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Home , Anterior pituitary, Endocrine system, Hypothalamus, Oxytocin, Pars intermedia, Pituitary gland

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Clinical Practice Keywords /Pituitary // Systems of This article has been Endocrine system double-blind peer reviewed In this article... ● Endocrine functions of the hypothalamus ● Hormones of the anterior and posterior ● Role of pituitary gland hormones in mediating the actions of the hypothalamus

Endocrine system 2: hypothalamus and pituitary gland

Key points Authors Zubeyde Bayram-Weston is senior lecturer in biomedical science; Maria The hypothalamus Andrade is honorary lecturer in biomedical science; John Knight is associate and pituitary gland professor in biomedical science; all at College of and Health Sciences, both in the cranial Swansea University. cavity of the Abstract The endocrine system consists of and tissues that produce and Two major secrete hormones to regulate and coordinate vital bodily functions. This article, the hormones released second in an eight-part series on the endocrine system, explores the and by the posterior of the hypothalamus and pituitary gland, and how they work together to pituitary gland are regulate and coordinate vital physiological processes in the body through hormonal antidiuretic action. It shows how many of the actions initiated by the hypothalamus are mediated and through hormonal produced by the pituitary gland beneath it. Citation Bayram-Weston Z et al (2021) Endocrine system 2: hypothalamus and The gland. Nursing Times [online]; 117: 6, 49-53. pituitary gland produces several stimulating he first article in this eight-part system is well developed in all higher ver- hormones that series on the endocrine system tebrates and plays a key role in emotional regulate the activity gave an overview of the of responses, long-term , of of other endocrine Tendocrine glands and high- smell (olfaction) and the acquisition of glands lighted the role of hormones as chemical new skills, as well as contributing to a signals that help maintain the homeostatic range of behavioural responses (Wróbel, Although the balance essential to health; the remaining 2018). The hypothalamus is the location of pituitary gland is articles will each explore different major the thermoregulatory centre, which regu- often referred to as endocrine glands and tissues. This article lates body temperature (VanPutte et al, the master gland, examines the anatomy and physiology of 2017); it plays an essential role in bal- many of its actions the hypothalamus and pituitary gland, ance, regulation of pressure and the are directed by the which lie in the cranial cavity of the skull. sensations of and . hypothalamus This article focuses on the endocrine The hypothalamus functions of the hypothalamus and its role Clusters of The hypothalamus is located at the base of as the key link between the nervous and in the hypothalamus the just below the . A small endocrine systems. The hypothalamus is synthesise releasing but vital region of the brain, it is roughly connected directly to the pituitary gland and inhibiting the size of an and weighs around via a thin stalk, called the infundibulum hormones that 4g (Saper and Lowell, 2014). It accounts for (Fig 1). Many actions initiated by the hypo- regulate the activity <1% of the total brain mass but performs a thalamus are mediated through secretions of the anterior multitude of functions that are essential to produced by the pituitary gland beneath it. pituitary survival and the enjoyment of life. The hypothalamus is part of the limbic The pituitary gland system, a region of the brain that also The pituitary gland is a pea-sized gland includes the thalamus, , hip- that is typically around 0.8-1.0cm in diam- pocampus and cingulate gyrus. The limbic eter and weighs around 500mg. It resides

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Fig 1. Anatomy of the hypothalamus and pituitary gland by ADH acting as a powerful vasopressor (which promotes the constriction of blood vessels). ADH-induced vasoconstriction, Hypothalamus particularly in the peripheral (small ), further increases and nor- malises (Kanbay et al, 2019). As a result, ADH is also known as vaso- pressin, particularly in the United States. Reduced of ADH can lead to Optic chiasm insipidus (DI). Patients with DI Infundibulum cannot concentrate their , resulting in . Large volumes of urine (3-20L/ Anterior pituitary day) are usually produced; if not treated, Infundibular stalk this can lead to severe dehydration. Pars distalis Pars nervosa DI is rare, affecting around 1 in 25,000 people; two major types are recognised: l Neurogenic or central DI is caused by the undersecretion (hyposecretion) of ADH by the posterior pituitary. This is most often due to trauma (commonly in the (Turkish saddle), a pro- l Antidiuretic hormone (ADH); head injuries), tumours affecting the tective pocket in the sphenoid of the l Oxytocin. hypothalamus or pituitary or, more skull (Fig 1). Increased pituitary size is These hormones are synthesised in the rarely, infections; often indicative of endocrine pathologies, cell bodies of neurons in the hypothalamus l Nephrogenic DI is a rarer form, in particularly tumours of the pituitary (De and transported down the of the which patients usually have normal Sousa et al, 2015). The pituitary gland com- neurons running through the infundib- ADH synthesis and secretion, but their prises two regions (Fig 1): ulum. ADH and oxytocin are concentrated kidneys are insensitive to the effects of l Posterior pituitary (neurohypophysis) and stored in the pars nervosa (Fig 3), ADH – most commonly due to – neural extends from the before being released into the blood when disease or drug-induced kidney hypothalamus through the required. Both are hormones and, damage (Kalra et al, 2016). infundibulum into a larger, bulbous as they are produced by neurons, they are DI requires careful management. Ini- region called the pars nervosa; this often called . tially patients may be severely dehydrated, forms the bulk of the posterior pituitary; feel nauseous and shivery, and experience l Anterior pituitary (adenohypophysis) Antidiuretic hormone ; careful monitoring of water – derived from the epithelial tissue of ADH plays a vital role in regulating fluid intake and urine output, with ongoing the embryonic oral cavity. balance and blood pressure. Specialised assessment of urine and blood concentra- During embryonic development, the located in the hypothal- tion, is essential. Neurogenic DI is usually roof of the mouth bulges upwards (invagi- amus continually monitor the solute con- treated with , a synthetic nates) to form a tiny, bubble-like structure centration of the blood. When the body analogue of ADH that acts on the kidneys known as Rathke’s pouch, which then loses water (for example, through sweating in the same way to concentrate the urine fuses with the posterior portion of the during exercise or following vomiting and and increase blood volume. Treatment of pituitary gland (Fig 2). Failure of this pro- diarrhoea) dehydration may occur and the nephrogenic DI is more complex and cess to occur normally may lead to an plasma solute concentration rises. This is depends on the underlying cause of the abnormal pituitary structure or the forma- detected by the hypothalamic osmorecep- disease (The Pituitary Foundation, 2016). tion of cysts and clefts (Babu et al, 2013). tors, which initiate the release of ADH The anterior pituitary accounts for from the posterior pituitary. Oxytocin approximately 70-80% of the total mass of ADH primarily acts on the kidneys, Oxytocin is released into the blood at high the gland and includes two major parts: increasing the volume of fluid absorbed concentration towards the end of the l Pars distalis – larger, bulbous portion; from the renal filtrate back into the blood. l Pars tuberalis – highly vascular sheath This reduces the volume of urine produced Fig 2. Pituitary gland origins wrapped around the infundibular stalk. (hence the name antidiuretic hormone), Base of brain A third (intermediate) region of the pitu- resulting in the urine being darker and () itary gland is often recognisable; this is more highly concentrated. By increasing Rathke’s known as the pars intermedia and is usually fluid back into the blood, pouch present as a thin band of tissue that marks ADH helps normalise the solute concen- the point where the anterior and posterior tration of the blood (VanPutte et al, 2017). Roof of mouth pituitaries fuse (Ilahi and Ilahi, 2020). ADH is also released after a drop in (stomadeum) blood volume or pressure. By promoting Stalk Hormones of the posterior water reabsorption in the kidney, ADH Anterior Posterior pituitary increases blood volume, which then starts gland gland Two major hormones are released from the to increase blood pressure. This normalisa- Cleft

JENNIFER N. R. SMITH JENNIFER posterior pituitary: tion of blood pressure is further enhanced

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gestational period and initiates parturi- Fig 3. Hormones of the posterior and anterior pituitary tion () by stimulating contrac- Internal-externalna stimuli tions of the myometrium (muscular layer of the ). Oxytocin secretion is regu- Hypothalamus lated by a positive mechanism, whereby increased oxytocin stimulates Hormones feedback Neurosecretory cells to anterior lobe of more-powerful myometrial contractions, the pituitary gland which in turn stimulate the release of more and hypothalamus Hypothalamic-pituitary portal oxytocin (VanPutte et al, 2017). This is pos- Anterior lobe sible because the uterine wall has receptors of the pituitary Posterior lobe of that monitor the strength of myometrial gland the pituitary gland contractions and generate impulses stimulating hormone Kidney (action potentials) that are relayed back to Anti-diuretic hormone the hypothalamus. Adrenocorticotropic Oxytocin also stimulates the ‘letdown hormone Oxytocin Uterus reflex’ in lactating mothers; here the Thyroid smooth muscle linings of the milk ducts in gland Follicle stimulating hormone, luteinising Adrenal the contract, making milk available Thyroid hormone hormones cortex to the baby during suckling. Again, this is Follicle stimulating hormone, regulated by , with the luteinising hormone mechanical of the baby’s suck- (interstitial cell stimulating) Oestrogens ling action triggering the release of more Corpus luteum oxytocin (Osilla and Sharma, 2020). , skeletal Oxytocin is often referred to as ‘the Testis muscle & various hormone’ because it plays an important role in promoting mother/baby bonding; it is also thought to facilitate pair bonding Growth hormone although associated with reduced height, between partners. Evidence is also As its name suggests, the primary func- is characterised by normal bodily propor- emerging that oxytocin has other psycho- tion of GH is to promote bodily growth. tions. Recombinant human GH is avail- logical effects, such as reducing , Most famously, GH promotes the widening able to treat children who are deficient in and promoting maternal behaviour of the growth plates in the epiphyses of the GH. It is usually injected subcutaneously (Parmar and Malik, 2017). long bones of the skeleton, which results once a day, and growth rate and potential in elongation of the major bones of the side-effects then carefully monitored Hormones of the anterior pituitary arms and legs, progressively increasing (Rose et al, 2014). The anterior pituitary produces a far height. GH also enhances Elevated secretion of GH in childhood greater range of hormones than the poste- uptake from the blood into cells, often leads to , in which rapid rior pituitary. The anterior pituitary’s role increasing the rate of synthesis in growth of the long bones can result in an in producing a variety of stimulating hor- tissues such as muscle; this is why it is adult height of >2.4m. Elevated secretion of mones that regulate the activity of many known as an anabolic hormone. GH in adults, after their epiphyseal growth other endocrine glands is why the pitui- T3 and T4 (thy- plates have fused, can lead to , tary is often referred to as the ‘master roxine), which regulate , are in which the hands, feet and some facial gland’. As explained below, this is a mis- necessary for GH to exert its effects effi- features (particularly the lower jawbone) nomer: the release of these stimulating ciently. The anabolic effects of GH are also can grow abnormally large and usually out hormones is governed by hormones enhanced by the presence of other anabolic of normal proportion (de Herder, 2009). released from the hypothalamus, which hormones such as testosterone. As well as ultimately acts as the true primary orches- promoting bone and muscle growth, GH Prolactin trator of endocrine function. also stimulates the growth of many of the Prolactin (lactogenic hormone) initiates The anterior pituitary’s cells are usually major internal organs (Devesa et al, 2016). milk secretion () in breast tissue. By classified into five major types based on the GH secretion is regulated by two hor- itself, prolactin has only a weak effect, but nature of their secretions. These are listed mones produced by the hypothalamus: during prolactin levels increase below with their hormonal secretions: l Growth hormone-releasing hormone and it acts synergistically with other hor- l Somatotrophs – somatotropin or stimulates the release of GH; mones – including oestrogens, proges- growth hormone (GH); l Growth hormone-inhibiting hormone terone and – to promote the enlarge- l Lactotrophs – prolactin; (GHIH) acts antagonistically to inhibit ment and engorgement of the breasts in l Thyrotrophs – thyroid-stimulating the release of GH (Table 1). preparation for lactation (Suarez et al, 2015). hormone (TSH); Deficiency of GH during childhood It has been hypothesised that the release l Corticotropths – adrenocorticotropic may result in pituitary ; this is of prolactin is regulated and fine-tuned by hormone (ACTH) and melanocyte- characterised by below-average growth the antagonistic actions of a prolactin- stimulating hormone (MSH); and, commonly, an underdeveloped releasing hormone and a prolactin-inhib- l Gonadotrophs – follicle-stimulating bridge of the and prominent fore- iting hormone, both of which are thought hormone (FSH) and luteinising head. Unlike achondroplastic dwarfism (a to be produced by the hypothalamus

JENNIFER N. R. SMITH JENNIFER hormone (LH). genetic disorder), pituitary dwarfism, (Table 1).

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Table 1. Major hypothalamic releasing and inhibiting hormones

Hypothalamic hormone secreted Target anterior Anterior pituitary gland Physiological result pituitary cells secretion/release

Growth hormone-releasing hormone Somatotrophs Growth hormone Stimulates growth Growth hormone-inhibiting Somatotrophs Inhibits growth hormone Inhibits growth hormone secretion Prolactin-releasing hormone Lactotrophs Prolactin Thought to stimulate lactation (hypothetical) Prolactin-inhibiting hormone Lactotrophs Inhibits prolactin secretion Thought to inhibit lactation (hypothetical) Thyrotropin-releasing hormone Thyrotrophs Thyroid-stimulating Stimulates release of T3 and T4 (thyroxine), hormone thereby increasing metabolism Corticotropin-releasing hormone Corticotrophs Adrenocorticotropic Regulates glucocoticoids, hormone and secretion by the Gonadothropin-releasing hormone Gonadotrophs Luteinising hormone Stimulates /progesterone secretion in females and testosterone secretion in males Gonadothropin-releasing hormone Gonadotrophs Follicle-stimulating hormone Stimulates maturation of ovarian follicles in females and in males

Tropic hormones . It is referred to as a glucocorti- Melanocyte-stimulating hormone Tropic hormones have a stimulating effect coid because it is produced by the adrenal MSH is synthesised by the pars intermedia on other endocrine glands, inducing the cortex and influences the concentration of region of the pituitary gland. Although synthesis and secretion of the target in the blood (VanPutte et al, 2017). this region marks the boundary where the hormone(s). Four major tropic hormones Following periods of chronic anterior and posterior portions of the pitu- are synthesised and secreted by the ante- (including classic biological such itary gland fuse, it is generally considered rior pituitary, as described below. as starvation or physical injury), the hypo- part of the anterior pituitary. The pars thalamus releases corticotropin-releasing intermedia atrophies (shrinks) with age Thyroid-stimulating hormone (thyrotrophin) hormone. This initiates the release of and, in adults, may only be present as a TSH stimulates the thyroid gland to secrete ACTH from the anterior pituitary and, vestigial remnant or, in some cases, is not the iodine-containing hormones T3 and T4. subsequently, stimulates the release of cor- recognisable at all. MSH exists in a range of These are primarily responsible for regu- tisol from the adrenal cortex (Table 1). structurally similar forms known as mel- lating metabolism, with T3 being the more Cortisol plays a key role in regulating anocortins, which are all small . potent. Most cell types in the body have metabolism and, during periods of As implied by its name, MSH stimulates internal receptors for T3 and T4. These hor- deprivation, stimulates the breakdown of the pigment-producing cells (melanocytes) mones are also vital for growth and devel- protein and fat to generate glucose for use in the epidermis to release the dark pig- opment, and play key roles in the normal as fuel in glucose-dependent tissues, such ment known as melanin, which is largely functioning of the cardiovascular, respira- as the brain. This process is called glucone- responsible for colour. All races are tory, skeletal and central nervous systems. ogenesis (literally, the creation of new glu- thought to have similar numbers of mel- The release of TSH is regulated by thy- cose). Cortisol also influences the / anocytes in their epidermis; it is the rela- rotropin-releasing hormone, which is pro- wake cycle, mood and behaviour, and has tive activity of these cells and the amount duced by the hypothalamus (Table 1). The potent anti-inflammatory/immunosupres- of melanin they synthesise and release that fine tuning of T3 and T4 release is regu- sant properties (Kandhalu, 2013). ultimately determines skin colour. lated by , through the ACTH also helps to regulate the release Melanocytes can synthesise MSH when sequential secretions of the hypothal- of other hormones produced by the exposed to the ultraviolet (UV) light in amus, anterior pituitary and thyroid gland adrenal cortex, including sunlight (Tsatmali et al, 2002). This is (Fitzgerald and Bean, 2018). This hormonal (which regulates the concentration of essential to protect the actively dividing cascade is referred to as the hypothalamic- sodium and potassium in the blood) and cells of the epidermis from the harmful pituitary-thyroid (HPT) axis and will be the group of testosterone-like hormones effects of UV, known to cause DNA damage explored in detail in part 3 of this series. known as (Gallo-Payet, 2016). that can lead to and, potentially, The complex interplay between the hypo- skin . Melanin is excellent at Adrenocorticotrophic hormone thalamus, anterior pituitary and the absorbing UV wavelengths of light and, as (adrenocorticotropin) adrenal cortex is referred to as the HPT axis it accumulates in the epidermis the skin, ACTH primarily regulates the production and will be examined in detail in part 4 of darkens and develops a protective suntan. and secretion of cortisol from the adrenal this series. During pregnancy, levels of MSH tend cortex (outer portion of the ). ACTH is also part of the to increase, which, together with changes Cortisol is a long-term stress hormone and group of hormones, which influence skin to the hormones oestrogen and proges- a steroidal hormone synthesised from pigmentation (see below). terone, often leads to hyper-pigmentation

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around the eye sockets, cheekbones, of the (causing the deepening of the Costin G-E, Birlea S-A (2006) What is the mechanism for melasma that so commonly and forehead. This is known as melasma or voice) and spermatogenesis, and is largely accompanies human pregnancy? International ‘the mask of pregnancy’; these pigmented responsible for the male sex drive. Union of Biochemistry and Molecular Biology Life; areas usually fade gradually after child- The role of the and male 58: 1, 55-57. De Herder WW (2009) Acromegaly and (Costin and Birlea, 2006). and female sex hormones will be discussed gigantism in the medical literature. Case ACTH (described above) is another hor- further in part 7 of this series. descriptions in the era before and the early years mone that can influence skin pigmenta- after the initial publication of Pierre Marie (1886). Pituitary; 12: 3, 236-244. tion through the direct stimulation of mel- Role of the hypothalamus De Sousa SMC et al (2015) Pituitary : anocytes. This is particularly true of The pituitary gland is often referred to as case series and literature review of an under- recognised and heterogeneous condition. certain forms of Cushing’s syndrome, in the master gland but, in fact, it plays more , Diabetes and Metabolism Case which excess ACTH often causes regions of a ‘middle-management’ role; many of its Reports; 2015: 150017. of dark, hyperpigmented skin; this will be actions are directed by the hypothalamus. Devesa J et al (2016) Multiple effects of growth hormone in the body: is it really the hormone for discussed further in part 4 of this series. growth? Clinical Medicine Insights. Endocrinology Hypothalamic nuclei and and Diabetes; 9: 47-71. Fitzgerald SP, Bean NG (2018) Thyroid stimulating Gonadotropins hypothalamic-pituitary portal system hormone (TSH) autoregulation reduces variation in These act on the (testes and ova- The hypothalamus contains discrete, the TSH response to thyroid hormones. ries) to stimulate the production of sex organised clusters of neurons called the Temperature; 5: 4, 380-389. Gallo-Payet N (2016) Adrenal and extra-adrenal hormones and or ova in males and hypothalamic nuclei, which synthesise the functions of ACTH. Journal of Molecular females respectively (see below). The main hypothalamic releasing and inhibiting Endocrinology; 56: 4, T135-T156. gonadrotrophins are FSH and LH; the hormones that regulate the activity of the Ilahi S, Ilahi TB (2020) Anatomy, Adenohypophysis (Pars Anterior, Anterior Pituitary). StatPearls release of both is regulated by gonado- anterior pituitary. Both the hypothalamus Publishing. tropin-releasing hormone, which is pro- and pituitary gland are highly vascularised Kalra S et al (2016) : the other diabetes. Indian Journal of Endocrinology and duced by the hypothalamus (Table 1). and have a dedicated network of blood ves- Metabolism; 20: 1, 9-21. In females, each month FSH initiates sels called the hypothalamic-pituitary Kanbay M et al (2019) Antidiuretic hormone and the development of immature follicles in portal system, which ensures rapid and osmolarity physiology and related outcomes: what is old, what is new, and what is the . As each follicle enlarges, it efficient delivery of the releasing and unknown? Journal of Clinical Endocrinology and secretes the female oestrogen, inhibiting hormones from the hypothal- Metabolism; 104: 11, 5406-5420. before maturing into a Graafian follicle, a amus to the anterior pituitary below (Bear Kandhalu P (2013) Effects of cortisol on physical and psychological aspects of the body and fluid-filled, pressurised sac containing a et al, 2021). effective ways by which one can reduce stress. mature ovum (egg), primed and ready to Berkeley Scientific Journal; 18: 1, 14-16 Osilla EV, Sharma S (2020) Oxytocin. StatPearls rupture. Ovulation is triggered by LH, Release of hypothalamic hormones Publishing. which initiates rupturing of the follicle and Secretion of the hypothalamic releasing Parmar P, Malik S (2017) Oxytocin: the hormone ovarian wall; this explosive event propels and inhibiting hormones is determined by of love. International Organization of Scientific Research Journal of Pharmacy and Biological the ovum into its adjacent fallopian tube. multiple sensory inputs, which continu- Sciences; 12: 6, 1-9. Following ovulation, the remnants of the ally monitor the changing physiological Pereira Suarez AL et al (2015) Prolactin in inflammatory response. Advances in Experimental Graafian follicle collapse to form a structure status of the body. Multiple parameters Medicine and Biology; 846: 243-264. known as the (yellow body). monitored continuously and in real time The Pituitary Foundation (2016) Diabetes This produces the second major female sex include temperature, pH, solute concen- Insipidus. The Pituitary Foundation. Rose SR et al (2014) hormone, progesterone, which maintains trations and current levels of circulating guidelines: clinical and managed care perspectives. the integrity of the endometrial lining of hormones. The hypothalamus functions American Journal of Pharmacy Benefits; 6: 5, the uterus to allow for the implantation of a as the key bridge between the nervous and e134-e146. Saper CB, Lowell BB (2014) The hypothalamus. fertilised ovum (VanPutte et al, 2017). endocrine systems, but many of the inter- Current Biology; 24: 23, R1111-1116. Despite their names being reflective of actions between the two remain poorly Tsatmali M et al (2002) Melanocyte function and its control by melanocortin peptides. Journal of the role played in the female ovarian cycle, understood. Histochemistry and Cytochemistry; 50: 2, 125-133. FSH and LH also play crucial roles in male Table 1 summarises the key hormones of VanPutte CL et al (2017) Seeley’s Anatomy and reproductive physiology. FSH is essential the hypothalamus and pituitary, and their Physiology. McGraw-Hill. Wróbel G (2018) The structure of the brain and in stimulating spermatogenesis, where relationships. Some of the better-studied human behaviour. Pedagogy and Psychology of diploid cells (containing 46 ) interactions between the hypothalamus, Sport; 4: 1, 37-51. undergo meiotic division to produce vast pituitary and peripheral endocrine glands numbers of haploid spermatozoa (each (such as the HPT axis and hypothalamic- CLINICAL containing 23 chromosomes). pituitary-adrenal axis) will be explored SERIES Endocrine system FSH also stimulates the activity of Ser- later in this series. Part 3 focuses on the thy- Part 1: Overview of the endocrine system toli cells (‘nurse’ cells) in the testes; these roid and parathyroid glands. NT and hormones May provide nutrition to the developing sper- Part 2: Hypothalamus and pituitary gland Jun References matozoa, allowing maturation into viable Thyroid and parathyroid glands Jul Babu R et al (2013) Symptomatic Rathke’s cleft Part 3: gametes that are capable of fertilisation. cyst with a co-existing pituitary tumor; brief review Part 4: Adrenal glands Aug LH stimulates the interstitial cells (Leydig of the literature. Asian Journal of ; 8: Part 5: Pineal and glands Sep cells) of the testes to synthesise and release 4, 183-187. Part 6: , , , small Babu SR et al (2004) Evaluation of FSH, LH intestine Oct the male sex hormone testosterone (Babu and testosterone levels in different subgroups et al, 2004). This powerful of infertile males. Indian Journal of Clinical Part 7: Ovaries and testes, stimulates development, Biochemistry; 19: 1, 45-49. (pregnancy) Nov Bear MH et al (2021) , Part 8: Kidneys, and skin Dec growth of facial and , expansion Hypothalamus. StatPearls Publishing.

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