Hormones are crucial for the normal functioning of every cell, organ, and organ system—essentially the entire organism. They are chemical substances secreted into body fluids by specific cells or groups of cells that trigger a physiological response in the body. Thus, they act on so-called target cells. Hormones are released into the bloodstream by endocrine glands and then transported via the blood to specific cells or organs. they are continuously excreted through the kidneys or deactivated by the liver. Hormones support better reproduction by maintaining an optimal internal balance and triggering or adjusting the correct response based on the level of urgency. All of this is controlled by two organ systems: the neurological and the endocrine. In women, the regulation of reproductive hormones occurs through the hypothalamic-pituitary-ovarian axis, the functioning of which is shown in Figure 1 (Blackburn, 2007a).
Figure 1: Illustration of the hypothalamic-pituitary-ovarian axis (Blackburn, 2007a).
Ovarian function during a woman’s reproductive years is controlled by periodic reproductive neuroendocrinology, which depends on the complex interaction of the feedback system between the ovaries, the hypothalamus, and the anterior pituitary gland. The secretion of hypothalamic-pituitary hormones stimulates the secretion of ovarian steroid hormones and folliculogenesis. Gonadotropic hormones (follicle-stimulating hormone – FSH and luteinizing hormone – LH) and gonadal steroids (estrogen and progesterone) trigger follicle maturation, ovulation, and pregnancy. This means that a woman’s reproductive status depends on the proper functioning of the neuroendocrine system. During pregnancy, the activity of the hypothalamic-pituitary-ovarian axis is suppressed. Serum LH and FSH levels remain low for two weeks after birth in both breastfeeding and non-breastfeeding women. As the pituitary gland resumes its function, FSH and LH levels gradually rise 4 to 6 weeks after birth (Blackburn, 2007a).
The pituitary gland consists of two lobes: the anterior and the posterior. It is pear-shaped and about 15 mm in size. In women, it is slightly heavier than in men (Blackburn, 2007a). During pregnancy, it increases by about 50–70% as part of normal lactotrophic hyperplasia and, in rare cases, can develop into an adenoma. A so-called prolactinoma may occur, which continues to develop and grow in the pituitary gland and can cause various symptoms. Due to this, or a cyst or adenoma, there is an increased secretion of prolactin, which triggers lactation (Robson et al., 2014). Most hormones are secreted from the anterior lobe (growth hormone, FSH, LH, prolactin, adrenocorticotropin, thyroid-stimulating hormone). Only two hormones are secreted from the posterior lobe: oxytocin and antidiuretic hormone. Good communication between the pituitary gland, hypothalamus, and target glands or cells is essential for the proper physiological release of hormones. Hormones released by the hypothalamus can be relaxing–stimulating or inhibiting and control the secretion of hormones from the anterior pituitary gland (Blackburn, 2007a).
In addition to this hypothalamic-pituitary-ovarian axis, we must not forget two others that are extremely important for progress, development, and adaptation in a “normal” pregnancy. Furthermore, they are important for fetal growth and development and its adaptation to extrauterine life. These are the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-thyroid (HPT) axis. The hormones from these glandular connections play a significant role in growth, reproductive function, and the development of the central nervous system. Any malfunction can lead to complications in fertility, during pregnancy, and right at the start of puberty. During pregnancy, HPA axis activity increases significantly (Blackburn, 2007b). The opposite occurs during lactation, when HPA responsiveness decreases. Naturally, during this period, the axis’s activity is reduced due to the infant’s sucking. As is well known, sucking is a very powerful neuroendocrine stimulant that, in addition to promoting the secretion of prolactin and oxytocin, inhibits the release of gonadotropins. With sucking, the concentration of adrenocorticotropic hormone (ACTH) and cortisol rises sharply. The HPA response to the newborn’s sucking likely has a significant impact on the action of glucocorticoids on milk-producing cells and on metabolism by diverting energy flow toward milk production. Exposure to physical stress (cold, physical exertion, forced swimming, etc.) or emotional stress (social stress, noise, etc.) stimulates HPA activity less during breastfeeding. When a breastfeeding mother experiences an increase in oxytocin secretion after sucking begins, the secretion of ACTH and cortisol subsequently drops. It is known that in humans, systemic oxytocin inhibits ACTH secretion; however, it is not known whether it has the same effect on the anterior pituitary gland during breastfeeding (Brunton et al., 2008).
1 Progesterone
Progesterone plays an important role in maintaining pregnancy. Throughout the entire pregnancy, progesterone levels remain elevated. It is precisely because of this high concentration that lactation is prevented until the very end. The inhibitory effects of progesterone are very strong. A delay in the onset of lactation can also occur if a fragment of the placenta remains in the uterus after birth. Progesterone levels drop after birth and by the fourth day have fallen so much that the inhibitory effect completely disappears (Riordan, 2010).
2 Prolactin
The discovery of prolactin dates back to 1928 (Lawrence and Lawrence, 2011b). Chemically, it is similar to growth hormone (Constanzo, 2010), which is why until 1971 it was thought to be the same hormone (Lawrence and Lawrence, 2011b). It plays an important role in milk production and also participates in breast development. It is synthesized by lactotrophs, which make up about 15% of the anterior pituitary tissue. Since prolactin consumption increases during pregnancy and lactation, the number of lactotrophs increases (Constanzo, 2010). Lawrence and Lawrence (2011b) state that in addition to the anterior pituitary, it is also secreted by the brain. It is also thought to be produced in the hypothalamus, specifically in the hypothalamic portal vessels. The synthesis and secretion of prolactin are not limited solely to the anterior pituitary; several sites in the brain (hippocampus, spinal cord, cerebellum, amygdala) are also involved. It is also found in the cerebrospinal fluid (Lawrence and Lawrence, 2011b). During pregnancy, it is also produced by the amniotic fluid (Murray and Hassall, 2014). Lawrence and Lawrence (2011b) add to this its synthesis in the placenta, decidua, and the uterus itself. They also emphasize that for the proper functioning of lactogen during lactogenesis, good cooperation between the hormones of the pituitary, ovaries, thyroid, pancreas, and kidneys is crucial (Lawrence and Lawrence, 2011b).
There are two patterns of prolactin release regulation controlled by the hypothalamus. One is inhibitory—involving dopamine, which inhibits the production of cyclic adenosine monophosphate (cAMP)—and the other is stimulatory, involving thyrotropin-releasing hormone (TRH). In a non-pregnant or non-breastfeeding woman, secretion is inhibited by dopamine released by the hypothalamus. Dopamine is also known as prolactin inhibitory factor (PIF), the function of which is presented in more detail below. The inhibitory effect of dopamine is dominant and prevails over the stimulatory effect of TRH. Prolactin can trigger its own inhibition by increasing the synthesis and secretion of dopamine (Constanzo, 2010). Prolactin affects the tuberoinfundibular neurons that control dopamine release. In fact, the influence of prolactin increases the activity of these neurons (Lawrence and Lawrence, 2011b). This is a so-called negative feedback loop, as the stimulation of dopamine secretion causes the inhibition of prolactin secretion. Pregnancy and breastfeeding are considered the two most important stimulants for its secretion. As mentioned above, during pregnancy, its action is inhibited by progesterone. Factors that change or influence prolactin secretion include: pregnancy, breastfeeding, sleep, stress, TRH, and prolactin antagonists (Constanzo, 2010).
During pregnancy, prolactin levels rise intensely and are as much as 10 times higher at the time of birth than in a non-pregnant woman (Murray and Hassall, 2014). It begins to rise as early as the first trimester (Lawrence and Lawrence, 2011b). Riordan (2010) states that blood prolactin levels rise to 200 to 400 ng/ml at term, while in non-pregnant women, values fluctuate between 10 and 20 ng/ml. Prolactin, along with estrogen and progesterone, influences breast development, stimulates milk secretion, and inhibits ovulation (Constanzo, 2010). After birth, when estrogen and progesterone levels drop drastically, the inhibitory effect of these two hormones on the pituitary gland is broken. In the following 24 hours, mostly during sleep, the pituitary gland secretes prolactin seven to twenty times. The drop in human placental lactogen after the birth of the placenta also influences the rise in prolactin. Human placental lactogen and prolactin share the same receptors located in the breasts during pregnancy (Riordan, 2010). Regarding the drop in prolactin levels in non-breastfeeding mothers, we find various data in the literature. Blackburn (2007b) states that prolactin levels normalize within 7–14 days after birth. Riordan (2010) shortens this period to seven days, while Lawrence and Lawrence (2011b) cite a 14-day period. Blackburn (2007b) notes that prolactin levels also decrease after 6 weeks in women who breastfeed, while Riordan (2010) emphasizes that with regular breastfeeding, prolactin remains elevated for the next 6 months. Prolactin levels can double during sucking even after 6 months (Riordan, 2010). It is also important to note that prolactin levels vary depending on the mother’s exposure to psychosocial stress (Lawrence and Lawrence, 2011b).
Stimulation of the nipple leads to the release of milk. At the same time, the hypothalamus inhibits the release of dopamine, which has an inhibitory effect on prolactin. This means that it is precisely this drop in dopamine during nipple stimulation that causes a rise in prolactin and thus milk production. As Kent (2007) and Riordan (2010) state, prolactin levels double during sucking and reach a peak 45 minutes after the start of breastfeeding or sucking. Walshaw (2010) states that prolactin is only released into the bloodstream 30–40 minutes after breastfeeding begins. It is important to emphasize that the prolactin level does not affect the amount of milk once lactation is fully established (Kent, 2007).
Prolactin is also found in milk. The secretion of prolactin into the intra-alveolar space maintains and continues the lactation process itself. The concentration of prolactin is lower in milk than in blood (Riordan, 2010). The value is highest during the transitional milk phase, i.e., the third to tenth day (Walshaw, 2010). The prolactin level is the same in both breasts and is highest in the morning. The amount of prolactin in mature milk slowly decreases until breastfeeding ceases (Riordan, 2010). Lawrence and Lawrence (2011b) state that the prolactin found in milk participates in the maturation of the newborn’s immune and neuroendocrine systems.
3 Prolactin Inhibiting Factor and Dopamine
Prolactin inhibiting factor is a substance secreted by the hypothalamus. Most often, this is dopamine itself, but other substances, so-called dopamine agonists, can also be the cause of this action. These substances stimulate dopamine secretion and consequently inhibit prolactin. Meanwhile, dopamine antagonists have the opposite effect (Riordan, 2010). Lawrence and Lawrence (2011b) describe that this inhibiting factor from the hypothalamus actually inhibits prolactin secretion. They also point out that it is unusual for the release of prolactin, a pituitary hormone, to be inhibited by the hypothalamus. Dopaminergic impulses trigger the release of catecholamines from the hypothalamus into the bloodstream, which then control the action of the inhibiting factor (Lawrence and
Lawrence, 2011b). The effect of the factor is suppressed by nipple stimulation and regular removal of milk from the breasts (Riordan, 2010).
Medications and, of course, events that lead to a decrease in catecholamines (e.g., stress) also reduce the activity of the inhibitory factor. This results in a rise in prolactin. Such preparations include phenothiazines and reserpines (Lawrence and Lawrence, 2011b).
Dopamine is a hormone of the hypothalamus and is chemically a catecholamine. The largest source of dopamine is the dopaminergic nerves in the hypothalamus, which synthesize and secrete dopamine into the median eminence. From there, it is transported via the hypothalamic-pituitary portal vein to the anterior pituitary, where it inhibits prolactin release. Just like dopamine, its agonists, such as bromocriptine, also inhibit prolactin secretion (Constanzo, 2010). Thus, dopamine itself can act directly on the anterior pituitary and reduce prolactin secretion (Lawrence and Lawrence, 2011b). As stated by Love (2014) and Bromberg-Martin et al. (2010), dopamine plays an important role in controlling motivation. It is also important for learning what in the world is good and what is not, and significantly influences the choice of positive or negative actions (Bromberg-Martin et al., 2010). This means that dopamine plays an important role in our behavior and social conduct. Heise (2011) states that dopamine is the mediator that causes the occurrence of D-MER; more on this later.
4 Thyrotropin-Releasing Hormone
Thyrotropin-releasing hormone (TRH) has the opposite effect of dopamine. It is a powerful stimulator of prolactin secretion, meaning it influences the rise of prolactin. However, its physiological role is not entirely clear. Thyrotropin levels remain unchanged during breastfeeding. In the postpartum period, a dose of TRH would cause a significant rise in prolactin concentration. This rise would also be felt by non-breastfeeding women as a rush and release of milk from the breasts (Lawrence and Lawrence, 2011b).
5 Oxytocin
Olff et al. (2013) state that it is known as the love hormone because it was believed to eliminate fear and loneliness and help in partnerships and sexual life. The name comes from the Greek phrase “quick birth” (Grigor’eva and Golubeva, 2009). It is a hormone of the posterior pituitary lobe (Blackburn, 2007a). Chemically, it is a peptide. It has been proven that under normal circumstances, it is released from various areas of the brain, confirming that it is a neuromediator. Oxytocin that has been secreted into the bloodstream cannot re-enter the brain, as large amounts of this hormone cannot pass through the blood-brain barrier. The secretion of oxytocin at the peripheral level and within the brain occurs simultaneously, but the actual secretion does not happen at the exact same time. To clarify: an acute osmotic stimulus causes an immediate release of oxytocin into the blood, while the release in the brain is delayed by 30 minutes or more despite the stimulation (Leng et al., 2008). The main organs for metabolic processing and inactivation are the liver and kidneys. In the liver, 50% of oxytocin is metabolically processed and inactivated, and 40% in the kidneys (Grigor’eva and Golubeva, 2009).
Oxytocin is released daily due to pain, heat, cold, hypovolemia, exercise, etc. The influence of all these stimulators on oxytocin secretion decreases during breastfeeding (Lawrence and Lawrence, 2011b). As Grigor’eva and Golubeva (2009) state, the main feature of the posterior pituitary is that the hormones secreted there are actually synthesized in the hypothalamus. Milk synthesis is the result of a complex interplay between the hypothalamus, pituitary, and gonads. Since this connection is quite susceptible to emotional shocks, milk release can also be inhibited. A mother’s calmness during breastfeeding is partly conditioned by the release of oxytocin. Once lactation is established, the milk-ejection reflex can be triggered by the mere thought of the child (Riordan, 2010). This is also confirmed by Lawrence and Lawrence (2011c), who add that seeing, hearing, touching, and smelling the child can lead to the milk-ejection reflex. Oxytocin can therefore be released into the bloodstream not only by nipple stimulation but also through other sensory pathways such as: visual, auditory, tactile, and olfactory (Lawrence and Lawrence, 2011b).
The role of oxytocin in childbirth and breastfeeding is well known. In women, oxytocin stimulates the contraction of myometrial muscles during labor and, by acting on myoepithelial cells in the mammary glands, the release of milk during lactation (Grigor’eva and Golubeva, 2009). The milk-ejection reflex is the result of oxytocin release from the posterior pituitary, which occurs in response to the newborn’s sucking (Riordan, 2010). Oxytocin release occurs at the very beginning of nipple stimulation (Lawrence and Lawrence, 2011b). Oxytocin is released in pulsating waves and is transported to the breasts via the bloodstream. There, it binds to the receptors of myoepithelial cells, causing contraction and the expulsion of milk from the alveoli into the milk ducts. Women feel pressure and a kind of tingling sensation. They may also feel warmth during the milk-ejection reflex. During a single feeding, a woman whose lactation is already fully established will experience several individual milk-ejection reflexes (Riordan, 2010). As Lawrence and Lawrence (2011b) explain, once sucking is established, the oxytocin response is not sustained or constant but is temporary and occurs at intervals. Plasma oxytocin levels return to basal levels between individual milk release reflexes, even though sucking continues (Lawrence and Lawrence, 2011b). Oxytocin plays an important, if not the primary, role in the continuation of lactation. During sucking and nipple stimulation, oxytocin is released in separate pulses. Within one minute of nipple stimulation, there is an increase in blood oxytocin concentration. The blood level returns to normal six minutes after the stimulation stops. Such fluctuations occur with every feeding of the newborn (Riordan, 2010). Plasma oxytocin levels are the same in men, non-pregnant, and pregnant women. Interestingly, the same concentration of oxytocin is found in both sexes, but it does not affect the same physiological processes. During childbirth and breastfeeding, plasma levels rise. Prostaglandins significantly influence the uterus’s reaction to oxytocin (Grigor’eva and Golubeva, 2009).
Women who have given birth for the first time often report an increase in thirst during breastfeeding. Because of this, it is suspected that the rise in blood oxytocin concentration influences this sensation. Oxytocin pulsations are significantly lower in women who have had a cesarean section or are exposed to stress (Riordan, 2010).
Grigor’eva and Golubeva (2009) state that both physical and psychological stress lead to a decrease in oxytocin, which subsequently affects lactation itself. Stress is also important for prolactin release. The well-being and behavior of pregnant and breastfeeding women also depend on this hormone (Grigor’eva and Golubeva, 2009). It participates in the development and formation of a new role: that of a woman, specifically the role of a mother; it influences sexual behavior, the relationship with the partner, the bonding between mother and child, and the mother’s emotional well-being. In fact, it influences an individual’s behavior toward their entire environment (Gu et al., 2015; Love, 2014).
Source: Thesis “A woman’s experience and feelings during breastfeeding” (2016) by Teja Šircelj, under the mentorship of Lecturer Tita Stanek Zidarič, RN, MSc, IBCLC
Read more: Breast changes during breastfeeding and lactogenesis
