The menstrual cycle can be divided into three phases: proliferative (follicular), ovulation, and secretory (luteal). The menstrual cycle is also described based on its length (number of days between onset of menstrual bleeding in one cycle and the onset of bleeding of the next cycle). The median duration of a menstrual cycle is 28 days [1–3]. Most individuals will describe a cycle length between 25 and 30 days [1–3]. The variability in length of a menstrual cycle is based on the variable length of the follicular phase. The luteal phase is constant in most women and is 14 days in length. Polymenorrhea is described as menstrual cycles that occur at intervals less than 21 days. Conversely, oligomenorrhea is described as menstrual cycles that occur at intervals more than 35 days. During menstruation, blood loss is typically 30 mL [4], and amounts greater than 80 mL (menorrhagia) are considered abnormal [4].

The proliferative phase begins at the onset of menses until ovulation takes place. Folliculogenesis takes place during this phase of the menstrual cycle. A dominant follicle is selected from a pool of growing follicles that will be destined to ovulate. The growth of follicles in this stage will depend on pituitary hormones such as FSH. The growth of the follicle also leads to production of estradiol from the layers of granulosa cells surrounding it. Estradiol is responsible for the proliferation of the endometrial lining of the uterus.

Ovulation happens at the peak of follicular growth in response to an LH surge [5]. Prior to ovulation, follicles grow to sizes greater than 20 mm in average diameter [6]. LH is then released in a positive-feedback manner from the anterior pituitary due to prolonged exposure to estradiol. For this positive feedback to take place, levels of estradiol above 200 pg/mL for approximately 50 h are necessary [7] (◘ Fig. 1.1). Approximately 12 h after the LH peak, the oocyte is released [8, 9]. In order for the oocyte to release from the follicle, several proteolytic enzymes and prostaglandins are activated, leading to the digestion of the follicle wall collagen [10]. Once an oocyte is released, the fallopian tube is responsible for picking it up where it will await fertilization.

The secretory phase starts after ovulation. During this phase, the remaining granulosa cells that are not released with the oocyte during the ovulation process enlarge and acquire lutein (carotenoids), which is yellow in color. These granulosa cells are now called the corpus luteum and predominantly secrete progesterone. Peak progesterone production is noted 1 week after ovulation takes place (see ◘ Fig. 1.1). Progesterone is required to convert the endometrial lining of the uterus from a proliferative one into a secretory endometrium in preparation for embryo implantation. The life span of the corpus luteum and, hence, progesterone production will depend on continued LH support from the anterior pituitary. If a pregnancy takes place, hCG (human chorionic gonadotropin ) of pregnancy will maintain the corpus luteum. However, if a pregnancy fails to happen, luteolysis takes place and the corpus luteum is converted to a white scar called the corpus albicans. The loss of the corpus luteum and the subsequent loss of progesterone lead to the instability of the endometrium and the sloughing of the endometrium, signaling a new menstrual cycle.

The initial signals for a menstrual cycle are initiated from the central nervous system. The pertinent endocrine portion of the central nervous system consists of the hypothalamus and the pituitary gland.

The hypothalamus consists of only 0.3% of the total brain, measuring 4 cm³, and weighing approximately 10 g. Despite its small size, it contains many nuclei that are responsible for endocrine regulation, reproduction, metabolism, temperature regulation, emotional responses, and electrolyte balance [11] (◘ Fig. 1.2). The hypothalamus lays beneath the thalamus, hence, the nomenclature. Laterally, it is bordered by the anterior part of the subthalamus, the internal capsule, and the optic tract [11]. The hypothalamus forms the lateral wall and floor of the third ventricle. The median eminence of the hypothalamus extends to the anterior pituitary and contains neurosecretory neurons that affect hormone production from the anterior pituitary. The hypothalamus is comprised of three zones: lateral, medial, and periventricular. Within each zone lie several nuclei, where the arcuate nucleus is pertinent to reproduction. The arcuate nucleus is responsible for the production of GnRH. GnRH is secreted into the portal pituitary circulation, reaching the anterior pituitary to affect FSH and LH release from the anterior pituitary. The hypothalamus also influences thyroid function via TRH (thyrotropin-releasing hormone), adrenal function via CRH (coricotropin-releasing hormone), and growth and metabolic homeostasis via GHRH (growth hormone-releasing hormone) [11].

The pituitary gland is a pea-sized gland, also known as the master endocrine gland. It measures 12 × 8 mm and weighs approximately 500 mg [11]. It is located beneath the third ventricle and above the sphenoidal sinus in a bony cavity called the sella turcica (see ◘ Figs. 1.2 and 1.3). The adult pituitary gland contains two major parts: the adenohypophysis and the neurohypophysis. The neurohypophysis is a diencephalic downgrowth connected with the hypothalamus, while the adenohypophysis is an ectodermal derivative of the stomatodeum [11]. The pituitary gland can also be divided into two major lobes: anterior and posterior. The anterior lobe is equivalent to the adenohypophysis, while the posterior lobe is equivalent to the neurohypophysis. The difference is that the nomenclature of anterior and posterior lobes does not include the infundibulum, which extends from the hypothalamus to the pituitary gland, which contains neural hypophysial connections and is continuous with the median eminence [11]. The anterior pituitary contains several cell types: gonadotropes (responsible for secretion of FSH and LH), thyrotropes (responsible for the secretion of thyroid-stimulating hormone [TSH]), adrenocorticotropes (responsible for the secretion of ACTH), somatomammotropes (responsible for the secretion of GH), and lactotropes (responsible for the secretion of prolactin) (◘ Table 1.2). In addition to these hormones, the anterior pituitary secretes activin, inhibin, and follistatin, which play a role in menstrual cycle regulation. The posterior pituitary lobe contains two cell types that secrete ADH (antidiuretic hormone) and oxytocin. The communication between the hypothalamus and the anterior pituitary is vascular; however, it is a neuronal connection between the hypothalamus and the posterior pituitary.

The uterus is largely a receptive organ to all the steroid hormones that emanate from the endocrine glands. The uterus is a fibromuscular organ that is bordered anteriorly by the urinary bladder and posteriorly by the rectum. The uterus can be divided into two major portions: an upper body (corpus) and a lower cervix. The hollow portion of the uterus contains a mucosal lining called the endometrium. The endometrium contains several layers of cells: the basal layer and the superficial layer. The basal layer is responsible for the regeneration of the endometrial cells. The superficial layers undergo the cyclic changes of the menstrual cycle. The endometrium normally proliferates in response to the rising estradiol levels in the first half of the menstrual cycle and in the second half of the menstrual cycle it is converted to a secretory layer in response to progesterone produced by the corpus luteum. If the cycle does not result in a pregnancy, where there is lack of hCG, progesterone production is not maintained by the corpus luteum, and the endometrium becomes unstable and sloughs in preparation for a new cycle and another attempt for pregnancy.

GnRH is a decapeptide synthesized in the hypothalamus and first described in the 1970s by Schally [12–14] and Guillemin [15] for which they received the Nobel Prize [14–18] (◘ Fig. 1.4). GnRH neurons can be detected in the fetal hypothalamus as early as 9–10 weeks of gestation [19]. GnRH neurons originate from the olfactory area [20], later migrating to the olfactory placode to rest in the arcuate nucleus of the hypothalamus [21]. The hypothalamic GnRH neurons then send projections to the pituitary. The association of GnRH neurons and the olfactory system can be demonstrated in a condition called Kallmann syndrome, where GnRH deficiency is coupled with anosmia [22]. Pheromones, small airborne molecules secreted by one individual and perceived by another individual, also suggest the common origin of GnRH molecules and the olfactory system. Pheromones may explain why women living or working in close proximity may develop synchrony in their menstrual cycles [23, 24].

To date, three types of GnRH (GnRH-I, GnRH-II, and GnRH-III) have been detected in humans [25, 26]. Many other GnRH types have been described in fish, amphibians, and protochordates [27, 28]. GnRH-I is the classic hypothalamic hormone responsible for the regulation, synthesis, and secretion of the pituitary gonadotropins FSH and LH [29]. GnRH-II was first described in brain tissue and has since been found in many other peripheral tissues, such as the endometrium, breast, and ovaries [30–33]. GnRH-III was first identified in Lamprey in 1993 [34], and Yahalom et al. described the presence of GnRH-III in neurons from the hypothalamus [25]. The role of GnRH-III in humans is unclear. GnRH-III does not have strong LH and FSH releasing potency, but it has been shown to exert a direct antiproliferative effect on cancer cells and is being studied for use as an antitumor agent [35].

GnRH-I is synthesized from a larger, 92 amino acid precursor [36]. After synthesis, GnRH-I travels to the median eminence of the hypothalamus and is released in the portal circulation in a pulsatile fashion. The GnRH-I molecule lifespan is very short, as it is cleaved rapidly, with a half-life of 2–4 min. Because of this rapid cleavage, peripheral levels of GnRH-I are difficult and do not correlate well to pituitary action.

GnRH-I acts on the anterior pituitary leading to the synthesis and storage of gonadotropins, movement of the gonadotropins from the reserve pool to a readily released point, and finally the secretion of gonadotropins. For this action to take place appropriately, pulsatile GnRH release is necessary [37, 38]. Continuous GnRH secretion will lead to the suppression of FSH and LH release as well as suppression of FSH and LH gene transcription by the anterior pituitary [39, 40]. This is the basis of use of GnRH agonists such as Lupron for the suppression of gonadotropin secretion. The pulse frequency of GnRH will vary depending on the menstrual cycle phase. LH pulse frequency is used to indicate GnRH pulse secretion (◘ Table 1.4).

GnRH-II differs from GnRH-I by three amino acids at positions 5, 7, and 8 [26, 41]. Also, in contrast to GnRH-I, GnRH-II is mainly expressed outside the brain [26, 42, 43], including the human placenta [44]. Similar to GnRH-I release from the hypothalamus, GnRH-II is released from the placenta in a pulsatile fashion [44, 45].

Various factors are believed to play a role in GnRH secretion. Estrogen has been shown to have a positive as well as a negative effect on GnRH-I secretion. Estrogen suppresses GnRH-I secretion in a negative-feedback fashion [46]. In addition, estrogen has a differential regulation on GnRH-I and GnRH-II mRNA levels. Estrogen increased GnRH-II mRNA levels while it decreased GnRH-I mRNA levels [47]. Progesterone is also noted to play a stimulatory role on GnRH-1 mRNA, which was decreased by the progesterone receptor antagonist RU48 [48]. However, no difference in the expression level of GnRH-II was seen with progesterone or the anti-progestin mifepristone [48].

Two types of GnRH receptors have been described in humans: GnRH-I receptor (GnRH-IR) and the GnRH-IIR (GnRH-IIR). The GnRH-IR is a G protein-coupled transmembrane receptor (GPCR) [49, 50]. However, the mammalian GnRH-IR lacks the carboxyl-terminal tail [50, 51]. Activation of the GnRH-IR leads to the activation of phospholipase C, which in turn generates the second messengers inositol triphosphate and diacyl glycerol, stimulating protein kinase, cyclic adenosine monophosphate (cAMP), and release [52] of calcium ions. In addition to the brain, GnRH-IR can be found in the human placenta [53, 54], ovarian follicles [33, 55], in myometrium and leiomyomata [56, 57], as well as human pancreas, liver, heart, skeletal muscle, kidney, and peripheral blood [58–61]. GnRH-IIR is also a GPCR, but unlike the GnRH I-R, it has a C-terminal cytoplasmic tail [62]. GnRH-IIR can be found in the pituitary, placenta, ovary, uterus, prostate, mature sperm, pancreas, small and large intestines, kidney, and liver [26, 33, 63–65].

GnRH analogues have been developed by changes made to the amino acid sequence of the GnRH molecule. These changes result in the extension of the GnRH half-life as well as its biologic activity. There are two major groups of GnRH analogues: GnRH agonists and GnRH antagonists (◘ Table 1.5) In the case of GnRH agonist use, the continuous activation of the GnRH receptor results in desensitization due to a conformational change of the receptor, uncoupling from G proteins, internalization of the receptor as well as reduced synthesis of the receptor [66, 67]. Prior to the desensitization by GnRH agonists, there is an initial flare where there is increased gonadotropin secretion. Desensitization then takes place 7–14 days later. Unlike GnRH agonists, GnRH antagonists do not cause a flare effect upon initial administration; instead, GnRH antagonists cause an immediate suppression of gonadotropin secretion that is rapid and is reversible [68]. Currently, GnRH analogues are available in injectable form in the treatment of many reproductive conditions, such as precocious puberty, endometriosis, and uterine leiomyomata; they are also being used in in vitro fertilization treatment cycles. Oral forms of GnRH analogues are under investigation. Elagolix is an orally active GnRH antagonist under investigation for use in reproductive conditions [69, 70].

GnRH acts on the anterior pituitary to secrete gonadotropins: FSH and LH. FSH is a glycoprotein dimer consisting of two subunits: α (alpha)- and β (beta)-subunits. The α-subunit is common in FSH and LH as well as TSH and hCG. The β-subunit is distinct and hormone-specific, which allows the differential function of each hormone. The α-subunit consists of 92 amino acids, while the FSH β-subunit consists of 118 amino acids and five sialic acid residues. Sialic acid residues are responsible for the half-life of the hormone, where the higher the sialic acid content the longer the half-life of that molecule [71]. FSH has a half-life of several hours. The addition of sialic acid to urinary obtained or recombinant FSH products leads to their longer half-life. The rate-limiting step in gonadotropin production is the availability of β-subunits. In addition to GnRH stimulation of FSH β-subunit synthesis, FSH β-subunit synthesis is dependent on the presence of activin [72, 73].