**Physiological and Pathological Hyperprolactinemia: Can We Minimize Errors in the Clinical Practice?**

Miguel Ángel Castaño López, José Luís Robles Rodríguez and Marta Robles García

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54758

#### **1. Introduction**

212 Prolactin

[31] Hovey RC, Trott JF, Ginsburg E, Sasaki MM, Fountain SJ, Sundararajan K, Vonderhaar BK (2001) Transcriptional and spatiotemporal regulation of prolactin receptor mRNA and cooperativity with progesterone receptor function during ductal branch growth in

[32] Grimm SL, Seagroves TN, Kabotyanski EB, Hovey RC, Vonderhaar BK, Lydon JP, Miyoshi K, Hennighausen L, Ormandy CJ, Lee AV, Stull MA, Wood TL, Rosen JM (2002) Disruption of steroid and prolactin receptor patterning in the mammary gland correlates with a block in lobuloalveolar development. *Mol Endocrinol* 16(12):2675-2691. [33] Goldhar AS, Duan R, Ginsburg E, Vonderhaar BK (2011) Progesterone induces expression of the prolactin receptor gene through cooperative action of Sp1 and C/EBP.

the mammary gland. *Dev Dyn* 222(2):192-205.

*Mol Cell Endocrinol* 335(2):148-157.

Human prolactin is a single-chain polypeptide hormone. It has a molecular weight of approximately 22,500 Da (figure 1). It takes part in lactation through physiological and biochemical events.

Its polypeptide chain consists of 198-200 amino acid remainders which complete sequence is unknown. Over 80% of the first 50 amino acids are identical or equivalent to the bovine prolactin.

The prolactin molecule is arranged in a single chain of amino acids with three intra molecular disulfide bonded between six cysteine residues (Cys4-Cys11, Cys58-Cys174, Cys191-Cys199 in humans). The sequence homology can vary from the striking 97% among primates to as low as 56% in rodents (1)

The sequence of the first 23 amino acid remainders corresponding to the N-terminal extreme

NH2-leu-pro-ile-cys-pro-gly-ala-ala-arg-cys-gln-val-thr-leu-arg-asp-leu-phe-asp-arg-ala-val

It's secreted by the anterior part of the hypophysis, the adenohypophysis (figure 2) that stimulates the milk production in the mammary glands and the progesterone synthesis in the corpus luteum.

Although the major form of prolactin found in the pituitary gland is 23 kDa, variants of prolactin have been characterized in many mammals, including humans. Prolactin variants can be results of alternative splicing of the primary transcript, proteolytic cleavage and other posttranslational modifications of the amino acid chain (1)

Physiological and Pathological Hyperprolactinemia: Can We Minimize Errors in the Clinical Practice? 215

It was discovered in 1928 in a cow´s hypophysis and it is phylogenetically considerated as the oldest known hormone in the animal kingdom. It has been detected in insects, amphibian, fish and mammals. Its luteotrophic activity was not discovered until 1945 (2-4).

Its isolation was difficult due to its structure, which is similar (in a 16%) to the growth hormone (GH) structure. Both are located in the hypophysis, but the GH is present in higher concentration. Its existence was demonstrated through a trial series performed between 1965 and 1971, it was discovered, as well, the way its secretion is performed, where some physiological factors are positive and negative hypothalamic neurohormonal compounds

Studies on the secondary structure of prolactin have shown that 50% of the amino acid chain is arranged in α-helices, while the rest of it forms loops. Although it was predicted earlier, there are still no direct data about the three-dimensional structure of prolactin. The tertiary structure of prolactin was predicted by homology modeling approach, based on the structural similarities between prolactin and other helix bundle proteins, especially growth

According to the current three-dimensional model, prolactin contains four long α-helices

It shows a synergic effect with the following hormones: estrogens, progesterone and GH.

This image is propriety of our laboratory and created by us. The data was taken from Benavides IZ, Castillo AP, Montemayor I, DeEstrada R,Onatra W, Posso H. Biorritmo de prolactina en mujeres de edad reproductiva

vs.Perimenopáusicas.Rev Coloma Menop.2003;9:153–8.[16 Sep 2009].

**Figure 3.** Prolactin's circadian rhythm

(5-6).

hormone.

arranged in antiparallel fashion (1).

Source: Originally from en.wikipedia; description page is/was here. Author: Original uploader was BorisTM at en.wikipedia Permission (Reusing this file): Released into the public domain (by the author); PDB

**Figure 1.** Prolactin´s structure

This image is propriety of our laboratory and created by us.

**Figure 2.** Prolactin's secretion.

It was discovered in 1928 in a cow´s hypophysis and it is phylogenetically considerated as the oldest known hormone in the animal kingdom. It has been detected in insects, amphibian, fish and mammals. Its luteotrophic activity was not discovered until 1945 (2-4).

Its isolation was difficult due to its structure, which is similar (in a 16%) to the growth hormone (GH) structure. Both are located in the hypophysis, but the GH is present in higher concentration. Its existence was demonstrated through a trial series performed between 1965 and 1971, it was discovered, as well, the way its secretion is performed, where some physiological factors are positive and negative hypothalamic neurohormonal compounds (5-6).

Studies on the secondary structure of prolactin have shown that 50% of the amino acid chain is arranged in α-helices, while the rest of it forms loops. Although it was predicted earlier, there are still no direct data about the three-dimensional structure of prolactin. The tertiary structure of prolactin was predicted by homology modeling approach, based on the structural similarities between prolactin and other helix bundle proteins, especially growth hormone.

According to the current three-dimensional model, prolactin contains four long α-helices arranged in antiparallel fashion (1).

It shows a synergic effect with the following hormones: estrogens, progesterone and GH.

This image is propriety of our laboratory and created by us. The data was taken from Benavides IZ, Castillo AP, Montemayor I, DeEstrada R,Onatra W, Posso H. Biorritmo de prolactina en mujeres de edad reproductiva vs.Perimenopáusicas.Rev Coloma Menop.2003;9:153–8.[16 Sep 2009].

**Figure 3.** Prolactin's circadian rhythm

214 Prolactin

Source: Originally from en.wikipedia; description page is/was here.

Permission (Reusing this file): Released into the public domain (by the author); PDB

Author: Original uploader was BorisTM at en.wikipedia

This image is propriety of our laboratory and created by us.

**Figure 2.** Prolactin's secretion.

**Figure 1.** Prolactin´s structure

The nipple suction during breastfeeding favors a bigger amount of hormone synthesis. Besides, it's one of the few physiological systems that have positive feedback, so the presence of prolactin in the organism favors this peptide production.

Physiological and Pathological Hyperprolactinemia: Can We Minimize Errors in the Clinical Practice? 217

It shows a synergism with the gonadal steroid hormones in the continuance of the corpus luteum and progesterone production, with action in the reproductive processes, according to some researches that revealed the presence of specific prolactin receptors in the mammal´s ovaries, transferring part of the progesterone function which, among other functions, stimulates the formation of membrane receptors for the follicle stimulating hormone (FSH) and the luteinizing hormone (LH) for the follicle growth and the estradiol synthesis. It was found, in the little antral follicles, a prolactin concentration 6 times higher than in circulation, when the follicle is 6-8 mm of diameter the levels drop, getting close to

Some secondary functions or less powerful have been reported, being related to androgenesis that takes part in the suprarenal cortex reticular area, where some specific receptors for prolactin have been found, the joint with those receptors stimulates the

Prolactin has also an inhibitory effect over the gonadotropin secretion, so its hypersecretion

In men, the prolactin behavior can affect the adrenal function, the electrolytic balance, gynecomastia, galactorrhea sometimes, libido decreasing and sexual impotence and some

Prolactin serum levels have daily and circadian variations, its secretion is pulsatile, as described by Sassin et al, measuring blood levels every 20 minutes with raises up to 50%

It shows a circadian rhythm with increases or secretory peaks during the sleep, started between 10 minutes and one hour after sleep beginning and reaching the highest values mainly in the deepest stages. These values do not go down in the next two hours after waking up and decrease slowly by the end of the afternoon, without any tendency to be repeated in the same individual in the days after, once in circulation prolactin mean life is

It seems that variation during time and sleep are due to the hypothalamus dopaminergic stimulus modifications, the circadian fluctuation is not affected by the use of oral

In blood, prolactin can be found from the 16th week of fetal life, increasing its levels due to active secretion, as in birth it shows higher amounts to the ones recorded in the mother.

The normal described limits (figure 4 y 5) for healthy population are the following:

the basal blood levels near the ovulation (3, 4, 12, 14).

secretion of **dehydroepiandrosterone** and its sulfate.

(13).

estimated around 14 minutes.

contraceptives (10-15).

Men: 2 - 18 ng/mL

 Non-pregnant women: 1 - 46 ng/mL Pregnant women: 35 - 600 ng/mL

**3. Limits of reference** 

can cause oligomenorrhea or amenorrhea in women (3,4, 14).

other actions in prostate, seminal vesicles and testicles (15-17).

Nipple and areola´s terminal nerves are stimulated when suction occurs. This stimulus travels via afferent nerve pathways to the hypothalamus, proving the prolactin release, by inhibition of the release of dopamine. (5-9)

Prolactin levels during pregnancy rise from its normal value up to 200 or 400 ng/ml. This increase starts around the 8th week in a simultaneous way with the estrogen increasing. The rising in prolactin secretion is due to the suppression that estrogens provoke over dopamine and the direct stimulation of the transcription of the prolactin gene in the hypophysis. (8)

Prolactin shows a circadian and pulsatile rhythm (figure 3) that starts raising 90 minutes after sleep beginning, with maximum peaks at 4-5 hours and it can stay high two hours after waking up (7-9).

It is known that its discharges are 20-30 minutes intervals and the mean life is 20-30 minutes (7-11).

The main circulating form is the monomeric prolactin (little prolactin) or native prolactin which is a non-glycosylated monomer that makes up the 80-90% of the total amount of prolactin in a normal individual.

Another circulating form in the big prolactin (big PRL) which consist in glycosylated dimers or trimers of 40.000-50000 daltons molecular weight, which is supposed to be a deposit form which is rarely detected in serum and which biological activity is nearly non-existent. However, it is detected in hyperprolactinemia without any pathological clinical signs.

Finally, big-big prolactin or macroprolactin wich is a dimer form of the big-PRL joined to IgG immunoglobulin with a molecular weight over 100000 daltons and without any biological activity (10-12).

#### **2. Effects**

The prolactin´s main function in women is to stimulate and maintain the puerperal breastfeeding, direct action over acidophilic cells known as lactotrophs cells of the mammary glands (6, 13). Estrogens, GH, corticoids, placental lactogenic hormones and prolactin are needed to increase the ductal system. Estrogens, progesterone and prolactin are needed to develop the lobuloalveolar system, so levels of these hormones should be considered in pathological states as fibrocystic mastopathy, mastodynia (breast pain), mammary carcinoma, etc.

Among its effects over the mammary alveolar cells there is an increase of the lactose synthesis and a higher production of lactose proteins as casein and lactalbumin.

It is related with the reproductive cycle, the pregnancy maintenance and the fetal growth, through an effect over the mother metabolism acting over different effector organs to facilitate its functions through synergy or inhibition of other hormones.

It shows a synergism with the gonadal steroid hormones in the continuance of the corpus luteum and progesterone production, with action in the reproductive processes, according to some researches that revealed the presence of specific prolactin receptors in the mammal´s ovaries, transferring part of the progesterone function which, among other functions, stimulates the formation of membrane receptors for the follicle stimulating hormone (FSH) and the luteinizing hormone (LH) for the follicle growth and the estradiol synthesis. It was found, in the little antral follicles, a prolactin concentration 6 times higher than in circulation, when the follicle is 6-8 mm of diameter the levels drop, getting close to the basal blood levels near the ovulation (3, 4, 12, 14).

Some secondary functions or less powerful have been reported, being related to androgenesis that takes part in the suprarenal cortex reticular area, where some specific receptors for prolactin have been found, the joint with those receptors stimulates the secretion of **dehydroepiandrosterone** and its sulfate.

Prolactin has also an inhibitory effect over the gonadotropin secretion, so its hypersecretion can cause oligomenorrhea or amenorrhea in women (3,4, 14).

In men, the prolactin behavior can affect the adrenal function, the electrolytic balance, gynecomastia, galactorrhea sometimes, libido decreasing and sexual impotence and some other actions in prostate, seminal vesicles and testicles (15-17).

Prolactin serum levels have daily and circadian variations, its secretion is pulsatile, as described by Sassin et al, measuring blood levels every 20 minutes with raises up to 50% (13).

It shows a circadian rhythm with increases or secretory peaks during the sleep, started between 10 minutes and one hour after sleep beginning and reaching the highest values mainly in the deepest stages. These values do not go down in the next two hours after waking up and decrease slowly by the end of the afternoon, without any tendency to be repeated in the same individual in the days after, once in circulation prolactin mean life is estimated around 14 minutes.

It seems that variation during time and sleep are due to the hypothalamus dopaminergic stimulus modifications, the circadian fluctuation is not affected by the use of oral contraceptives (10-15).
