Amenorrhea. A Case-Based, Clinical Guide

1. The Hypothalamic-Pituitary-Ovarian Axis

Cary DickenMarie Menke and Genevieve Neal-Perry 

(1)

Department of Gynecology and Obstetrics and Women’s Health and Domnick Purpura Department of Neuroscience, Albert Einstein College of Medicine of Yeshiva University, Jack and Pearl Resnick Campus, 1211 Ullmann Building, 1300 Morris Park Avenue, Bronx, NY 10461, USA

Genevieve Neal-Perry

Email: Sienna3598@aol.com

Abstarct

The hypothalamic-pituitary unit is the most evolutionarily conserved brain ­structure. It is responsible for integrating incoming information from the external (e.g., light, pain, temperature, smell) and internal environment (e.g., blood pressure, blood glucose, blood osmolality) and maintaining physiological homeostasis by coordinating endocrine, autonomic, and behavioral responses. In addition to preserving physiological homeostasis, the hypothalamic-pituitary axis synchronizes neuroendocrine physiology essential for ovarian physiology and reproduction. Key hormones responsible for hypothalamic-pituitary-gonadal (HPG) axis competency and reproductive success include gonadotropin releasing hormone (GnRH), follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, progesterone, inhibin, activin, and follistatin. While the hypothalamic-pituitary axis is important for homeostasis, this chapter will primarily describe the role of HPG axis in the regulation of the menstrual cycle.

Introduction

The hypothalamic-pituitary unit is the most evolutionarily conserved brain ­structure. It is responsible for integrating incoming information from the external (e.g., light, pain, temperature, smell) and internal environment (e.g., blood pressure, blood glucose, blood osmolality) and maintaining physiological homeostasis by coordinating endocrine, autonomic, and behavioral responses. In addition to preserving physiological homeostasis, the hypothalamic-pituitary axis synchronizes neuroendocrine physiology essential for ovarian physiology and reproduction. Key hormones responsible for hypothalamic-pituitary-gonadal (HPG) axis competency and reproductive success include gonadotropin releasing hormone (GnRH), follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, progesterone, inhibin, activin, and follistatin. While the hypothalamic-pituitary axis is important for homeostasis, this chapter will primarily describe the role of HPG axis in the regulation of the menstrual cycle.

The Neuroendocrine Axis

Hypothalamus

Anatomy

The hypothalamus forms the floor of the third ventricle and is located beneath the thalamus at the base of the brain. Although the hypothalamus is small, occupying about 10 of the total 1,400 g of adult human brain, it is composed of a complex group of highly specialized cells that are responsible for homeostasis and reproduction, and exhibit physiological characteristics consistent with neurons and endocrine gland cells [1].

The hypothalamus can be grossly divided in the medial–lateral plane into the medial, lateral, and periventricular regions. It can also be divided in the anterior–posterior plane to yield the anterior, posterior, and middle regions. It has several specific nuclei including the arcuate, supraoptic, suprachiamatic, paraventricular, dorsal medial, ventromedial, posterior hypothalamic, premammillary, lateral mammillary, and the medial mammillary. The periventricular region consists of the regions bordering the third ventricle and houses neurons important for the preservation of the circadian rhythm and autonomic neuroendocrine responses to stress. The periventricular fiber system conveys the axons of the parvocellular neuroendocrine neurons in the paraventricular and arcuate nuclei to the median eminence for control of the anterior pituitary. They are met in the median eminence by the axons from the magnocellular neurons, which continue down to the posterior pituitary. The medial region of the hypothalamus participates in the control of reproduction, osmoregulation, and thermoregulation. The lateral region of the hypothalamus is involved in behavior and arousal. The most anterior aspect of the hypothalamus overlies the optic chiasm and is called the preoptic area. The preoptic area houses the preoptic nuclei which contain neurons responsible for the regulation of blood pressure and body temperature. The middle region of the hypothalamus, located just above the pituitary stalk, contains the dorsomedial, ventromedial, paraventricular, supraoptic, and arcuate nuclei. The paraventricular, arcuate, and supraoptic nuclei all contain neuroendocrine neurons that regulate pituitary physiology. The dorsomedial and ventromedial nuclei project mainly within the hypothalamus and to the periaqueductal gray matter. These nuclei regulate growth, feeding, maturation, and reproduction. Finally, the posterior third of the hypothalamus includes the mammillary body and the overlying posterior hypothalamic area. The function of the mammillary bodies is unknown. The posterior portion of the hypothalamus contains the tuberomammillary nucleus, a histaminergic cell group that regulates arousal and wakefulness. From a reproductive perspective, the arcuate nucleus and the preoptic area are the most critical regions because they house GnRH neurons, the primary controllers of pituitary reproductive function.

Maintenance of the human menstrual cycle is directly dependent upon coordinated complex changes in patterns of neurotransmitter and neuropeptide released from the hypothalamus from the median eminence into portal system. These hypothalamic neuropeptides and neurotransmitters communicate with the anterior pituitary and affect anterior pituitary peptide secretion. Retrograde flow will bring pituitary hormones from the pituitary to the hypothalamus for feedback control. Conversely, the axons of the magnocellular neurons in the paraventricular and supraoptic nuclei project directly to the posterior pituitary to release oxytocin and vasopressin.

Physiology

Once the menstrual cycle is established, an event which on average is achieved within 5 years postmenarche, women enter into their reproductive prime. This period is most often coincident with maximal reproductive potential and characterized by the existence of a mature and functional hypothalamic-pituitary axis. The mature hypothalamic-pituitary axis subsequently functions to regulate ovarian physiology and menstrual cyclicity.

GnRH Neurons

Hypothalamic GnRH neurons, the maestros of reproductive success, originate from epithelial cells located in the olfactory placode. GnRH neurons, like olfactory neurons, have cilia and migrate along the cranial nerves until they reach the forebrain and their final residence within the medio-basal hypothalamus of the preoptic area and the arcuate nucleus. Critical to this migration is a neuronal cell surface glycoprotein that mediate cell-to-cell adhesion. Several genes and their related proteins are involved in cell adhesion and are important for GnRH neuronal migration. An example is anosmin-1, a protein encoded by the KAL1 gene, which is responsible for X-linked Kallmann syndrome [2]. Mutations of genes that encode adhesion molecules are often associated with anosmia, GnRH deficiency, and hypogonadotropic hypogonadism. Fibroblast growth factor receptor one also plays a role in GnRH neuronal migration, and mutations in this receptor generate a Kallmann syndrome phenotype [3].

About 1,000–3,000 GnRH neurons can be found in the arcuate nucleus. GnRH neurons exist in a complex network that involves interconnections between GnRH neurons and several other neurotransmitter systems that modulate GnRH release and GnRH neuronal activation. This complex arrangement allows GnRH neurons to communicate with each other and to integrate and transmit input received from multiple estradiol-responsive neurotransmitter systems and growth factors that affect gonadotropin release. Delivery of GnRH to the portal circulation occurs via an axonal pathway – the GnRH tubero-infundibular tract. Axons from GnRH neurons project to the median eminence and terminate in the capillaries that drain into the portal vessels. The portal vein is a low-flow transport system that descends along the pituitary stalk and connects the hypothalamus to the anterior pituitary. The direction of the blood flow in this hypophyseal portal circulation is generally from the hypothalamus to the pituitary. The peak concentration of GnRH in human portal blood is about 2 ng/mL.

GnRH is a 10 amino acid neuropeptide derived from the posttranslational ­processing of a large 92 amino acid precursor molecule (pre-pro-GnRH) that contains 4 parts: a 23 amino acid signal domain, the GnRH decapeptide, a 3 amino acid proteolytic processing site, and a 56 amino acid GnRH-associated peptide (GAP) [1]. GnRH and GAP are transported to the nerve terminals before secretion into the portal circulation. Pre-pro-GnRH is the product of the short arm of chromosome 8. The physiologic role of GAP has not yet been established. GnRH peptide has a half-life of 2–4 min. The short half-life of GnRH reflects rapid cleavage of the bonds between several amino acids (5 and 6, 6 and 7, and 9 and 10).

The short half-life and the large peripheral dilution effect of the vascular system prohibit the measurement of GnRH outside the central nervous system. LH has a half-life that is approximately 10–15 times longer than that of GnRH and each pulse of LH measured in the peripheral blood corresponds to a hypothalamic pulse of GnRH in the portal system in a one-to-one relationship [4]. Therefore, LH pulsing is often used as a surrogate marker for GnRH pulsatile secretion.

GnRH neurons release GnRH in a pulsatile fashion. The periodicity and amplitude of the pulsatile rhythm of GnRH are critical to reproduction because it ultimately drives gonadotropin and gonadal steroid secretion, gamete maturation, and ovulation. GnRH peptide regulates GnRH receptor expression on gonadotropin-producing cells by a process also known as self-priming. GnRH self-priming is maximized when GnRH release occurs every 60–90 min. Less frequent GnRH pulse frequency results in anovulatory amenorrhea. Slow pulse frequency also decreases gonadotropin secretion due to inadequate stimulation. In contrast, prolonged exposure or increased GnRH frequency results in gonadotroph receptor downregulation and decreased gonadotropin secretion.

During puberty, hypothalamic reproductive activity begins with a low frequency of GnRH–LH release and proceeds with cycles of accelerated frequency characterized by passage from relative inactivity, to nocturnal activation, and finally to the full adult pattern. In adult females, LH pulse amplitude increases throughout the menstrual cycle, peaking in the early luteal phase. Pulsatile frequency of LH in the early follicular phase is every 90 min. The frequency increases to every 60 min in the late follicular phase and decreases to 100 min during the early luteal phase and 200 min in the late luteal phase. Normal menstrual cycles depend on maintaining the pulsatile release of GnRH within this critical range of amplitude and frequency. In general, more rapid pulse frequency favors LH secretion, whereas a slower pulse frequency favors that of FSH.

Control of the reproductive system by GnRH is governed by gonadal steroid feedback effects. Negative feedback prevents the growth of multiple large follicles and positive feedback is necessary for the LH surge and ovulation. Multiple neurotransmitters and neurohormones have been implicated as having roles in the control of GnRH secretion. An example of some of these neuroendocrine modulators includes catecholamines, opiates, neuropeptide Y (NPY), corticotrophin-releasing hormone, prolactin, and gonadal steroids. Sex steroids have both positive and negative feedback effects on GnRH pulse frequency. Estrogen alpha receptors (ERα), the mediators of estradiol positive feedback, have not been localized in hypothalamic GnRH-secreting neurons [5]. Adjacent neurons have been found to have ERα and are therefore likely to be critical in transmitting sex steroid feedback to GnRH neurons [6].

Estradiol increases GnRH pulse frequency, whereas elevated progesterone levels decrease GnRH pulsatility. Although GnRH neurons only express ERβ, studies with transgenic ERα and ERβ knockout mice demonstrate that ERα is necessary for estradiol positive feedback control of the hypothalamic-pituitary axis. This suggests that gonadal steroids do not directly regulate GnRH activity. Instead, estradiol mediates its effects on GnRH neurons through indirect mechanisms that most likely involve regulation of other hormone-responsive neurotransmitter systems like glutamate, GABA, norepinephrine, endorphins, and others.

Hypothalamic Neuropeptides and GnRH Neurons

Neuropeptide Y

NPY is a 36 amino acid peptide neurotransmitter whose main role is the regulation of energy balance. The majority of NPY expressing hypothalamic neurons are located in the arcuate nucleus [7]. The regulation of NPY secretion stems from nutritional status. States of negative energy balance in which circulating leptin is reduced are associated with the stimulation of NPY [8]. It is hypothesized that NPY increases food intake by modulating corticotropin releasing hormone (CRH) and decreases physical activity, thereby increasing the proportion of energy stored as fat [910].

In addition to its stimulatory effect on food intake, NPY is hypothesized to affect reproduction positively through regulation of GnRH pulsitility. GnRH neurons expressing one or more of the six NPY receptor subtypes receive direct synaptic input from NPY-containing neurons [11]. The effect of NPY on GnRH depends on the presence or absence of gonadal steroids. In the presence of gonadal steroids, NPY stimulates the pulsatile release of GnRH and potentiates gonadotropin response to GnRH neurons by increasing the number of GnRH receptors on the pituitary gonadotrophs. However, in the absence of gonadal steroids, NPY inhibits gonadotropin secretion.

Proopiomelanocortin

Proopiomelanocortin (POMC) is a precursor polypeptide composed of 241 amino acids and part of the endogenous opiod peptide family. It undergoes extensive posttranslational processing via cleavage enzymes and has eight potential cleavage sites. Depending on the type of cleavage enzyme present within the tissue, POMC has the potential to yield ten biologically active peptides.

POMC is split into two fragments – an ACTH intermediate fragment and β-lipotropin. β-Lipotropin has no opioid activity, but is broken down in a series of steps to αβ, and γ melanocyte stimulating hormone (MSH); enkephalin; and the µ´ -, β-, and γ-endorphins. MCH interacts with one of five distinct receptor subtypes (MCR). αMSH is important for the regulation of skin pigmentation and, through interactions with NPY, food intake and energy homeostasis. Enkephalin and the µ´ -, β-, and γ-endorphins act at opioid receptors. β-Endorphin and other opioids affect reproduction by suppressing GnRH release [12].

Kisspeptin

Kisspeptin, a 54 amino acid peptide, is the product of the Kiss1 gene and binds to an endogenous receptor G-protein coupled receptor 54 (GPR54). Kisspeptin neurons are found in both the arcuate and anteroventral periventricular nucleus, and send their projections to GnRH cell bodies. Kisspeptin and its cognate receptor GPR54 directly and indirectly contribute to regulation of GnRH secretion and have an important role in the pubertal transition [13]. Mutations in GPR54 are responsible for some cases of hypogonadotropic hypogonadism and a failed pubertal transition [14].

Kisspeptin may have a role in mediating feedback control on GnRH secretion. Studies in rodents suggest kisspeptin neurons located in the anteroventral periventricular nucleus are proposed to be important for positive feedback effects of estradiol on the LH surge [15] and kisspeptin neurons located in the arcuate nucleus are proposed to be important for negative feedback [16].

Hypothalamic Neurotransmitters and GnRH Neurons

In addition to peptidergic input, GnRH neurons receive afferent input from a variety of neurotransmitter pathways. Changes in the release of amino acid neurotransmitters glutamate and GABA in response to gonadal steroids are critical for the pubertal transition, the LH surge, and reproductive senescence [1722]. Similarly, the neurotransmitters norepinephrine and dopamine are thought to be important modulators of GnRH neuron activity and gonadotropin release [2326]. Dopaminergic neurotransmission also regulates prolactin secretion.

Pituitary

Embryology and Anatomy

Fetal pituitary is derived from the fusion of the neuroectoderm that gives rise to Rathke’s pouch and the diencephalon, and begins to develop approximately between the fourth and fifth weeks of gestation. By the ninth week of gestation, a ­rudimentary anterior pituitary can be recognized and between the 12th and 17th week of ­gestation, a functional hypothalamic-pituitary axis is established.

Several transcription factors have been linked to embryologic pituitary development, including HESX1, LHX3, LHX4, PIT1 (PROP1), POU1f1, PITX2, T-PIT (TBX19), SOX2, and SOX3 [27]. Mutations in these genes have been associated with syndromes that include pituitary abnormalities ranging from combined ­pituitary hormone deficiency to isolated hormonal deficiencies [28]. Although genetic variants include phenotypes with primary amenorrhea, the deficiency is more often identified in childhood as part of a wider clinical syndrome such as septo-optic dysplasia [29]. When hormone deficiencies do occur, abnormalities in growth hormone production and its consequences are usually the earliest sign.

With an average weight between 0.4 and 0.8 g in human adults, the pituitary can be found in the sella turcica where it is covered by dura. The sella turcica is located at the base of the brain and inferior to the hypothalamus. The optic chiasma lies just above the sellar diaphragm, with visual symptoms presenting as an early clinical sign of gross pituitary enlargement.

The arterial vascular supply to the pituitary consists primarily of the superior and inferior hypophysial arteries; branches of the internal carotid arteries. Venous blood return occurs through the internal jugular veins [30]. Blood supply to the median eminence and infundibular stalk arises from the superior hypophysial arteries. From these sites, a dense capillary network coalesces to allow blood flow directly to the anterior pituitary through a portal system that traverses the pituitary stalk. This capillary network supplies approximately 80–90% of blood pituitary flow [12].

The Anterior Pituitary

The anterior pituitary is derived from Rathke’s pouch and the posterior pituitary is derived from the diencephalon. The anterior hypothalamus, also known as the adenohypophysis, is composed of the pars distalis, pars intermedia, and pars tuberalis, all of which account for 80% of the pituitary gland. Of these structures, the pars distalis and pars tuberalis represent the sites of hormonal synthesis. The pars intermedia has no known function in humans. The anterior pituitary lacks direct innervation; regulation is solely through hypothalamic hormonal control via the portal system. Retrograde flow allows feedback loops between the hypothalamus and anterior pituitary.

Six major cell types reside in the anterior pituitary: 40–50% somatotrophs (growth hormone), 14–25% lactotrophs (prolactin), 10–20% corticotrophs (adenocorticotrophic hormone), 5% thyrotrophs (thyroid-stimulating hormone), 10% gonadotrophs (FSH and LH), and folliculostellate cells. The anterior pituitary’s intimate role in reproduction results from the secretion of the glycoproteins FSH and LH. Until recently, histologic classification of anterior pituitary cells rested entirely on immunohistochemical findings of acidophilic, basophilic, or chromophobic cells. This classification system has largely been replaced with descriptive terms ­determined by cellular peptide production. Acidophilic cells are now classified as somatotropes or lactotropes, and basophilic cells are classified as corticotropes, thyrotropes, or gonadotropes. Cells previously classified as chromophobic generally fall into one of the above hormone-producing cell types.

The Posterior Pituitary

The posterior pituitary, also called the neurohypophysis, is composed of the infundibular stalk and the pars nervosa. The infundibular stalk is surrounded by the pars tuberalis, and together they constitute the hyopophyseal stalk. The posterior pituitary has a collection of nerve terminals that arise from magnocellular secretory neurons located within the paraventricular and supraoptic nuclei of the hypothalamus. Upon stimulation, the nerve terminals secrete vasopressin and oxytocin into the pituitary capillary plexus in close proximity to the axons. Alteration in concentrations of these neuropeptides within the peripheral vasculature results in changes in blood osmolality, blood pressure, and fluid balance.

The pituitary gland is regulated by three interacting elements: hypothalamic inputs, steroid feedback, and pituitary paracrine and autocrine actions. Hypothalamic input to the pituitary varies according to local hormonal and physiological cues that modulate neuropeptide and neurotransmitter secretion into the median eminence and the pituitary capillary plexus. Thus steroid feedback directly and indirectly affects pituitary reproductive physiology.

Pituitary Gonadotropins

FSH and LH belong to a superfamily of heterodimeric glycoprotein hormones. They are formed by noncovalent linkage of the α- and β-subunits. Like other members of this superfamily, FSH and LH share a common 92 amino acid α polypeptide stabilized by five disulfide bonds on ten cysteine residues and composed of asparagine-linked glycosylation sites. The human α-subunit gene is located on the short arm of chromosome 6 (p21.1-23). Although encoded from different chromosomes, a high degree of sequence homology exists among the β-subunits. FSH and LH bind to different transmembrane G protein-coupled receptors with unique ligand recognition domains. Mutations in the β-subunit of FSH or LH or their cognate receptors have been described and are generally equated with precocious puberty, primary amenorrhea, and/or infertility [3132].

By 16 weeks of gestation, portal circulation is developed and fetal secretion of all pituitary hormones is detectable with peak levels achieved by 28 weeks of gestation. Postnatally, gonadotropins rise briefly during the first year of life. A wide range of values are observed in neonates, with FSH ranges of 12–26 IU/L and less marked elevations of LH (0.5–3.5 IU/L) [33]. In premature infants born between 24 and 29 weeks of gestation, these variations are even more pronounced. FSH levels have been reported to range between 1.2 and 167.0 IU/L and LH levels to range between 0.2 and 54.4 IU/L. The progressive decline of FSH levels with fetal maturity suggests ongoing maturation of the hypothalamic-pituitary-ovarian axis, which subsequently continues postnally [34]. After the first year of life, childhood levels of gonadotropins are nearly undetectable, with little additional change occurring before the onset of puberty [35].

FSH

FSH has a molecular weight of approximately 29,000 Da. The human β-subunit gene for FSH is located on the short arm of chromosome 11 (p13). The FSH β-subunit contains 111 amino acids, 5 sialic acid residues, and 2 asparagine-linked glycosylation sites. Circulating estradiol (E2) affects FSH isoforms by modulating carbohydrate moieties. Elevated serum E2 levels increase an FSH isoform with decreased sialic acid residue sites. Reduced numbers of sialic acid residue sites shorten the half-life of FSH and increase receptor affinity [36]. In contrast, FSH isoforms with increased numbers of sialic acid residues have reduced receptor affinity and lengthened half-lives [37].

LH

LH is composed of the shared α-subunit and a 121 amino acid β-subunit. As with FSH, the oligosaccharide component of the β-subunit specifies the half-life of LH. The Gal-N-Ac sulfate located on LH allows rapid recognition and metabolism by hepatic cells and results in its 20–30 min half-life [37]. Mutations of the LH β-subunit gene have been associated with primary infertility [38] and precocious puberty in males [3940]. Although LH β-subunit variants have been identified in subgroups of PCOS women, they do not demonstrate differences in prevalence between normal and polycystic ovarian syndrome populations [41].

Prolactin

Lactotropes secrete prolactin. Transcription of the prolactin gene is regulated by Pit-1, which also plays a role in secretion of growth hormone and thyroid stimulating hormone. As previously described, mutations in Pit-1 have been implicated in defects of the anterior pituitary, including combined pituitary hormone deficiency. Although prolactin’s primary function is thought to be regulation of lactogenesis, prolactin is also synthesized in the uterus where it is believed to play a role in implantation.

Roles for prolactin outside of pregnancy and lactation are not known. However, transgenic prolactin receptor knockout mice have disordered estrous cycles [4243]. Additionally, prolactin receptor knockout mice have fewer primary follicles, fewer ovulatory events, poor progression of fertilized oocytes to the blastocyst stage, and decreased estradiol and progesterone levels. These studies strongly suggest that prolactin may also be important for gonadotropin secretion.

Hyperprolactinemia inhibits GnRH secretion [44]. In conditions of hyperprolactinemia, LH pulse amplitude and frequency are decreased [4546]. LH secretion normalizes when prolactin levels are normalized [47]. Short-term treatment with opioid antagonists suggests that prolactin inhibition is mediated by opioid activity [48]. However, long-term opioid antagonist treatment does not restore menstrual cycles resulting from hyperprolactinemic states [49].

The Ovary

Ovarian Embryology

Embryonic gonadal development follows a pre-programmed transition from the indifferent gonad stage to sex-specific female or male germ cells. In the indifferent gonad stage, primordial germ cells first appear in the endoderm of the yolk sac, allantois, and hindgut. By way of ameboid movement, primordial germ cells migrate to the genital ridge by 5–6 weeks of gestation. The mechanism for this migration is not fully understood; however, electron microscopic studies demonstrate formation of pseudopod-like cytoplasmic processes that allow movement through the mesenchyme [50].

Upon arrival to the genital ridge, replication of germ cells occurs via mitotic division with differentiation into primary oocytes occurring as early as the 11th week of gestation. By the 14th week of gestation, a portion of these oocytes will have entered meiosis, and replication is arrested in the diplotene stage of prophase I. A single flattened layer of granulosa cells will eventually surround these oocytes giving rise to primordial follicles. By midgestation, primary follicles are discernable in the fetal ovary. Mitotic growth continues and the number of oocytes peaks at a total of 6–7 million by 16–20 weeks of gestation [5152]. Rapid atresia follows, with approximately 1–2 million oocytes remaining in the ovary at birth. Germ cells that fail to enter meiosis by this stage are among those that undergo cell death [53]. An example of this clinical scenario can be found in Turner syndrome (45,X), whereby accelerated loss of fetal oocytes due to failure to undergo meiosis frequently leads to the formation of streak gonads. Additionally, terminal deletions from Xp11 to Xp22.1 and X13 to Xq26 are associated with primary amenorrhea and premature ovarian failure [5455]. Postnatally, additional oocyte loss ensues, with 300,000–500,000 oocytes remaining at the beginning of puberty. Of the remaining oocytes, approximately 400–500 will ovulate during the reproductive years.

Transcription of proteins such as bone morphogenic protein-4 (BMP-4), steel factor (c-kit ligand), TIAR (an RNA recognition motif/ribonucleoprotein-type RNA-binding protein), and leukemia inhibitor factor (LIF) is required for successful proliferation and migration of germ cells [5657]. In addition, distribution of fibronectin appears to play a role in the migratory route [58]. Successful migration is critical for gonadal development, as germ cells that fail to migrate undergo apoptosis.

Ovarian Anatomy

The ovary lies in the peritoneum attached to the uterus through ovarian ligament. Grossly, the ovary consists of the outer cortex, medulla, and hilum. The cortex can be further divided into the overlying tunica albuginea and the inner cortex. Surrounded by stromal tissue, oocytes are located in the inner cortex. Innervation and blood flow to ovarian tissue occur through the hilum [59]. The suspensory ligament of the ovary, through which the vascular flow and innervation to the ovary occur, also serves to tether the ovary to the pelvic sidewall. The ovarian artery originates from the aorta and provides oxygenated blood flow to the organ. Venous blood return occurs by way of ovarian veins, with drainage directly to the inferior vena cava on the right and to the renal vein on the left. The autonomic nervous system provides ovarian innervation. Interestingly, alterations in ovarian autonomic tone may affect ovarian function by predisposing females to the formation of ovarian cysts (reduced tone) or a polycystic ovarian phenotype [60]. In culture, addition of sympathomimetics enhances theca-interstitial androgen production by 100–300% in response to hCG [61]. Animal studies suggest a role for vasoactive intestinal peptide from nerve fibers in granulosa cell development and follicular atresia [6264].

Follicular Development and Atresia

The menstrual cycle has classically been described as consisting of a 28-day cycle characterized by an early follicular phase with multifollicular development, mid-follicular stage with selection of a dominant follicle, followed by ovulation before transition of the remnant follicle into a corpus luteum. Follicles not destined for dominance experience developmental arrest and atresia. Growth from the secondary follicle into preovulatory follicles occurs in approximately 85 days [65], with complete development from the primary to the preovulatory follicle requiring approximately 220 days [66].

Early Follicular Development

As previously described, follicular growth begins mid-gestation with formation of primary follicles and arrest of the oocyte in the diplotene stage of meiosis I. Follicular growth and development begins with a gonadotropin independent stage, as granulosa cells change from flattened to cuboidal shape, with a subsequent fivefold increase in proliferation [67]. These changes are followed shortly thereafter with an increase in oocyte diameter, and formation of the zona pellucida [65]. To differentiate it from cyclic recruitment, which occurs post-puberty through direct stimulation by FSH, this process is also called the initial recruitment [66].

Following transformation of granulosa cells from flattened to cuboidal shape, oocyte growth proceeds without resumption of meiosis. Theca interna formation occurs at the end of the primary follicle stage; apparent paracrine regulation occurs from the oocyte-derived growth differentiation factor-9 (GDF9) as, in its absence, the theca layer fails to develop [1268]. Other necessary paracrine regulators of both granulosa and oocyte growth include kit ligand (expressed in granulosa cells), BMP-15 (oocyte-derived), connexin 37 (found at oocyte-granulosa gap junctions), and cyclin D2 (expressed in granulosa cells) [66]. At this stage, FSH and activin appear to have little role in follicular progression as mouse models and case reports of novel human FSH receptor mutations demonstrate development through the secondary follicle stage [6970]. Nevertheless, preparation for future response to FSH does occur as primordial and primary follicles respond to cAMP activation with increased expression of aromatase and FSH receptors [64].

Secondary Follicles

During the secondary follicle or preantral stage, granulosa cells continue to develop receptors for FSH, estradiol, and androgens [1266]. Progression to the antral stage is marked by cell proliferation and oocyte growth. Although alternate signaling pathways have been described, FSH induces aromatization in granulosa cells primarily through an adenylate cyclase-mediated mechanism. Elevated levels of estradiol, in turn, act to upregulate the FSH receptors, thereby increasing the sensitivity to FSH. FSH induces granulosa cell proliferation and communication by increasing the number of gap junctions. FSH also upregulates transcription of LH receptors in granulosa cells of the preovulatory follicle [59].

Theca cells arise from mesenchymal cells of the stroma and are primarily responsible for androgen synthesis in the ovary. Theca layer development continues to progress as secondary follicles develop. Interactions with granulosa cells occur through growth factors such as keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF). Kit ligand produced by granulosa cells then stimulates further organization of the theca layer by way of a positive feedback loop [71].

Antral Follicle

Formation of the antral follicle requires an increase in transcellular permeability followed by a rapid influx of water mediated through channels formed by aquaporins [72]. Evidence also suggests a change in the collagen composition of the follicular extracellular matrix [73]. Within the antral cavity, granulosa cells surrounding the oocyte become a morphologically distinct layer of cumulus cells.

During the menstrual cycle, circulating FSH allows a cohort of antral follicles to escape apoptosis; however, through a mechanism not fully elucidated, a dominant follicle emerges early in the follicular phase; FSH receptor concentration, ­aromatase activity, and intrafollicular levels of estrogen all increase in the chosen follicle. Selection of a dominant follicle allows a progressive increase in the concentration of estrogen that results in estrogen negative feedback on gonadotropin release and atresia of the remainder of the previously responsive cohort. The subsequent decline in FSH results in decreased estrogen production, with a further decrease in responsiveness to gonadotropins by nondominant follicles that progressed into the preantral stage. In a natural cycle, this process may be detected as early as day 5 of the menstrual cycle [74].

The mid-cycle LH surge precedes ovulation and completion of meiosis I by approximately 24–36 h. Cumulus cell expansion occurs in response to increased synthesis of hyaluronic acid [59]. Mural granulosa cells express high levels of LH receptors; however few, if any, LH receptors proliferate in cumulus cells [75]. Instead, a complex signaling cascade of LH and epidermal growth factor-like growth factors such as amphiregulin, epiregulin, and betacellulin likely plays a role in cumulus cell differentiation [76]. Proteolytic enzymes, produced by granulosa and theca cells, are ultimately responsible for follicular rupture [59]. Prostaglandin synthesis is required for ovulation and appears to act through promotion of protease function [77].

Ovarian Physiology

Estrogen

Estradiol is the major form of circulating estrogen and is produced in its highest concentrations by the antral follicle during the follicular phase. Theca cell response to LH results in increased androgen production through transcription of P450scc, P450c17, and 3β-hydroxysteroid dehydrogenase. The classic two-cell model of steroid production describes the aromatization of androgens produced by theca cells and androgen diffusion into adjacent granulosa cells where FSH regulates aromatase synthesis of estradiol. Thus, the follicular phase of the menstrual cycle is marked by granulosa cell-mediated increased production of estradiol. Elevated estrogen levels act through negative feedback at the hypothalamic and pituitary level to inhibit pituitary release of FSH. As previously mentioned, increasing concentrations of estrogen also affect FSH isoform production, a physiological change with an unknown clinical relevance.

The majority of estradiol lies bound either to sex hormone binding hormone (SHBG; 69%) or albumin (30%); only approximately 1% circulates freely. Estrone, a weak estrogen, circulates more freely (8% bound to SHBG, 85% to albumin). Multiple factors affect SHBG levels, with subsequent changes to the amount of free estradiol to follow. These include body mass index, tobacco use, modulators of hepatic P450 enzymes, and diabetes.

Estrogen is primarily metabolized in the liver through the P450 cytochrome mechanism. The major metabolite progesterone imposes in urine is 3-methoxy-2-hydroxyestrone glucuronide; however, up to 20% may be excreted in the feces.

Progesterone

In addition to preparing the endometrium for implantation, luteal phase progesterone mediates negative feedback at the hypothalamic-pituitary level primarily by inhibiting GnRH neurons [7880]. Progesterone also plays an obligate role in ovulation, with a small increase in synthesis noted in the periovulatory period [81]. Like estradiol, circulating free progesterone makes up a small percentage of the total concentration. Less than 2% of progesterone circulates as free hormone, with the remainder bound primarily to albumin (80%). Progesterone is principally metabolized in the liver by the 5α-reductase pathway, resulting in pregnanediol and pregnanetriol and conjugation with glucuronide. Pregnanediol glucuronide is excreted in the urine and can be used in research to assess ovulation.

Inhibin

Isolated in the 1980s, inhibin A and inhibin B are disulphide-linked dimers and members of the transforming growth factor-β family. Similar to other glycoproteins, they share a common α-subunit with one of two distinct β-subunits (βA and βB) [8283]. Inhibin is primarily secreted by granulosa cells; however, mRNA for both subunits has been identified in gonadotropes [8485]. Both inhibins affect gonadotropins almost exclusively through suppression of FSH secretion and augmentation of LH-stimulated androgen production [12].

Activin

Activin is a heterodimer composed of β-subunits of inhibin (βAB, βAA, βBB). The β-subunits are relatively ubiquitous; however, the α-subunit is restricted to the pituitary, gonads, and adrenal glands. Activin is synthesized in granulosa cells and also appears to have an autocrine function in the pituitary through its effects on gonadotropin synthesis. It stimulates FSH secretion in cultured pituitary cells by upregulation of β-subunit mRNA levels and augments LH- and IGF-stimulated androgen production by theca cells [5986]. Activin is required for adequate pituitary response to GnRH.

Follistatin

Follistatin is a relatively ubiquitous protein that directly affects FSH by inhibition of its synthesis and GnRH responsiveness [87]. Follistatin is upregulated by activin and downregulated by inhibin [88]. FoxL2 (associated with the syndrome of blepherophimosis, ptosis, and epicanthus inversus as well as premature ovarian failure) has been implicated in the enhancement of follistatin gene transcription [89].

Summary

Female reproduction is a complex process that involves the integration of messages directly and indirectly received by the hypothalamus about the nutrient status, stress, and hormone exposure from external and internal environments. Information processed by GnRH neurons affects the pulse amplitude and frequency of gonadotropin release from the pituitary. This in turn affects gonadal steroidal production, and ovarian folliculogenesis and ovulation. The failure of any one organ in this triad results in disruption of female reproduction. The remaining chapters in this book will expound on factors that disrupt the function of the hypothalamic-pituitary-ovarian axis and give rise to reproductive dysfunction or amenorrhea.

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