Luteinizing Hormone and Follicle-Stimulating Hormone Secretion in the Fetus and Newborn Infant

Hypothalamus

The hypothalamus ( Table 142.1 ) develops from the primitive forebrain (prosencephalon). By approximately the fifth week after conception, the forebrain differentiates into the cerebral hemispheres and the diencephalon; the ventral aspect of the diencephalon then develops into the hypothalamus. By 14 to 16 weeks gestation, hypothalamic nuclei and fiber tracts become differentiated.

GnRH, the major secretagogue of pituitary LH and FSH, is a decapeptide released by specific neurosecretory cells in the hypothalamus and is carried by portal circulation to the pituitary. The hypothalamic content of GnRH has been reported to rise during the first half of gestation and GnRH has generally been reported to be similar in male and female fetuses, with some exceptions. Little is known about the early postnatal development of hypothalamic GnRH in humans, although an increase in immunoreactive GnRH neurons in the hypothalamuses of human neonates compared with those of late-gestation fetuses has been seen. The GNRH gene is expressed in the hypothalamus during early stages of development. GnRH has been detected by radioimmunoassay as early as 4.5 weeks gestation. GnRH has been identified within the hypothalamus by 8 to 13 weeks gestation ^{, ,} and by 16 weeks gestation, GnRH-containing neurons are known to terminate on portal vessels.

As indicated above, GnRH neurons originate in the embryonic olfactory placode as early as 4.5 weeks gestation and undergo a unique pattern of axophilic migration across the terminal nerve to their ultimate location in the hypothalamus by mid-gestation. Then they extend axonal processes into the median eminence to establish neurovascular connections.

GnRH neuronal migration is complex and is influenced by many genes, proteins, and nuclear transcription factors (summarized in Table 142.2 ), and is essential for cell survival, growth, and differentiation. The chemical guidance for axonal routing and GnRH neuron migration is provided by axonal guidance molecules, extracellular matrix proteins, growth factors, and neurotransmitters. The molecular pathways involved in GnRH cell migration include the Rho GTPase family, phosphatidylinositol 3-kinase, mitogen-activated protein kinase, and the Ras family. For a detailed review of this process, the reader is referred to the articles by Tobet and colleagues, Gonzalez-Martinez and colleagues, and Wierman and colleagues. Studies on human GnRH cells in long-term cell cultures have shown that GnRH can also modulate the differentiation and migration of GnRH-secreting neurons in an autocrine fashion. Various genes that have been implicated in GnRH neuronal migration include the Kallmann syndrome gene (ANOS1) located on Xp22.3, KAL2 (which encodes fibroblast growth factor receptor 1 [FGFR-1]), and the G protein–coupled receptor 54 gene (GPR54) , also (KISS1R) .

The KAL1 gene and its product, anosmin, are implicated in the X-linked form of Kallmann syndrome, whereas FGFR-1 is implicated in autosomal dominant hypothalamic hypogonadism seen in males and females. ^, FGFR-1 is a member of the receptor tyrosine kinase superfamily, and it regulates cell proliferation, migration, differentiation, and survival. Hence, mutations in FGFR1 are associated with other congenital malformations in addition to hypogonadotropic hypogonadism and may explain some forms of Kallmann syndrome that are not associated with anosmia. KISS1R and its ligand kisspeptin have been described as major neuromodulators of the gonadotropic axis.

Recently, a variety of strategies including high throughput genome and exome sequencing, functional phenotyping and genetic association studies using large cohorts of patients have resulted in identification of a number of genes regulating GnRH neuronal migration, synthesis, and release. Moreover, these studies have also identified that defects in GnRH regulation can result from multiple mutations in the same patient and manifest as diverse phenotypes. ^,

Complex molecular mechanisms are responsible for tissue-specific transcriptional activity of the GNRH gene. The human GnRH-encoding gene (GnRH-I) , located on 8p21-p11.2 and comprising three exons encoding a protein of 92 amino acids, ^, is the form found in hypothalamic neurons and regulates pituitary gonadotropins. A second gene, GnRH-II , encodes a decapeptide neurotransmitter in the midbrain. Other GnRH-encoding genes have been described in mammals and nonmammalian vertebrates. The GnRH-I gene is thought to be targeted to hypothalamic neurons by enhancer and promoter elements acting in concert with the transcription factors Otx2, Brn-2, and Oct-1 ^, and the pituitary octamer unc (POU) domain of the transcription factors SCIP, Pct-6, and Tst-1. A variety of hormones and second messengers also influence GNRH gene expression. Nuclear receptors DAX-1 (dosage sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) and splicing factor 1 (SF-1) have been shown to be important for the proper development and function of the entire hypothalamic-pituitary-gonadal (HPG) axis. ^,

Pituitary

The pituitary gland arises from ectoderm, with the adenohypophysis (anterior pituitary) originating from oral ectoderm and the neurohypophysis (posterior pituitary) deriving from the neuroectoderm. Pituitary development starts on embryonic day 8.5 in the mouse. In humans, terminal differentiation of cells is completed in the first trimester. Pituitary development has been identified in the human fetus by the third week of pregnancy, with Rathke pouch, the precursor of the anterior pituitary, developing as an evagination of the primitive stomodeum in the fourth week of gestation, with subsequent separation from the stomodeum by the fifth week of gestation. The floor of the sella turcica forms by the seventh week of gestation, and, by the eighth week, the connection of the pouch with the oral cavity fully disappears.

The anterior pituitary is populated in a temporally and spatially specific fashion by the corticotrophs (which secrete adrenocorticotropic hormone), the somatotrophs (which secrete growth hormone), the lactotrophs (which secrete prolactin), the thyrotrophs (which secrete TSH), and the gonadotrophs (which secrete LH and FSH). ^{, ,} Two important principles that have emerged from ongoing studies are (1) the differentiation of specific cell types in the pituitary follows a highly ordered sequence, and (2) the coordinated expression and down-regulation of homeodomain transcription factors plays a critical role in controlling the differentiation. ^{, ,} For example, rodent studies indicate that differentiation of all cell types requires transient expression of HESX homeobox 1 (HESX1) and paired-like homeodomain 1 (PITX1) , but then, on approximately embryonic day 10, the cells divide into LIM homeobox 3 (Lhx3)-dependent and Lhx3-independent lineages ( Fig. 142.1 ).

The main population of corticotrophs is Lhx3 independent and appears by embryonic day 12 or 13; the other cell lineages appear to be Lhx3 dependent. Under the influence of PROP paired-like homeobox 1 (PROP1) , the LHX3-dependent lineage further bifurcates into POU class 1 homeobox 1 (POUF1)-dependent and POUF1-independent pathways. The POUF1-dependent pathway leads to the differentiation of somatotrophs, lactotrophs, and thyrotrophs by embryonic day 16. The POUF1-independent pathway, under the influence of other factors, including SF-1, leads to differentiation of the gonadotrophs by embryonic day 17. In addition to intrinsic pituitary factors, there is evidence that, at distinct developmental stages, inductive processes from adjacent tissue are also important for proper cell differentiation and expansion of pituitary cell lineages. In animal models, other signaling molecules, such as GNRH2, activin A receptor type 2A (ACVR2) , bone morphogenetic protein 4 ( BMP4 ), fibroblast growth factor (FGF), Wnt gene family (Wnt), and Sonic hedgehog (SHH) , have been found to be critical for pituitary development. Of note, Insm1 has been shown to be required for differentiation of all endocrine cells in the pituitary gland, and mutation of this gene leads to a normal-sized anterior pituitary without the ability for hormone production. Detailed discussion of this topic is available in the articles by Cohen and Radovick, Zhu and colleagues, and Quentien and colleagues. Recent studies with human patients and genetically modified mouse models have identified putative pituitary stem cells/progenitors that give rise to multiple hormone-producing cell types. Two master regulators known as Sox2 and Prop1 orchestrate these developmentally regulated cell fate decisions. The importance of these basic components of pituitary development to human physiology is emphasized by identification of corresponding human mutations that cause predictable pituitary cell phenotypes. ^,

The fetal pituitary secretes LH and FSH in culture at 5 to 7 weeks of gestation. ^, LH and FSH have been detected in the pituitary as early as 9.5 to 11 weeks of gestation. The pituitary content of LH and FSH then rises sharply, with pituitary LH and FSH content peaking at 25 to 29 weeks of gestation in female fetuses and at 35 to 40 weeks of gestation in male fetuses. The pituitary content of LH and FSH is higher in female fetuses than in male fetuses between approximately 10 and 25 weeks of gestation. ^, This sexual dimorphism may reflect testosterone production by the male fetus, with resulting inhibition of pituitary gonadotropin production during early pituitary development.

Early in gestation, the predominant pituitary glycoprotein fraction is the common α-glycoprotein hormone subunit. ^{, ,} As gestation progresses, the relative amount of the β-subunit and intact gonadotropin appears to rise. ^{, ,} Kaplan and colleagues found that the content and concentration of pituitary LH and FSH in 2- to 6-month-old infants were higher than in late-gestation female fetuses.

It is not clear to what extent GnRH normally contributes to the functional development of the gonadotroph. In vitro, GnRH can stimulate differentiation of fetal rat gonadotrophs ^, and LH synthesis in cultured fetal human pituitary cells. Human anencephalic fetuses have reduced pituitary gonadotropin content, as well as persistent predominant secretion of the α-glycoprotein hormone subunit, ^, suggesting that GnRH normally contributes to gonadotroph development and function. At 17 to 18 weeks of gestation, the number, size, and distribution of gonadotropin-containing cells was similar in anencephalic fetuses and normal fetuses. However, after 26 weeks of gestation, anencephalic fetuses appeared to have fewer cells containing SF-1 and the β-subunits of both LH and FSH than did normal fetuses. The fetal pituitary also has potential for some differentiation in the absence of direct hypothalamic influences, as suggested by studies on anencephalic fetuses and transplanted rat pituitary. ^,

Portal Circulation

Work using vascular casts suggests that the hypothalamic pituitary portal system is intact by 11.5 to 12 weeks of gestation, earlier than originally estimated. It has been suggested that local diffusion may allow communication between the hypothalamus and pituitary before that time.