3 Derrick Ebot, Haider Hilal, Michael Carroll, and James Coey After the development and differentiation of the gonads and external genitalia (see Chapter 1), the nascent reproductive organs remain in relative quiescence until the onset of puberty. Puberty is marked by the maturation of the genital organs, development of the secondary sex characteristics, acceleration of growth, and the occurrence of menarche in the female. The age at onset of puberty and the cadence at which puberty develops is dependent on many factors. In girls, increased ovarian and adrenal sex steroid secretion leads to the indicators of puberty such as breast development (thelarche) and appearance of pubic hair (pubarche). Usually these changes occur between 8 and 13 years of age. The mean age at menarche among different ethnic groups is between 12 and 13 years. In boys, the earliest physical appearance of puberty is an increase in testicular volume, usually occurring between 9 and 14 years of age. This early sexual development in both sexes is mostly due to the activity of the adrenal cortical steroids dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and androstenedione, and is referred to as adrenadarche. Adrenadarche is distinct from hypothalamic pituitary gonadal regulation of reproductive physiology (gonadarche). Increased gonadal steroidogenesis and the completion of gametogenesis during gonadarche are stimulated by enhanced secretion of the gonadotropins: luteinizing hormone (LH) and follicle‐stimulating hormone (FSH). The production of gonadal steroidogenesis is regulated by the hypothalamic gonadotropin‐releasing hormone (GnRH). GnRH is a 10‐amino‐acid peptide that is synthesized in specialized neuronal bodies of the arcuate nucleus of the medial basal hypothalamus. These GnRH‐producing neurons are limited in number (approximately 1000 to 2000). Normal gonadotropin secretion requires pulsatile release of GnRH. This pulsatile, rhythmic activity is an inherent property of GnRH neurons (termed the GnRH‐pulse generator), and various hormones and neurotransmitters can temper this rhythm. GnRH is transported to the anterior pituitary via the hypophyseal portal circulation where it activates gonadotropin secretion. Enhanced secretion of the gonadotropins, LH and FSH, stimulate increased gonadal steroidogenesis and the completion of gametogenesis during gonadarche (see Figure 3.1 for an outline of steroidogenesis). Figure 3.1 Steroidogenesis. A simplified scheme of steroidogenesis showing the various pathways and associated enzymes involved in the synthesis of the adrenal and gonadal steroid hormones. The timing of puberty is precisely controlled by a plethora of endogenous signals and environmental cues that impinge at different levels of the hypothalamic–pituitary–gonadal axis. The role of leptin and kisspeptin are key regulators of GnRH release and are important in the timing of puberty, where they act directly on the GnRH pulse generator. Furthermore, metabolic conditions and the amount of energy reserves play an essential role in the modulation the GnRH‐pulse generator and hence the timing of puberty. This makes good biological sense, especially in the female, so that the reproductive capacity, which implies the potential metabolic drainage of pregnancy and lactation, is only acquired when threshold energy stores and optimal metabolic conditions are achieved. Successful reproduction requires intact, healthy reproductive anatomy and functional endocrine signalling. This chapter will give an overview of the control of female and male reproductive endocrinology. The female reproductive system is responsible for the production and release of oocytes (oogenesis and ovulation), fertilization, embryo implantation and gestation, parturition (expelling the fetus from the uterus), and lactation (provision of milk during nursing). Reproduction function in the female is characterized by cycles of follicular development, ovulation and endometrial receptivity, and menstruation. From birth the ovaries contain a number of immature, primordial follicles. These follicles each contain similarly immature primary oocytes. The start of puberty in females is associated with the start of folliculogenesis and the onset of regular ovulatory and menstrual cycles. These cycles represent complex hormonal changes involving the hypothalamic–pituitary–ovarian axis (Figure 3.2). Figure 3.2 Female reproductive endocrinology. GnRH released from the hypothalamus stimulates the release of luteinizing hormone (LH) and follicle‐stimulating hormone (FSH) from the anterior pituitary. These gonadotropins stimulate the synthesis of the ovarian reproductive hormones. Oestrogen and progesterone are released into the circulation where they exert various hormonal responses including preparing the endometrium for implantation. They also have a negative effect, where increasing levels decrease gonadotropin release. Mid cycle, increasing oestrogen levels stimulates a surge of LH release. Inhibin, an ovarian peptide hormone, downregulates FSH release. This section will give a brief overview of the ovary and ovarian control. See Chapter 4 for more detail on the ovarian anatomy, the oocyte, and folliculogenesis. The ovary constantly alternates between two phases: The early stages of preantral follicular growth that precede the follicular phase do not require GnRH. Hormonal support from LH and FSH is required for further follicular development and antral formation. GnRH acts directly on the pituitary regulating the synthesis and release of these gonadotropins. Under the influence of FSH and LH, granulosa cells secret high levels of oestrogen along with inhibins that exert negative feedback on the pituitary. LH stimulates the theca interna cells to convert cholesterol to androgens (androstenedione), which is converted by FSH‐stimulated granulosa cells to oestrogen (estradiol). Oestrogen contributes to antral formation locally whilst rising; circulating levels have effects throughout the body. The marked increase in circulating levels that occur around mid‐cycle act on the pituitary and the hypothalamus through positive feedback causing a sudden surge in LH levels. This LH surge triggers the onset of ovulation. Ovulation is the process by which the oocyte is expelled from a bulge on the ovarian surface of the late tertiary (dominant or mature) follicle. This process is facilitated by a release of enzymes from follicular cells that digest connective tissue in the follicular wall, in turn triggered by the aforementioned burst in LH secretion. Just before ovulation the oocyte completes its first meiotic division. The resulting secondary oocyte, surrounded by the zona pellucida and granulosa cells (corona radiata), is expelled into the abdominal cavity. A rise in basal temperature occurs about 2 days prior to ovulation. Following ovulation, the remaining granulosa and surrounding capsule differentiate to form the CL. LH maintains the CL, which secretes large amounts of progesterone and smaller amounts of oestrogen and inhibin. Progesterone and inhibin exert negative feedback on the anterior pituitary preventing a further LH surge. The CL functions for approximately 2 weeks before degenerating to form corpus albicans if fertilization does not occur, otherwise the CL will become the CL of pregnancy. The placenta will then continue to secret the oestrogens and progesterone for the maintenance of pregnancy. The mechanisms that govern the degeneration of the CL have yet to be fully elucidated but are thought to involve a complex interplay between declining levels of LH along with prostaglandins and oestrogen released from the luteal cells. The demise of the CL marks the end of the luteal phase and the start of a new follicular phase as a result of a fall in plasma progesterone and oestrogen levels. Withdrawal of the inhibitory effect of these hormones on the anterior pituitary stimulates the production of LH and FSH. Fluctuations in circulating levels of oestrogen and progesterone during the ovarian cycle bring about a menstrual cycle of a similar, 28‐day duration. The most obvious manifestation is menstrual bleeding over 3–5 days in a fertile female, although less obvious changes take place throughout the cycle. The uterus is comprised of two main layers: (1) the myometrium – an outer smooth muscle layer and (2) the endometrium – an inner lining containing numerous blood vessels and glands. Raised oestrogen levels from during the follicular phase of the ovarian cycle stimulates the growth of both the endometrium and myometrium. The hypertrophic effect on the cells of the endometrium (proliferative phase of menstrual cycle) brings about a two‐ to threefold increase in thickness by the time ovulation takes place. It also induces the synthesis of progesterone receptors; thus progesterone can only have an effect on the endometrium after being primed by oestrogen. Progesterone facilitates the endometrial implantation of a fertilized ovum through the accumulation of electrolytes, water, and the glandular secretion of large amounts of glycogen. The menstrual cycle consists of three phases: menstrual, proliferative, and secretory or progestational phases.
Fundamentals of Reproductive Endocrinology
Introduction
Female Reproductive Endocrinology
The Ovaries and Ovarian Cycle
Folliculogenesis
Control of the Ovarian Cycle
Control of Ovulation
Control of the Corpus Luteum
The Uterus and Menstrual Cycle
Menstrual Phase
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