Anterior pituitary consists of cells that can be classified based on their specific secretory products as somatotrophs (growth hormone [GH]-secreting cells), lactotrophs (prolactin [PRL]-secreting cells), thyrotrophs (cells secreting thyroid-stimulating hormone [thyrotropin; TSH]), corticotrophs (cells-secreting ACTH [corticotropin] and related peptides), and gonadotrophs (luteinizing hormone [LH]– and follicle-stimulating hormone [FSH]–secreting cells). During pregnancy, these hypothalamic-pituitary axes present the following physiological adaptations. 

Hypothalamic–Pituitary–Adrenal Axis

Corticotropin-releasing hormone (CRH) gets released from the paraventricular nucleus of the hypothalamus in response to stress. It stimulates the release of adrenocorticotropin hormone (ACTH) from the pituitary gland. Following that, ACTH stimulates the adrenal cortex to secrete cortisol into the bloodstream. During pregnancy, the maternal hypothalamic–pituitary–adrenal axis (HPA) activity increases, although the corticotroph number in the anterior pituitary remains stable. This activity leads to an increase in plasma adrenocorticotropic hormone (ACTH), cortisol (both free and protein-bound), free urinary cortisol, and corticosteroid-binding globulin (CBG). The majority of ACTH in plasma comes from the pituitary, although the placenta produces ACTH as well.[2] Pregnant women do not exhibit signs of hypercortisolism, despite the fact that plasma and free urinary cortisol concentrations are increased 2 to 3 times. Under the effect οf placental estrogen, the hepatic CBG production increases, leading to a temporary drop in free cortisol levels; this leads to increased ACTH stimulation to maintain adequate serum free cortisol levels.[3] This high total cortisol level could be harmful to the fetus if it were not protected by the enzyme 11-beta- hydroxysteroid dehydrogenase type 2. This enzyme is located in the syncytial trophoblastic cells and regulates the amount of maternal cortisol that reaches the fetus. In late gestation, the active form of cortisol is enzymatically favored because it is vital for fetal lung maturation. At 25 weeks of gestation, the saccular phase of lung development begins, during which adequate numbers of primitive alveoli and lamellar bodies appear. In this period, the administration of antenatal corticosteroids can lead to the maturation of the lungs and improved lung function. According to a recent retrospective study, the exposure to corticosteroids decreases the mortality of premature infants born at 22 to 23 weeks gestation.[4] The mechanism underlying the efficacy of corticosteroid medications to reduce the incidence of respiratory distress syndrome remains unclear.[4] However, it seems that they are not related to an increase of the surfactant production from type II alveolar cells or the structural lung development, as previously believed, but with an increased expression of epithelial sodium channels (ENaC).[4] At present, prenatal corticosteroid therapy is recommended in all pregnancies with threatened preterm birth before 34 weeks' gestation.[5] As the pregnancy progresses, the increasing concentrations of circulating cortisol downregulates CRH, so the HPA axis does not respond adequately to physiological and psychological stress, especially during late pregnancy.[6] Still, in case of inflammation and infections, higher levels of glucocorticoids get transferred from the mother to the fetus, because the maternal HPA axis and the HSD11B2 enzymatic activity can adjust to maternal stress levels.[6] The interaction between the mother and fetus is so intricate that during the third-trimester placental CRH appears to be the major determinant of the maternal HPA axis.

GH – Insulin-like Growth Factor-1 Axis  

GH mediates multiple anabolic effects on the body, particularly somatotrophic, lactogenic, and lipolytic, by interacting with a specific GH receptor (GHR). In pregnancy somatotroph, cells become reduced. However, maternal levels of insulin-like growth factor-1 (IGF-1) are slightly elevated. There are two origins of GH: placental and maternal. The syncytiotrophoblast produces placental GH. The pituitary somatotroph cells produce GH as well, and this is the main form in the maternal circulation from conception to 15 weeks of gestation. Between 15 and 17 weeks of gestation, the placental form almost entirely replaces it; this happens because placental GH binds to hepatic GH receptors and stimulates IGF-1 production, causing negative feedback to the pituitary GH production. Research suggests that placental GH induces maternal insulin resistance to ensure the adequacy of nutrients supply to the growing fetus. Moreover, there is blockage of the production of IGF-1 by maternal GH due to high levels of estrogen.[2][3]

Prolactin Axis 

The increase in PRL secretion is important for the development of breast tissue for lactation. Prolactin is the only anterior pituitary hormone that does not have an endocrine target tissue, so it is not under the regulation of classical hormonal feedback. Instead, there is short loop feedback, where prolactin stimulates the secretion of its own inhibitor, dopamine. The dopamine neurons are present in the arcuate nucleus of the hypothalamus. In pregnancy, the lactotroph cells' hyperplasia leads to the enlargement of the pituitary gland. Estrogen and progesterone both stimulate maternal PRL production. The majority of PRL derives from the maternal pituitary gland, while a contribution of the decidua and the fetal pituitary gland is small. Other factors which stimulate maternal pituitary PRL secretion, is thyrotropin-releasing hormone (TRH), arginine, meals, and sleep similar to what we expect in nonpregnant women.[7][3][2]

TRH–TSH Axis

Thyroid hormones are indispensable for the differentiation of most tissues during ontogenesis. They have a direct effect on brain development, somatic growth, bone maturation, and metabolic regulation. There are two sources of thyroid hormones: the developing fetal and maternal thyroid gland. Both of them require a sufficient amount of iodine intake.[8] Especially during the first half of pregnancy, before the fetal thyroid becomes able to produce its own hormones, maternal thyroxine (T4) is indispensable for the fetus. At 24–28 weeks of gestation, serum T4, and tri-iodothyronine (T3) begin to rise progressively, while the TSH concentration peaks.[9] This hormonal transfer occurs via the blood-placenta barrier by transthyretin. Placental deiodinases deactivate thyroxine, thereby regulating the amount of T4 entering the fetal circulation. Thyroid binding globulin (TBG) is a protein, which binds thyroid hormones, and its production increases from the presence of estrogen and corticosteroids. TBG concentration rises in pregnancy, due to the concurrent increase in estrogen production. It binds more thyroid hormones as the pregnancy progresses and reaches a plateau after 12 to 14 weeks of gestation. As a result, free thyroid hormones concentrations in the blood drop, stimulating TSH production. At the same time, the fetal hypothalamic-pituitary-thyroid axis develops, as reflected by an increase in fetal serum endogenous T4 levels. Thyroid hormone concentrations are adjusted to match the fetal developmental requirements and reflect in an increase in serum TBG.[3] TSH is chemically similar to human chorionic gonadotropin, which could bind the TSH-receptor, with a lower affinity. Since the serum concentrations of HCG markedly increase during the first six months of pregnancy, this may act as a negative feedback stimulus to the pituitary, resulting in decreased TSH levels.[9]

Gonadotropin Axis

During pregnancy, gonadotrophs decline in number, leading to a decline in maternal serum gonadotropins by 6 to 7 weeks of pregnancy.[9] These become undetectable during the second trimester. Also, FSH and LH do not respond to GnRH stimulation, and their synthesis becomes suppressed due to the high concentrations of sex-steroids (17-beta-estradiol and progesterone), as well as inhibin.[10]

Posterior Pituitary 

Vasopressinergic and oxytocic neurosecretory neurons are present in the supra-optic (SON) and paraventricular (PVN) nuclei of the hypothalamus. These neurons synthesize vasopressin (AVP) and oxytocin, which get stored in the posterior pituitary. AVP secretion maintains serum osmolarity within a tight range (284 to 295 mOsmol/kgH2O). The mean osmotic threshold of thirst is 281 mOsmol/kgH2O, whereas the threshold for of AVP release is 284 mOsmol/kgH2O. When plasma osmolality rises beyond these thresholds, it stimulates thirst, and AVP is released. The peripheral actions of vasopressin are the stimulation of renal water reabsorption (via V2 receptors) and vasoconstriction (via V1a receptors).[10]

Oxytocin, like vasopressin, is secreted in conditions of hyperosmolarity of the extracellular fluid and has peripheral natriuretic actions. These actions consist of direct effects in the kidney, as well as effects in the right atrium, aiming to stimulate atrial natriuretic peptide (ANP) secretion. During pregnancy, osmolarity becomes adjusted to a 10 mOsm/kg lower level. This decrease begins at the first missed menstrual period and gradually decreases until the tenth week of gestation. Serum sodium is decreased by about 4 to 5 mEq/ml as well. As a result, the osmotic threshold for AVP secretion becomes altered during pregnancy.[3] Moreover, circulating levels of ANP also get reduced. Also, the kidney is resistant to the natriuretic actions of ANP through increased phosphodiesterase-5 activity. During pregnancy, blood volume increases significantly, and plasma osmolality is reduced, due to mild hyponatremia despite the action of relaxin and an increase in salt appetite. Relaxin gets produced by corpora lutea and acts via the lamina terminalis when estrogen and progesterone concentrations reach the pregnancy levels. Relaxin stimulates vasopressin secretion and water intake, resulting in hypervolemia and hyponatremia. Consequently, with reduced ANP secretion and action, sodium is not excreted, and hypervolemia maintained.[11]

LACTATION

During pregnancy, although lactation practically does not happen, the increased serum concentrations of prolactin, placental lactogen, estrogen, and progesterone favor the development of the milk-secretory alveolar apparatus. The breast tissue in non-pregnant women has small, solid alveoli filled with a mass of granular tissue. During pregnancy, the final differentiation of the mammary gland takes place between 6 and 8 weeks of gestation. The breasts increase in size and volume, through the effects of progesterone, estrogen, insulin, prolactin, thyroid hormones, and multiple other growth factors.[12] The development of breast alveolar lobules includes two phases: mammogenesis and lactogenesis.[13] The period of mammogenesis requires the presence of pituitary hormones (PRL, GH) as well as estrogen, progesterone, and glucocorticoids.[13] PRL is essential for structural changes in the mammary gland and the expression of milk proteins. This state is evident with hypophysectomy, or pharmacological inhibition of PRL itself, or the PRL receptor leads to lactation suppression.[14]

Lactogenesis requires PRL and non-pituitary hormones (insulin, adrenal steroids) and is associated with further enlargement of the lobules as well as with synthesis of milk proteins. Moreover, PRL induces maternal behavior, stimulates food intake, potentiates oxytocin secretion, stimulates neurogenesis, suppresses stress responsiveness, and inhibits the hypothalamic-pituitary-ovarian axis.[13]  As far as mammogenesis is concerned, the mammary epithelial cells obtain secretory differentiation around mid-pregnancy. At first, mammary epithelial cells become able to produce and secrete milk, referred to as colostrum thanks to the expression of several milk protein genes, the production of lactose, and the accumulation of lipid droplets. In the middle of pregnancy, the proliferation of the alveolar epithelium ceases, since there is a decrease in the number of cell mitoses. Following this, the alveolar tissue begins to differentiate into a secretory epithelium, which is reflected by the increased numbers of Golgi apparatus and rough endoplasmic reticulum. Toward the end of gestation, the alveoli begin to fill up with amorphous material that consists of proteins, desquamated cells, and leukocytes. At late pregnancy, milk production is inhibited by high plasma concentration of progesterone and estrogen until parturition.[12] Inhibitory and stimulatory factors regulate the secretion of prolactin. The hypothalamic prolactin inhibitory factors (dopamine, g-aminobutyric acid [GABA] system) act along with the hypothalamic prolactin-releasing factors (thyrotropin, vascular intestinal peptide, angiotensin II). Other factors (oxytocin, serotonin, opioids, histamine, substance P, arginine-leucine) regulate prolactin release in an autocrine/paracrine manner. Dopamine binds to type-2 dopamine receptors (the predominant pituitary dopamine receptor), which are linked functionally to membrane channels and G-coupled proteins, which, in turn, suppress the high secretory activity of the pituitary lactotrophs. Thyroid hormones are necessary to secure the activity of prolactin.[12] In this way, the pituitary gland prepares the breast tissue in the process of secretory differentiation to achieve lactation. 

The involvement of the pituitary becomes significant in Sheehan syndrome, which is related to ischemic pituitary necrosis as a result of massive postpartum hemorrhage. The pituitary gland, during pregnancy, has increased volume because of the lactotroph hyperplasia. However, this enlargement takes place in the limited space of the sella turcica, and as a result, the pituitary gland is susceptible to ischemia. There are also suggestions that specific antibodies contribute to the pathogenesis of Sheehan syndrome. In these cases, the onset of symptoms takes place many years after postpartum hemorrhage.[15] Necrotic areas of the pituitary are organized to fibrous tissue, rendering the gland dysfunctional. This condition leads to a failure to lactate, disruption of the menstrual cycle, and rarely adrenocortical failure occurs. The symptoms may be evident immediately after labor (acute onset adrenal insufficiency, along with severe headache) or may delay. Therefore, clinical signs vary from an acute life-threatening situation to milder symptoms of chronic development of hypopituitarism.[16]