Prolactin is a hormone that is best known for allowing pregnant and breastfeeding women to produce milk. It also plays a role in many other functions throughout the body in both males and females.
- Introduction to Prolactin
- What Increases Prolactin
- What Decreases Prolactin
- What You Don’t Know About Prolactin
- Prolactin is an Immune Stimulant
- Prolactin Can Cause Weight Gain and Hunger
- Prolactin May Cause Skin and Hair Problems
- Prolactin May Cause Cystic Fibrosis
- Prolactin Can Cause Anxiety and Depression
- Prolactin May Worsen Migraines and Cause Pain
- Prolactin Inhibits Blood Vessel Growth
- Prolactin Influences Cancer
- Prolactin Influences Electrolyte Balance
- Prolactin Is an Important Hormone During Sex
- Main Functions of Prolactin
- Structure of Prolactin
- Synthesis, Secretion, and Reception of Prolactin in the Body
- High Levels of Prolactin
- Low Levels of Prolactin
- Technical Section
- Normal Levels of Prolactin
Introduction to Prolactin
Prolactin is a peptide hormone made by the pituitary gland and various other parts of the body. It is also referred to as the luteotropic hormone (luteotropin), PRL, and LTH. Prolactin is encoded by the PRL gene on the 6th chromosome (R).
Even though it is present in both males and females, the hormone’s primary role is to help pregnant women produce milk in order to breastfeed after giving birth. When a woman is pregnant, prolactin levels increase by up to 10-20 times the normal amount. The levels return to normal within a few weeks after the mother stops breastfeeding (R).
Despite what its name suggests, prolactin does much more than only promote lactation. It is recognized as a multipurpose hormone with one of the widest ranges of physiological actions of any extracellular transmission molecule in the body (R).
What Increases Prolactin
Prolactin levels are the highest during sleep, shortly after you wake up, and during times of physical or emotional stress (R).
In a study on female volunteers under hypnosis, prolactin surges resulted from the evocation of rage or humiliating experiences, but not from the fantasy of nursing. Interestingly, compared to single males, fathers generally have higher prolactin concentrations (R).
Conditions that may cause increased levels of prolactin include pregnancy, liver disease, stress, depression, kidney disease, hypothyroidism, epileptic seizures, psychogenic non-epileptic seizures, some drugs and medications, tumors of the pituitary gland (prolactinomas), surgery, trauma, intercourse, nipple stimulation (i.e. suckling), and exercise (R).
- Estrogen (R)
- TRH (R)
- Progesterone – increases prolactin synthesis in the endometrium and decreases it in the myometrium and breast glandular tissue (R)
- Interval exercise (R)
- Sauna (R)
- Calcitriol (R)
- Low DHEA (R)
- Lactate (R)
- Hypothalamus extract (R),
- 5HT2A agonism, 5HT2C agonism,
What Decreases Prolactin
The primary Prolactin Inhibiting Factor (PIF) is the neurotransmitter dopamine. When prolactin is produced, the secretion of dopamine increases as well. However, dopamine restricts prolactin production, so the more dopamine there is, the less prolactin is released. This creates a negative feedback loop (R).
Treatment with dopamine or compounds that activate dopamine receptors suppresses prolactin secretion (R).
Estrogen is another key regulator of prolactin in the body. Studies have shown that increased levels of estrogen correlate to higher amounts of prolactin secretion. This is confirmed by the fact that women have higher levels of prolactin in their blood during stages of pregnancy and their reproductive cycle when estrogen levels are higher too (R).
Estrogen enhances the growth of prolactin-producing cells, stimulates prolactin production directly, and suppresses the production of dopamine (R).
Progesterone increases prolactin synthesis in the endometrium and decreases it in the myometrium and breast glandular tissue (R).
What You Don’t Know About Prolactin
Prolactin is an Immune Stimulant
Prolactin is mostly an immune stimulant.
Prolactin acts in a cytokine-like manner and plays a significant role as a regulator of the immune system, affecting proliferation and production of many immune system cells (R).
The hormone plays a role in the regulation of the humoral and cellular immune responses in physiological as well as pathological states, such as autoimmune diseases. A large number of immune disturbances were found to be associated with prolactin deficiency (R).
The prolactin receptor is widely found in immune cells, and some types of lymphocytes synthesize and secrete prolactin. These observations suggest thatprolactin may act as a hormonal controller of immune activity (R).
Suppression of prolactin secretion led to a reduction of humoral or cell-mediated immunity that could be reversed by treatment with external prolactin (R).
Prolactin is also required for mitogen-stimulated proliferation of lymphocytes. Nb2 cells, derived from immature T lymphocytes, are dependent on the mitogenic activity of prolactin. In addition, prolactin is involved in the immunoregulation of ovarian steroids (R1,R2).
Immune responses in organisms are also enhanced by prolactin (R).
Skin transplants elevate prolactin levels and during graft rejection, lymphocytic prolactin gene production is also increased. These data suggest that lymphocytic prolactin plays a specific role in skin graft rejection and other transplantation responses (R).
Interestingly, mice with homozygous deletions of the prolactin gene fail to show significant abnormalities in immune responses. As a result, prolactin has a modulatory role in several aspects of immune function but is not strictly required for these responses (R).
Excess prolactin is one of the important factors in the development and course of autoimmune diseases such as autoimmune thyroid disease, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, polymyalgia rheumatica and Sjogren’s syndrome. Excess prolactin is diagnosed in nearly one-third of these patients (R, R2).
Drugs that lower prolactin help psoriatic arthritis and improves joint and skin symptoms (R).
Treg cells help create tolerance and an anti-inflammatory environment.
Both the percentage and function of Treg cells decrease in SLE patients compared to healthy individuals with statistical significance. The prolactin receptor is regularly found on Treg and effector T (Teff) cells in SLE patients, and this production is higher than in healthy individuals (R).
Prolactin Can Cause Weight Gain and Hunger
Prolactin receptors are found in multiple tissues involved in metabolic regulation, including fat tissue, liver, pancreas and the brain. It appears to play a broad role in both pancreatic and fat development (R).
In fat tissue, prolactin is essential in fat cell production and differentiation, as well as regulation of fat metabolism. It also increases the secretion of leptin and inhibits adiponectin. Fat mobilization from stores and utilization in the mammary gland is promoted by prolactin (R).
In the pancreas, it promotes the growth of islets during development, increasesinsulin production, and increases glucose-stimulated insulin secretion. It also increases production of glucose transporter 2 and promotes glucose entry into the β-cells, resulting in enhanced activity of glucose-sensitive enzymes such as glucokinase (R).
Prolactin can cause disturbances in phospholipid metabolism due to the activation of phospholipase enzymes in the cell membrane. As a result, protein kinase C can be activated and control prostaglandin production and/or intracellular calcium ions (R).
Adaptive changes in glucose homeostasis are also important during pregnancy. Maternal tissues develop insulin resistance to preferentially direct glucose to the fetal/placental compartment, and to ensure the maternal tissues continue to receive the nutrients required, there is increased demand for maternal insulin secretion, and glucose-stimulated insulin secretion increases (R).
To adapt to this altered demand, there is a significant proliferation of β-cells in the islets, enhanced insulin synthesis, and a decreased threshold for glucose-stimulated insulin secretion, with prolactin playing a critical adaptive role in promoting these changes. Failure of this adaptive response results in gestational diabetes (R).
Prolactin promotes appetite and contributes to the rapid increase in food intake during pregnancy and nursing (R).
Prolactin also induces functional leptin resistance, which would contribute to increased food intake, potentially mediating the well-established leptin resistance of pregnancy. Prolactin receptors are found in many of the areas involved in the regulation of food intake, including the arcuate, ventromedial and paraventricular nuclei. Localized injections of prolactin directly into the paraventricular nucleus stimulate food intake in a dose-dependent manner in female rats (R).
Interestingly, genome-wide association studies have revealed that a common variant adjacent to the prolactin gene is associated with obesity suggesting that abnormalities in prolactin or prolactin transmission may contribute to human obesity (R).
Prolactin May Cause Skin and Hair Problems
Prolactin plays important roles in the skin. Both Prolactin-Receptor and Prolactin have been detected in human hair follicles and skin glands, and human Prolactin has been associated with skin pathologies such as psoriasis and alopecia (R).
In mice without prolactin receptors, however, the hair cycle is disrupted such that shedding occurred earlier and there was a reduced duration of the telogen phase (R).
Prolactin May Cause Cystic Fibrosis
Prolactin is one of the possible pathogenic factors in cystic fibrosis (R).
Prolactin Can Cause Anxiety and Depression
A byproduct of prolactin (vasoinhibins) causes depression and anxiety.
There is a correlation between prolactin and anxiety in men (R).
Prolactin levels in unipolar depressive patients are related to dissociative symptoms (R).
Prolactin controls these critical functions by regulating receptor potential thresholds, neuronal excitability and/or neurotransmission efficiency (R).
Prolactin May Worsen Migraines and Cause Pain
Prolactin Inhibits Blood Vessel Growth
Prolactin increases vasoinhibins, which are known for their inhibiting effects on blood vessel growth, vasopermeability, and vasodilation (R).
Disturbances of the prolactin/vasoinhibin axis are associated with the development of retinal diseases, cardiac diseases, and diseases occurring during pregnancy (R).
Prolactin Influences Cancer
Prolactin may increase breast and prostate tumors (R).
Prolactin Influences Electrolyte Balance
Prolactin is responsible for fluid, sodium, chloride, and calcium transport across intestinal epithelial membranes (R).
Prolactin acts on the kidney to promote sodium, potassium, and water retention (R).
The hormone stimulates the uptake of amino acids by the rat mammary gland (R).
Prolactin Is an Important Hormone During Sex
Prolactin provides the body with sexual gratification after sexual acts. The hormone counteracts the effect of dopamine, which is responsible for sexual arousal. This is thought to cause the sexual refractory period (R).
The amount of prolactin can be an indicator of the amount of sexual satisfaction and relaxation. Unusually high amounts are suspected to be responsible for impotence and loss of libido (R).
Prolactin levels have also been found to rise with use of the drug MDMA (Ecstasy) (R).
Main Functions of Prolactin
Primarily, prolactin is responsible for the stimulation of the biological actions of milk production (lactogenesis) and maintenance of milk production (galactopoiesis) (R).
However, prolactin has been shown to have more than 300 separate functions in various vertebrates. These can be divided into a number of areas such as osmoregulation, metabolism, reproductive behavior, and regulation of the immune, endocrine, reproductive, and central nervous systems (R).
Prolactin Creates Milk
Milk production and lactation occur after birth by allowing prolactin levels to remain elevated without inhibition while progesterone and estrogen undergo an abrupt drop as they are rapidly cleared from the body. Estradiol levels, rising throughout pregnancy, act at the hypothalamic level to increase prolactin secretion. It takes approximately seven days for prolactin to reach non-pregnant levels, while estrogen and progesterone elevations are cleared in three to four days after birth (R).
In the process of milk production, prolactin, along with cortisol and insulin, act together to stimulate transcription of the genes that encode milk proteins. Together, they stimulate the uptake of various amino acids, the synthesis of the milk proteins casein and α-lactalbumin, the uptake of glucose, and the synthesis of milk fats and the milk sugar lactose. Increased prolactin levels are required for lactogenesis; however, nonpregnant levels are sufficient to maintain lactation (R1,R2,R3).
In breastfeeding mothers, prolactin is mainly secreted in response to stimulation of the nipples and breast by a suckling infant. The neuronally mediated suckling stimulus blocks the secretion of hypothalamic dopamine (which normally inhibits prolactin) into the hypophyseal-portal circulation of the pituitary gland. This results in a sharp rise in prolactin concentrations in the blood, followed by a prompt fall when feeding stops (R).
The suckling activates mechanoreceptors in and around the nipple. These signals are carried by nerve fibers through the spinal cord to the hypothalamus, where changes in the electrical activity of neurons that regulate the pituitary gland increase prolactin secretion (R).
Bone mobilization is essential during lactation because of the large amount of calcium that is exported into milk. If the flux from the bone calcium pool were not stimulated during lactation, blood calcium would become unstable because of hysteresis in the normal calcium homeostasis pathways (R).
Prolactin Plays a Role in Mammary Development
Normal breast development depends on a combination of appropriate fat deposition, blood supply, and hormone interactions. Mammary development occurs at different times during a female’s life like during puberty and pregnancy (R).
Growth factors such as the insulin-like growth factor and epidermal growth factor have been reported to cause the production of mammary cells and may play a role in the effects of prolactins (R).
Prolactin is merely a player in an orchestra of hormones and growth factors that affect the mammary gland (R).
The major influence on breast growth during puberty is estrogen, which acts by the development of prolactin-dependent estrogen receptors. The primary effect of estrogen is to stimulate growth in the ductal parts of the breast (R).
Normal development requires prolactin, estrogen, progesterone, growth hormone, insulin, cortisol, thyroid and parathyroid hormone, and growth factors. All of these together result in a functional gland (R).
Cyclic changes in estrogen and progesterone during the menstrual cycle result in continued development of breast structures (R).
Production of the breast into its mature functional state occurs by the third month of pregnancy. The true alveoli develop under the influence of prolactin, human placental lactogen, estradiol, progesterone, insulin, cortisol, growth hormone, thyroid hormones, IGF-1, and EGF (R).
In addition, increased concentrations of prolactin in the blood during pregnancy cause enlargement of the mammary glands in order to prepare for milk production(R).
It is clear that these elevated levels of lactogenic hormones are required for the development of the mammary gland during pregnancy and for milk production during lactation (R).
Prolactin Influences Reproductive Behavior
Prolactin has been implicated in parental behavior ranging from nest fanning in fish to incubation and brooding behavior in birds, to lactation and maternal behavior in mammals. When viewed from an evolutionary context, it seems logical that the nurturing parental behavior actions of prolactin might have evolved in parallel with a nutrient synthesis and secretion role (R).
In humans, high prolactin levels are associated with psychosomatic reactions including pseudopregnancy. The best-characterized prolactin-driven behaviors are the parental behaviors. There are prolactin receptors in the ventromedial nucleus of the hypothalamus, an area which controls female sexual behavior (R).
Prolactin, by itself, does not initiate maternal behavior, but merely decreases the latency to the onset of maternal behavior. Production of prolactin-Receptor in the brain increases with age, exposure to estrogens, elevation in prolactin levels, and by pup contact (R).
When given in the third ventricle of estrogen and progesterone-primed rats without ovaries, prolactin diminishes sexual receptivity. When given in the midbrain of estradiol-treated rats, prolactin enhances sexual receptivity (R).
Elevation of prolactin secretion in response to the nursing stimulus diminishes sexual behavior (R).
Suppression of internal prolactin release prevents the onset of maternal behavior, whereas superimposition of prolactin promotes it (may be acting on medial preoptic area of the hypothalamus) (R).
Pup contact has been shown to induce transcription of prolactin-Receptors in the brain of female rats and this requires prolactin, estrogen and/or progesterone (R).
Prolactin may have a role in paternal care as well. The data for this role are most convincing in fish and birds but somewhat less convincing in mammals. This is emphasized by the significant stereotypical paternal role of non-mammalian vertebrates and the almost nonexistent role in most mammals (R).
In species where the male plays some role in the rearing of the offspring, including humans, studies have found an association between prolactin and paternal care. Paternal recognition of offspring is consistent among most species. Pup-contact by male rats can lead to some forms of parental care behavior. This is associated with an increase in prolactin in the blood, as well as increased production of the long form of the prolactin receptor in the brain (R).
Prolactin suppresses the stereotypical male sexual behavior in rats and sheep (R).
Fathers without prolactin fail to distinguish adult offspring from non-offspring, as a result of the failure of prolactin-induced neurogenesis in the subventricular zone and the dentate gyrus (R).
The most consistent stimulus for prolactin secretion in males is stress. At lower levels, prolactin contributes a range of functions in the male reproductive tract, revealed by subtle reproductive deficits in the prolactin receptor-deficient mice (R).
In addition, many of the metabolic and immune functions of prolactin can be observed in males, but whether prolactin levels are ever sufficient for these effects to be of physiological significance is uncertain (R).
Prolactin Contributes to Fetal Development
Prolactin stimulates the growth, development, and metabolism of the fetus. It alsostimulates the rapid increase of oligodendrocyte precursor cells which turn into the cells responsible for the formation of myelin coatings on axons in the central nervous system (R).
Prolactin promotes neurogenesis in maternal and fetal brains, immune tolerance of the fetus by the parent during pregnancy and contributes to the development of the fetal lungs (R).
Prolactin also plays a role in pregnancy maintenance and when there are unusual levels it is associated with spontaneous abortion (R).
Prolactin Acts as a Luteotropic Hormone
Since prolactin induces the corpus luteum of the ovary (the source of the female sex hormone progesterone) to produce progesterone, it also helps to sustain pregnancies. Progesterone is essential for the implantation of the fertilized ovum, maintenance of pregnancy, luteal cell enlargement, and inhibition of ovulation (R).
Prolactin enhances progesterone secretion in two ways: prolactin potentiates the steroidogenic effects of luteinizing hormone (LH) in granulosa-luteal cells, and it inhibits the 20α-hydroxysteroid dehydrogenase enzyme, which inactivates progesterone (R).
There is a directly proportional relationship between prolactin and progesterone during gestation, with the cause of sterility in prolactin gene knockout rodents being attributed to the absence of sufficient progesterone for implantation, decreased ovulation rate, the inadequate creation of ovum, and a lack of placental development and maintenance (R1,R2).
Prolactin Affects Multiple Other Hormones
Prolactin affects a large number of cytokine receptors (R).
Elevated levels of prolactin decrease the levels of estrogen in women and testosterone in men. The effects of altered levels of prolactin on sex hormones are much more profound in women, substantially increasing or decreasing estrogen levels (R).
Prolactin within the normal reference ranges can act as a weak gonadotropin (R).
High prolactin concentrations inhibit secretion of gonadotropin-releasing hormone(GnRH) from the hypothalamus, thereby decreasing the secretion of gonadotropins(luteinizing hormone and follicle-stimulating hormone), and may also inhibit the action of gonadotropins on the gonads. Thus, high prolactin concentrations during lactation reduce fertility, protecting lactating women from a premature pregnancy(R).
Women with pathologically elevated prolactin secretion (hyperprolactinemia) were found to have lower concentrations of hepcidin (a central regulator of human iron metabolism) compared to those with normal prolactin levels. The prolactin-reducing drug bromocriptine mesylate resulted in an elevated production of the hepcidin in hyperprolactinemia patients. These findings suggest that prolactin decreases hepcidin (R).
Prolactin indirectly leads to the release Parathyroid hormone-related peptide (PTHrP) is secreted in large quantities from the lactating mammary glands, causing bone resorption and other physiological effects. Prolactin is implicated in its regulation (R).
Structure of Prolactin
The body produces 3 different forms of prolactin: little, big, and big-big prolactin, respectively. These isoforms have molecular masses of about 14,000, 16,000, or 23,000 Daltons depending on the variation (R).
Studies indicate that 14 kDa prolactin makes up more than 50% of all prolactin production in the body. It’s most responsive to stimulation or suppression outside the pituitary gland (R).
The 16 kDa isoform of prolactin acts through a specific receptor and has inhibitory effects on blood vessel and tumor growth (R).
The largest isoform, 23 kDa prolactin, acts via its membrane PRL receptor (PRL-R). It’s a member of the hematopoietic cytokine superfamily (R).
Synthesis, Secretion, and Reception of Prolactin in the Body
Prolactin is synthesized from the prolactin gene.
Prolactin is primarily synthesized and secreted by the pituitary gland. These cells are where PRL is stored in small containers called vesicles. Prolactin is then released into the bloodstream by a process called exocytosis. It is secreted in response tostimuli such as eating, mating, ovulation, nursing, estrogen treatment, and some medications (R1,R2).
In addition, prolactin is found to be secreted from other areas of the body such as the uterus, placenta, immune cells, brain, breasts, prostate, skin, and fat tissue. Production of PRL outside of the pituitary gland is thought to be specific to humans and primates (R).
Prolactin is secreted in a pulse-like fashion with a pulse frequency ranging from about 9-14 pulses per 24 hours depending on the phase of the menstrual cycle. Secretion also follows a diurnal cycle, which means different amounts are found present depending on the time of day. Levels rise starting one hour after a person falls asleep until peak amounts are reached between 5:00 and 7:00 AM. The lowest levels occur during the midmorning after waking (R).
The hypothalamus controls the secretion of anterior pituitary hormones. These hypothalamic releasing factors mediate the neural control of pituitary secretions. However, one study noted that cutting the pituitary stalk did not stop lactation, leading to the conclusion that a hypothalamic prolactin-releasing factor was not the only thing necessary to stimulate prolactin secretion (R).
Prolactin receptors are present in the mammary glands, ovaries, pituitary glands, heart, lung, thymus, spleen, liver, pancreas, kidney, adrenal gland, uterus, skeletal muscle, skin and areas of the brain (R).
High Levels of Prolactin
Prolactin is found at low levels normally. The exception to the usually low levels of prolactin are pregnancy and lactation (R).
High levels of prolactin in a woman may be the cause of abnormal nipple discharge, difficulty getting pregnant, low estrogen levels, or not getting her period (R).
High prolactin causes a decrease in progesterone production (R).
A tumor in the epithelial cells of the gland (adenoma) is found in over one-third of women with high levels of prolactin. Patients can generally be reassured that the microadenoma is benign and rarely progresses to macroadenomas (R).
Symptoms of microadenomas include tiredness, headaches, nausea, dizziness, vision problems, menstrual or breast changes, and/or paralysis of the extraocular muscles that control the movements of the eye (R).
Macroadenoma symptoms are similar to microadenoma symptoms but more serious. They include severe headaches and dizziness, significant visual field changes, diabetes, and blindness (R).
Low Levels of Prolactin
Low prolactin is associated with ovarian dysfunction in women.
In men, it is associated with erectile dysfunction, premature ejaculation, low sperm count, reduced sperm motility, a decreased function of seminal vesicles, and hypoandrogenism. In one study on low prolactin in men, normal sperm function was restored when prolactin levels were raised back to their correct values (R).
- In humans, prolactin increased spermine and spermidine synthesis which are required for milk production. These polyamines stabilize membrane structures, increase transcriptional and translational activities, and increase enzyme amounts (R).
- Prolactin binding which activates the Jak2/STAT5 pathway responsible for both mammo- and lactogenesis (R).
- Induction of PTHrP by serotonin is mediated by 5-HT2B receptors, which are G-protein coupled (Gq/11) (R).
- In Nb2 lymphocytes, activation of the prolactin receptor is associated with rapid tyrosine phosphorylation of STAT5a, STAT5b, STAT1α, and STAT3, rapid and selective formation of STAT5a/b heterodimers, marked Ser (R).
Normal Levels of Prolactin
The upper threshold of normal prolactin is about 25 µg/L for women and 20 µg/L for men. Prolactin levels below 3 µg/L in women and 5 µg/L in men are considered too low. Prolactin levels may be checked as part of a sex hormone workup since elevatedprolactin secretion can suppress the secretion of other hormones like FSH, GnRH, and sex hormones (R).
Prolactin level blood tests are most accurate if conducted during the midmorning and not after stress, breast stimulation, physical examination, or other prolactin-increasing stimuli. In addition, elevated levels of prolactin should always be rechecked due to the variability of secretion and inaccurate test readings (R1,R2).
Normal Prolactin Levels in the Blood
|Nonpregnant women||4-23 nanograms per milliliter (ng/mL) or 4-23 micrograms per liter (mcg/L)|
|Men||3-15 ng/mL or 3-15 mcg/L|
|Pregnant women||34-386 ng/mL or 34-386 mcg/L|
|Children||3.2-20 ng/mL or 3.2-20 mcg/L|