Reproductive endocrinology is the study of hormones and neuroendocrine factors that are produced by and/or affect reproductive tissues. These tissues include the hypothalamus, anterior pituitary gland, ovary, endometrium, and placenta. A hormone is classically described as a cell product that is secreted into the peripheral circulation and that exerts its effects in distant target tissues. This is termed endocrine secretion. Additional forms of cell-to-cell communication exist in reproductive physiology. Paracrine communication, common within the ovary, refers to chemical signaling between neighboring cells. Autocrine communication occurs when a cell releases substances that influence its own function. Production of a substance within a cell that affects that cell before secretion is termed an intracrine effect.
A neurotransmitter, in classic neural pathways, crosses a small extracellular space called a synaptic junction and binds to dendrites of a second neuron. Alternatively, these factors are secreted into the vascular system and are transported to other tissues where they exert their effects in a process termed neuroendocrine secretion or neuroendocrine signaling. One example is gonadotropin-releasing hormone (GnRH) secretion into the portal vasculature with effects on the gonadotropes within the anterior pituitary gland.
Normal reproductive function requires precise quantitative and temporal regulation of the hypothalamic-pituitary-ovarian axis. Within the hypothalamus, specific centers or nuclei release GnRH in pulses. This decapeptide binds to surface receptors on the gonadotrope subpopulation of the anterior pituitary gland. In response, gonadotropes secrete glycoprotein gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), into the peripheral circulation. Within the ovary, LH and FSH bind to the theca and granulosa cells to stimulate folliculogenesis and ovarian production of steroid hormones (estrogens, progesterone, and androgens), gonadal peptides (activin, inhibin, and follistatin), and growth factors. Among other functions, these ovarian-derived factors feed back to the hypothalamus and pituitary gland to inhibit or, at the midcycle surge, to augment GnRH and gonadotropin secretion. The ovarian steroids are also critical for preparing the endometrium for placental implantation if pregnancy ensues.
Hormones can be broadly classified as either steroids or peptides, each with their own mode of biosynthesis and mechanism of action. The receptors for these hormones can be divided into two groups: (1) those present on the cell surface, which in general interact with hormones that are water soluble, namely peptides, and (2) those that are primarily intracellular and interact with lipophilic hormones such as steroids. Hormones are normally present in serum and tissues in very low concentrations. Therefore, receptors must have both high affinity and high specificity for their ligand to produce the correct biologic response.
The gonadotropins LH and FSH are biosynthesized and secreted by the gonadotrope subpopulation of the anterior pituitary gland. These hormones play a critical role in stimulating ovarian steroidogenesis, follicular development, and ovulation. The closely related peptide human chorionic gonadotropin (hCG) is produced by placental trophoblast and is important for maintenance of pregnancy.
LH, FSH, and hCG are heterodimers consisting of a common glycoprotein α-subunit linked to a unique β-subunit, which provides functional specificity. Although glycoprotein α- and β-subunits can be found in their unassociated form in the circulation, these “free” subunits are not known to have biologic activity. Nevertheless, their measurement may be useful in screening tests for conditions such as pituitary adenomas and pregnancy.
The LH and hCG β-subunits are encoded by two separate genes within a gene grouping called the LH/CG cluster. The amino acid sequence of the human LH and CG β-subunits demonstrates approximately 80-percent similarity. However, the hCG β-subunit contains an additional 24-amino-acid extension on the carboxy terminus. The presence of these additional amino acids has allowed the development of highly specific assays that can distinguish LH from hCG.
In pituitary thyrotropes, the shared glycoprotein α-subunit also interacts with the thyroid-stimulating hormone β-subunit to form thyroid-stimulating hormone (TSH). This similarity between TSH and hCG can have clinical sequelae. For example, molar pregnancies frequently produce very high levels of hCG, which can bind to TSH receptors, resulting in hyperthyroidism.
This glycosylated peptide hormone is produced by the placental syncytiotrophoblast. With this molecule, the degree and type of glycosylated moieties attached to the peptide frame is variable and may indicate pregnancy stage, placental function, or pathology. One example is the hyperglycosylated hCG that is found more commonly in gestational trophoblastic neoplasia.
hCG can be detected in serum as early as 7 to 9 days after the LH surge. In early pregnancy, hCG levels increase rapidly, doubling approximately every 2 days. Levels of this peptide hormone peak at approximately 100,000 mIU/mL during the first trimester of pregnancy. This is followed by a relatively sharp decline in the early second-trimester concentrations and then maintenance at lower levels throughout the remainder of pregnancy.
hCG binds to LH/CG receptors on corpus luteum cells and stimulates steroidogenesis in the ovary. To maintain endometrial integrity and uterine quiescence, hCG levels are critical. Namely, hCG supports corpus luteum steroid production during early pregnancy before the placenta attains adequate steroidogenic capability. The transition in production of estrogens and progesterone from the ovary to the placenta is often called the “luteal-placental shift.” In addition to effects on ovarian function, hCG exerts autocrine/paracrine effects in the placenta, promoting syncytiotrophoblast formation, trophoblast invasion, and angiogenesis.
As the placenta is the primary source for hCG production, measurement of plasma hCG levels has proved to be an effective screening tool for pregnancies with altered placental mass or function. Relatively elevated levels of hCG are observed in multifetal gestations and fetuses with Down syndrome. Lower hCG levels are observed in cases of poor placentation including ectopic pregnancy or spontaneous miscarriage. Serial hCG measurements can be very helpful to monitor these latter conditions as the doubling time is relatively reliable. Markedly abnormal elevations in hCG levels are most often observed in the presence of gestational trophoblastic disease, discussed in Chapter 37.
Human CG is also secreted by nontrophoblastic neoplasias and can serve as a useful tumor marker. Ectopic (nonplacental) production of hCG, either the intact dimer or the β-subunit, is frequ
