundamental cause of sexual problems.
What is interesting about prolactin (PRL)? Most urologists know it only as a bit player in the androgen and erectile dysfunction (ED) arena. It is considered problematic (should the PRL levels be routinely measured in men with ED?) and is usually associated with alterations in desire or libido (although this is more legend than fact). We are inclined to forget that PRL plays similar but mirror image roles in female reproductive medicine, with the addition of eponymous roles in lactation.
There are interesting things about this ancient peptide hormone, however, including its position as an integral player in anterior pituitary hormonal politics. The anterior pituitary and its connection with the hypothalamus regulate the hormonal heart of man and are responsible for many vital ingredients of sexuality and aging, which is reason enough to revisit the subject along a single strand - prolactin. As we learn more about the processes dependent on this neuroendocrine region, we will certainly hear more about PRL.
There are 6 anterior pituitary hormones: PRL, adrenocorticotropic hormone, thyroid-stimulating hormone (TSH), growth hormone (GH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). PRL is the only one under inhibitory control from the hypothalamus via the hypothalamo-pituitary portal system. Dopamine (DA) has been shown to be the hypophysiotropic hormone responsible for the inhibition of prolactin. 1 All 6 hypophysiotropic hormones (including DA) act through typical transmembrane coupled receptors, have neurotransmitter functions elsewhere in the brain, and can be found in the gastrointestinal tract.
PRL is similar in structure to GH and has a comparable half-life (about 20 minutes). It contains 199 amino acid residues and 3 disulfide bridges. The PRL receptor is similar to those for GH, many cytokines, and hematopoietic growth factors.
PRL secretion is tonically inhibited by DA from the hypothalamus in competition with PRL release promoted by recently identified prolactin-releasing peptide. 2This peptide also acts to inhibit GH secretion from the anterior pituitary by increasing the secretion of somatostatin into the portal vessels, thus setting up a basis for hormonal cross-talk between these 2 important age-related hormones. 3 Prolactin-releasing peptide has activity outside PRL control, and has been shown to increase REM sleep in a rodent model. 4In women , melatonin plays an important role in the presence of hyperprolactinemia (HPRL). 5 PRL has several clinical effects in addition to the commonly known sexual implications (Table 1). 6
Clinical effects of prolactin in humans
â€¢ Decreased pulsatile gonadotropin secretion
- Decreased sperm count and motility
- Erectile dysfunction
- Decreased libido
Note: While osmoregulation has been reported in animals, it is not definitely seen in humans. 6
As in hypothalamic-controlled processes, many factors affect PRL secretion. Serum PRL rises during the onset of sleep and remains elevated during sleep. Drugs that increase or decrease DA formation impact PRL levels because of the dominant inhibitory control that DA exerts on PRL secretion, forming the basis for management of PRL-related clinical disease. Thyrotropin-releasing hormone and TSH stimulate the release of PRL, as do other less important polypeptides. PRL also affects its own secretion by facilitating DA secretion in the median eminence - creating a negative feedback loop through the hypothalamus.
Sex and prolactin
The association of HPRL with hypogonadism and desire disorders seems to be the stuff of urologic legend. Modern studies, however, are beginning to shed some light on how HPRL causes hypotestosteronemia and affects libido, desire, and erectile function.
How does HPRL cause hypogonadism? A recent animal study suggests that decreases in testosterone secretion can be attributed to changes in Leydig cell sensitivity to LH stimulation during chronic PRL elevation. 7 Other interstitial cells play a role in the modulation of steroidogenesis in Leydig cells. A clear association between HPRL and low levels of testosterone can be seen during the treatment of HPRL. A clear basis for a biological link, however, has not yet been established.
What happens to erectile function in patients with HPRL? Is the change in testosterone level enough to account for any decrease in erectile function? Apart from changes in testosterone level and erectile function, does PRL have a specific effect on sexual desire? A recent study has documented a central nervous system (CNS) effect of HPRL on erectile function that impairs penile responses independent of serum testosterone level. 8 Treatment of HPRL-associated hypogonadism by replacement of testosterone did not seem to affect the impaired penile reflexes as documented by study of centrally mediated penile reflexes. In terms of the changes in penile function, lowered serum testosterone is a secondary phenomenon. This may be consistent with the recent report suggesting that severe ED may be a better clinical marker for HPRL than hypotestosteronemia or desire changes. 9
What links PRL and desire? The most recent information on PRL and desire suggests that PRL may represent a peripheral regulatory factor for reproductive function, and/or a feedback mechanism that signals CNS centers controlling sexual arousal and behavior. The extensive role of DA in regulating several aspects of sexual function in the hypothalamus and the intimate relationship between DA and PRL make this type of role for PRL quite plausible. Plasma PRL concentrations are substantially increased in both men and women for over 1 hour following orgasm induced by coitus or masturbation. Plasma PRL, however, is unchanged following sexual arousal without orgasm. Hence, some clinicians suggest that PRL plays a role in the neuroendocrine reproductive reflex. 10,11
Sexual behavior is substantially involved with increased midbrain DA release and activity and prolactin levels may remain depressed due to the prolactin-inhibitory hormone properties of DA. Orgasm may induce changes in the hypothalamus that overwhelm PRL inhibition, causing an increase in serum PRL. It is interesting to speculate on the phylogenetic advantage of shutting down sexual activity centrally, specifically in response to orgasm. That PRL should be the orgasm-related systemic signal to shut down sexual function allows possible insight into the postorgasmic refractory interval in men but falls short of explaining why this phenomenon is not seen in multiorgasmic women. It has been suggested that this same PRL control of sexuality (high DA/low PRL/high sexual activity) may contribute to the hypersexuality of some treated Parkinsonian patients. 12
For most urologists, a serum prolactin value arrives in response to an order for a laboratory test, and as such, has the aura of a secure biochemical truth. But, like the shifting importance of various testosterone measurements, PRL determination is colored by the fact that some patients with HPRL, in fact, have a significant proportion of macroprolactin (MPRL). MPRL is usually a complex of normal PRL with anti-PRL autoantibody and has little clinical relevance. 12 The high molecular weight forms termed "big-big" (150 kDa) and "big" (50 to 60 kDa) PRL are less active in vivo and/or are transported less easily across the capillary bed than the normal 22 kDa PRL molecules, and do not appear to contribute to ED. 14-17
In the conventional immunoassays in widespread use, MPRL may account for 10% of HPRL cases. 18 Newer assays, however, measure the level of biologically active PRL alone, eliminating the vast majority of spurious high values. Urologists undertaking PRL testing should check with their laboratory to ensure that PRL determination is optimal.
Clinical HPRL and its treatment
HPRL is caused by or associated with a number of conditions, the most important being prolactinoma (Table 2). As mentioned previously, HPRL may be due to MPRL in an assay. Various medications, including antipsychotics, have been known to elevate PRL levels. 19 Elevations may also be seen in patients with colorectal cancer. 20 Prolactinomas are benign, functioning pituitary tumors that can cause reproductive dysfunction in men and women. PRL-secreting microadenomas have a benign clinical course and may even disappear without treatment. The finding of HPRL should be evaluated in clinical context.
Causes of hyperprolactinemia
â€¢ Spurious (macroprolactinemia)
â€¢ Central nervous system
- Pituitary tumors
(PRL, GH, ACTH, nonsecreting)
- Stalk effect
- Hypothalamic tumors
- Granulomatous disease
- Histamine blockers
- Neuroleptic agents
â€¢ Primary hypothyroidism
â€¢ Chronic renal failure
â€¢ Chest trauma
Signs and symptoms. In men, symptoms of HPRL include decreased libido, ED, headache, visual impairment, galactorrhea, and symptoms of general hypopituitarism (low levels of thyroid or adrenal hormones). Presenting complaints of sexual dysfunction (ED, loss of desire) seen by urologists may be the result of HPRL alone or secondary hypogonadism (low testosterone levels). Possible physical signs include visual field defects, gynecomastia, galactorrhea (rare), and less specifically, loss of musculature, loss of body hair, or signs of hypopituitarism.
Appropriate testing. Biochemical tests may show elevated PRL, low testosterone, low FSH and low LH levels. High PRL values should be confirmed and the MPRL effect eliminated through use of the newer assays. In cases where the pituitary adenoma presents late, it is possible to document abnormal visual fields. MRI (Figures 1 through 3) and CT show even small pituitary tumors with good sensitivity. Pituitary imaging with dynamic MRI techniques improves the likelihood of finding pituitary microadenomas. 21
Treatment.The absolute indications for treatment of HPRL include the desire to restore fertility and the presence of a microadenoma. The first line of therapy for microprolactinomas is medical. 22 Regardless of tumor size, a DA agonist is the treatment of choice. In most cases, the correct dose will normalize PRL levels and normalize symptoms. Treatment is usually continuous and life-long. The remission rate for microprolactinomas in patients with initial prolactin levels below 200 ng/mL is around 82%.
Bromocriptine mesylate is the established agent for the medical management of HPRL and microadenoma. Treatment is initiated at 2.5 mg a day, with dosage increases every 3 to 7 days until the clinical benefit plateaus and the serum PRL normalizes. The typical longer-term dosage is 5 to 7.5 mg a day, but ranges from 2.5 to 15 mg a day.
Cabergoline (Dostinex, Pharmacia & Upjohn), a newer dopaminergic agent, may also be considered for therapy. While it has been shown to normalize PRL levels more quickly than bromocriptine, 23 resistance may be seen. 24 Treatment with cabergoline is initiated at a dosage of 0.25 mg twice a week. The dosage may be increased every 4 weeks, as needed to normalize serum PRL levels, to a usual maximum of 1 mg twice a week. HPRL may also be treated with pergolide mesylate (Permax, Amarin) 25 and quinagolide (Europe and Canada only). 26
Surgical treatment is primarily reserved for patients who cannot tolerate medical treatment or whose tumors are unresponsive to DA agonists. The remission rate for surgically treated prolactinomas varies from 54% to 86% in large series. 27
Prolactin and ED
Because HPRL is an uncommon cause of ED (seen in
Prolactin is an important sex hormone with potentially far-reaching daily consequences. It has a fundamental role in sexual activity, and may be the first candidate for a circulating molecule with the capacity to regulate sexual feelings and preparedness. While hypersecretion of PRL occurs infrequently in urologic practice, its recognition provides an opportunity to treat a fundamental cause of sexual problems.
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Dr. Heaton is Professor, Department of Urology, Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
Jeremy Heaton. Prolactin: An integral player in hormonal politics. Contemporary Urology June 2003;15:17-25.
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