The Prolactin Family of Hormones as Regulators of Maternal Mood and Behavior

Transition into motherhood involves profound physiological and behavioral adaptations that ensure the healthy development of offspring while maintaining maternal health. Dynamic fluctuations in key hormones during pregnancy and lactation induce these maternal adaptations by acting on neural circuits in the brain. Amongst these hormonal changes, lactogenic hormones (e.g., prolactin and its pregnancy-specific homolog, placental lactogen) are important regulators of these processes, and their receptors are located in key brain regions controlling emotional behaviors and maternal responses. With pregnancy and lactation also being associated with a marked elevation in the risk of developing mood disorders, it is important to understand how hormones are normally regulating mood and behavior during this time. It seems likely that pathological changes in mood could result from aberrant expression of these hormone-induced behavioral responses. Maternal mental health problems during pregnancy and the postpartum period represent a major barrier in developing healthy mother-infant interactions which are crucial for the child's development. In this review, we will examine the role lactogenic hormones play in driving a range of specific maternal behaviors, including motivation, protectiveness, and mother-pup interactions. Understanding how these hormones collectively act in a mother's brain to promote nurturing behaviors toward offspring will ultimately assist in treatment development and contribute to safeguarding a successful pregnancy.

Maternal hypothyroidism in rats reduces placental lactogen, lowers insulin levels and causes glucose intolerance

Hypothyroidism increases incidence of gestational diabetes mellitus (GDM) but the mechanisms responsible are unknown. This study aimed to assess the pathophysiological mechanisms by which hypothyroidism leads to glucose intolerance in pregnancy. Hypothyroidism was induced in female Sprague-Dawley rats by adding methimazole (MMI) to drinking water at moderate (MOD, MMI at 0.005% w/v) and severe (SEV, MMI at 0.02% w/v) doses from one week prior to pregnancy and throughout gestation. A non-pregnant cohort received the same dose for the same duration but were not mated. On gestational day 16 (GD16), or non-pregnant day 16 (NP16), animals were subjected to an intraperitoneal glucose tolerance test. Tissues and blood samples were collected four days later. Hypothyroidism induced a diabetic-like phenotype by GD16 in pregnant females only. Pregnant MOD and SEV females had reduced fasting plasma insulin, less insulin following a glucose load and altered expression of genes involved in insulin signalling within skeletal muscle and adipose tissue. Hypothyroidism reduced rat placental lactogen concentrations, which was accompanied by reduced percentage beta-cell cross-sectional area (CSA) relative to total pancreas CSA, and a reduced number of large beta cell clusters in the SEV hypothyroid group. Plasma triglycerides and free fatty acids were reduced due to hypothyroidism in pregnant rats, as was the expression of genes that regulate lipid homeostasis. Hypothyroidism in pregnant rats results in a diabetic-like phenotype that is likely mediated by impaired beta cell expansion in pregnancy. This pregnancy specific phenomenon is likely due to reduced placental lactogen secretion.

Prolactin-Induced Adaptation in Glucose Homeostasis in Mouse Pregnancy Is Mediated by the Pancreas and Not in the Forebrain

Adaptive changes in glucose homeostasis during pregnancy require proliferation of insulin-secreting beta-cells in the pancreas, together with increased sensitivity for glucose-stimulated insulin secretion. Increased concentrations of maternal prolactin/placental lactogen contribute to these changes, but the site of action remains uncertain. Use of Cre-lox technology has generated pancreas-specific prolactin receptor (Prlr) knockouts that demonstrate the development of a gestational diabetic like state. However, many Cre-lines for the pancreas also express Cre in the hypothalamus and prolactin could act centrally to modulate glucose homeostasis. The aim of the current study was to examine the relative contribution of prolactin action in the pancreas and brain to these pregnancy-induced adaptations in glucose regulation. Deletion of prolactin receptor (Prlr) from the pancreas using Pdx-cre or Rip-cre led to impaired glucose tolerance and increased non-fasting blood glucose levels during pregnancy. Prlrlox/lox/Pdx-Cre mice also had impaired glucose-stimulated insulin secretion and attenuated pregnancy-induced increase in beta-cell fraction. Varying degrees of Prlr recombination in the hypothalamus with these Cre lines left open the possibility that central actions of prolactin could contribute to the pregnancy-induced changes in glucose homeostasis. Targeted deletion of Prlr specifically from the forebrain, including areas of expression induced by Pdx-Cre and Rip-cre, had no effect on pregnancy-induced adaptations in glucose homeostasis. These data emphasize the pancreas as the direct target of prolactin/placental lactogen action in driving adaptive changes in glucose homeostasis during pregnancy.

Case-Control study of prolactin and placental lactogen in SGA pregnancies

Prolactin and placental lactogens increase during pregnancy and are involved with many aspects of maternal metabolic adaptation to pregnancy, likely to impact on fetal growth. The aim of this study was to determine whether maternal plasma prolactin or placental lactogen concentrations at twenty weeks of gestation were associated with later birth of small-for-gestational-age babies (SGA). In a nested case-control study, prolactin and placental lactogen in plasma samples obtained at 20 weeks of gestation were compared between 40 women who gave birth to SGA babies, and 40 women with uncomplicated pregnancies and size appropriate-for-gestation-age (AGA) babies. Samples were collected as part of the “Screening of Pregnancy Endpoints” (SCOPE) prospective cohort study. SGA was defined as birthweight < 10th customised birthweight centile (adjusted for maternal weight, height, ethnicity, parity, infant sex and gestation age) in mothers who remained normotensive. No significant differences were observed in concentrations of prolactin or placental lactogen from women who gave birth to SGA babies compared with women with uncomplicated pregnancies. However, a sex specific association was observed in SGA pregnancies, whereby lower maternal prolactin concentration at twenty weeks of gestation was observed in SGA pregnancies that were carrying a male fetus (132.0  46.7 ng/ml vs 103.5  38.3 ng/ml, mean ± SD, p=0.036 Student’s t-test) compared to control pregnancies carrying a female fetus. Despite the implications of these lactogenic hormones in maternal metabolism, single measurements of either prolactin or placental lactogen at 20 weeks of gestation are unlikely to be useful biomarkers for SGA pregnancies.

STUDY OF THE INFLUENCE OF HORMONAL FUNCTION IMPAIREMENT OF THE PLACENTA ON THE STATE OF FETUS AND NEWBORN IN WOMEN WITH NODULAR GOITER

The thyroid gland pathology is one of the most common in the world and is on the samelevel with diabetes mellitus and diseases of the cardiovascular system in its importance.Extragenital pathology, in particular, nodular goiter in pregnant women acts as anadditional stress factor that can negatively affect hormonal relationships in the motherplacenta-fetus system and contribute to an increase in the frequency of complications ofpregnancy, childbirth, and impairment of the fetus and newborn condition.The aim of this work – to study the disturbance effect in the hormonal function of theplacenta on the condition of the fetus and newborn from women with nodular goiter.Material and methods. The analysis of the state of the fetus and newborn of 20 apparentlyhealthy women (control group) and 54 women with nodular goiter (main group). Of these,30 newborns from women with grade I nodular goiter were included into group I, and24 newborns from women with grade II nodular goiter were included into group II. Theintrauterine fetus state was judged about according to the data of cardiotocography, fetalbiophysical profile (FBP), ultrasound examination, and Doppler results. The functionalstate of the fetoplacental complex was assessed by determining the serum concentrationof estradiol (Е2), estriol Е3), progesterone, placental lactogen, as well as the results ofhistological examination of the placentas.Results. The study of the placenta hormonal function, the results of ultrasound diagnosticsand histological examination of the placentas indicate the presence of placentaldysfunction in pregnant women with nodular goiter, that affected the condition of thefetus and newborn. Thus, the cardiotocographic index in fetuses from pregnant women,suffering from nodular goiter, is significantly less than in healthy pregnant women(p<0.05). The average PPI score in women with nodular goiter is also significantly lowerthan in the control group (p<0.05). Doppler data indicate a change in the parameters of the maternal hemodynamics, that led to a violation of the uteroplacental blood flow, thedevelopment of fetal hypoxia.Conclusions. The presence of nodular goiter in the mother is a risk factor for placentaldysfunction. Starting from the second trimester of pregnancy, there are significant changesin the content of placental hormones in the blood. A decrease in the concentration ofprogesterone in the blood serum in pregnant women with nodular goiter, in the latestages of pregnancy, can serve as a marker of the threat of termination of pregnancyand premature birth. A decrease in the content of estradiol and placental lactogen inthe maternal blood serum can be used as a marker of fetal distress in pregnant womenwith nodular goiter. The condition of the fetus and newborn is in direct proportion to thedegree of manifestation of the nodular goiter and the functional state of the placenta.

Changes in the level of fetoplacental complex hormones in pregnant women with miscarriage

The purpose of the study was TO analyze the fetoplacental complex hormone levels and changes in their dynamics in pregnant women with miscarriage and the impact of these features on the subsequent course of pregnancy. Hormone levels were determined at different stages of gestation in 50 healthy women with a physiological course of pregnancy (control group) and 50 pregnant women with a history of miscarriage (main group). The women of the main group had a significantly slower rate of increase in hormones and a lag in quantitative indicators than the control group. The estradiol level indicators were 4.1 times (76.0%) and 2.89 times (65.5%) lower in women with miscarriage in the embryonic and late fetal period, respectively, compared to healthy women. Indicators of the level of placental lactogen and chorionic gonadotropin in the embryonic period in women with miscarriage were lower by 39.1% and 50.9%, respectively, compared to healthy women. In the late fetal period, the level of these hormones was lower by 72.9% and 35.4%, respectively. In the embryonic and late fetal periods, progesterone levels were lower by 67.4% and 68.4%, respectively, compared to the control group. The data obtained are evidence of a pronounced hormonal abnormality of the placenta, and hence a marker of fetoplacental dysfunction, which on the background of miscarriage develops at the early stages and continues to progress with the course of pregnancy.

Unique Aspects of Human Placentation

Human placentation differs from that of other mammals. A suite of characteristics is shared with haplorrhine primates, including early development of the embryonic membranes and placental hormones such as chorionic gonadotrophin and placental lactogen. A comparable architecture of the intervillous space is found only in Old World monkeys and apes. The routes of trophoblast invasion and the precise role of extravillous trophoblast in uterine artery transformation is similar in chimpanzee and gorilla. Extended parental care is shared with the great apes, and though human babies are rather helpless at birth, they are well developed (precocial) in other respects. Primates and rodents last shared a common ancestor in the Cretaceous period, and their placentation has evolved independently for some 80 million years. This is reflected in many aspects of their placentation. Some apparent resemblances such as interstitial implantation and placental lactogens are the result of convergent evolution. For rodent models such as the mouse, the differences are compounded by short gestations leading to the delivery of poorly developed (altricial) young.

Features of the functional state of the fetoplacental complex in pregnant women with a history of sexually transmitted infections

The objective: a study of the features for the formation and functioning of the fetoplacental complex in pregnant women with a history of sexually transmitted infections.Materials and methods. We examined 50 pregnant women with a history of sexually transmitted infections (I group – the main group). The control group consisted of 30 pregnant women without somatic and gynecological pathology, who had vaginal delivery. All pregnant women underwent a comprehensive clinical examination, taking into account complaints, medical history, objective and additional methods of examination. The levels of estriol, cortisol, placental lactogen and progesterone in the blood serum of pregnant women and the state of fetoplacental complex in terms of 18–20th, 28–30th and 38–40th weeks were determined.Results. In the pregnant women in I group, starting from the 18th weeks there was a significant decrease in the secretion of progesterone (160,8±15,9 nmol/L versus 202,4±5,5 nmol/L, respectively; p<0,05), placental lactogen (77,5±13,2 nmol/L versus 91,3±23,8 nmol/L)/ This means that already in these stages of pregnancy there are signs of placental dysfunction in pregnant women with a history of sexually transmitted infections. The changes in the functional state of the fetoplacental complex at the 28–30th weeks are more pronounced, as evidenced by an increase in the frequency of early intrauterine growth restriction (12.0 %), disorders of fetal breathing (11.0 %) and fetal movements (18.0 %) (according to the biophysical profile score assessment); premature of the placenta, increased hormonal insufficiency of the fetoplacental complex and the first signs of hemodynamic disorders (an increased blood flow in the umbilical artery and uterine arteries and a slight decrease in blood circulation in the middle cerebral artery of the fetus). At the final assessment of the condition of the fetoplacental complex at the 38–40th weeks in pregnant women with a history of sexually transmitted infections, a satisfactory condition was observed in 24 % of cases, compensated ultrasound changes occurred in 46.0 % of cases; subcompensated – in 20.0 % and decompensated – in 10.0 % of cases, respectively, which causes a high frequency of obstetric and perinatal complications in this group of pregnant women.Conclusions. The formation and functional state of the fetoplacental complex in pregnant women with a history of sexually transmitted infections, from early pregnancy is characterized by a significant level of functional disorders of the fetus, placenta and the amount of amniotic fluid on the background of pronounced hemodynamic and endocrinological disorders, which requires prevention in the pre-pregnancy period.

A Case of Improvement of Insulinoma Symptoms in Pregnancy

Background: Insulinomas are rare tumors with an incidence of approximately 4 cases per million person per year. Only 39 cases of pancreatic neuroendocrine tumors have been reported in pregnancy. We report a case of pregnancy protecting the mother from manifesting the symptoms of insulinoma. Clinical Case: This case describes a 25-year old female who initially noticed symptoms of generalized weakness and oral tingling sensation in Fall 2018. She became pregnant in March 2019. She noticed an immediate reduction of the intensity of her symptoms during pregnancy. Her pregnancy was uneventful, and she delivered a healthy newborn in November 2019. Two months postpartum, she had worsening symptoms including syncopal episodes, confusion, difficulty ambulating and visual changes that improved with PO intake specifically carbohydrate intake. She was evaluated in March 2020 and labs showed the following: venous glucose 32 mg/dL, C-peptide 1.7 nmol/L, BOHB 0.4 mmol/L, Insulin 6.1 microU/ml, Proinsulin 25.8 pmol/L, IGF-2 354 ng/mL, negative insulin antibodies and negative oral hypoglycemic agent screen. TSH was unremarkable and AM cortisol was 16.1 mcg/dL. She was started on diazoxide twice a day. She underwent MRI of abdomen, which was negative followed by an EUS which was also negative. She had run out of her diazoxide and became severely symptomatic resulting in an ER visit where she was found to be hypoglycemic. Further evaluation was done with a Triple Phase spiral CT which showed a 1 cm arterial enhancing focal lesion within the pancreatic neck compatible with insulinoma. This was further evaluated with EUS FNA which confirmed the diagnosis of insulinoma on pathology. Her chromogranin A was 46.5 ng/mL. She is scheduled for surgical removal of the lesion. Conclusion: Pregnancy leads to an increased insulin resistance through hormonal changes with increased expression of placental growth hormone, human placental lactogen and the placental variant of corticotrophin-releasing hormone (via ACTH and cortisol production), TNF-alpha and leptin. These changes that increase the insulin resistance act as a protective mechanism against the detrimental effects of an insulinoma. Pregnancy most likely also delayed the diagnosis of the insulinoma in this patient. Further research is warranted to evaluate the effects of an insulinoma on the mother and fetus. References: 1) Lowy AJ, Chisholm DJ. Insulinoma masked by pregnancy. Intern Med J. 2001 Mar;31(2):128-9. doi: 10.1046/j.1445-5994.2001.00017.x. PMID: 11480477.