After studying this chapter you should be able to:
Knowledge criteria
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Describe the basic principles of the formation of the gametes
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Describe the physiology of the normal menstrual cycle
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Describe the physiology of coitus, fertilization and implantation
Clinical competency
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Counsel a couple about the fertile period
Oogenesis
Primordial germ cells originally appear in the yolk sac and can be identified by the fourth week of fetal development ( Fig. 2.1 ). These cells migrate through the dorsal mesentery of the developing gut and finally reach the genital ridge between 44 and 48 days post-conception. Migration occurs into a genital tubercle consisting of mesenchymal cells that appear over the ventral part of the mesonephros. The germ cells form sex cords and become the cortex of the ovary.
The sex cords subsequently break up into separate clumps of cells and by 16 weeks these clumped cells become primary follicles, which incorporate central germ cells.
These cells undergo rapid mitotic activity and, by 20 weeks of intrauterine life, there are about 7 million cells, known as oogonia . After this time, no further cell division occurs and no further ova are produced. By birth, the oogonia have already begun the first meiotic division and have become primary oocytes. The number of primary oocytes falls progressively and by birth is down to about 1 million and to about 0.4 million by puberty.
Meiosis
The process of meiosis results in 23 chromosomes being found in each of the gametes, half the number of chromosomes found in normal cells. With the fertilization of the egg by a sperm, the chromosome count is returned to the normal count of 46 chromosomes. Fusion of the sperm and the egg occurs when the first of two meiotic divisions of the oocyte have already been completed; with the second meiotic division occurring subsequently and being completed prior to the 23 chromosomes of the male gamete joining those of the female gamete within the nucleus of the cell, and forming what is called the zygote that will become the embryo.
In meiosis, two cell divisions occur in succession, each of which consists of prophase, metaphase, anaphase and telophase. The first of the two cell divisions is a reduction division and the second is a modified mitosis in which the prophase is usually lacking ( Fig. 2.2 ). At the end of the first meiotic prophase, the double chromosomes undergo synapsis, producing a group of four homologous chromatids called a tetrad . The two centrioles move to opposite poles. A spindle forms in the middle and the membrane of the nucleus disappears. During this prophase period of meiosis I the double chromosomes, which are closely associated in pairs along their entire length, undergo synapsis, crossing over and undergoing chromatid exchange, with these processes accounting for the differences seen between two same sex siblings despite the fact the female gametes came from the same mother.
The primary oocytes remain in suspended prophase until sexual maturity is reached, or even much later, with meiosis I not recommencing until the dominant follicle is triggered by luteinizing hormone (LH) to commence ovulation. In anaphase, the daughter chromatids separate and move towards opposite poles. Meiosis II commences around the time the sperm attached to the surface of the oocyte and is completed prior to final phase of fertilization.
Thus, the nuclear events in oogenesis are virtually the same as in spermatogenesis, but the cytoplasmic division in oogenesis is unequal, resulting in only one secondary oocyte. This small cell consists almost entirely of a nucleus and is known as the first polar body. As the ovum enters the Fallopian tube, the second meiotic division occurs and a secondary oocyte forms, with the development of a small second polar body. In the male the original cell containing 46 chromosomes ultimately results in 4 separate spermatozoa, each being of the same size but containing only 23 chromosomes (see Spermatogenesis, below).
Follicular development in the ovary
The gross structure and the blood supply and nerve supply of the ovary have been described in Chapter 1 . However, the microscopic anatomy of the ovary is important in understanding the mechanism of follicular development and ovulation.
The surface of the ovary is covered by a single layer of cuboidal epithelium. The cortex of the ovary contains a large number of oogonia surrounded by follicular cells that become granulosa cells. The remainder of the ovary consists of a mesenchymal core. Most of the ova in the cortex never reach an advanced stage of maturation and become atretic early in follicular development. At any given time, follicles can be seen in various stages of maturation and degeneration ( Fig. 2.3 ). About 800 primary follicles are ‘lost’ during each month of life from soon after puberty until the menopause, with only one or two of these follicles resulting in release of a mature ovum each menstrual cycle in the absence of ovarian hyperstimulation therapy. This progressive loss occurs irrespective of whether the patient is pregnant, on the oral contraceptive pill, having regular cycles or is amenorrhoeic, with the menopause occurring at the same time irrespective of the number of pregnancies or cycle characteristics. The vast majority of the follicles lost have undergone minimal or no actual maturation.
The first stage of follicular development is characterized by enlargement of the ovum with the aggregation of stromal cells to form the thecal cells. When a dominant follicle is selected at about day 6 of the cycle, the innermost layers of granulosa cells adhere to the ovum and form the corona radiata . A fluid-filled space develops in the granulosa cells and a clear layer of gelatinous material collects around the ovum, forming the zona pellucida . The ovum becomes eccentrically placed and the Graafian follicle assumes its classic mature form. The mesenchymal cells around the follicle become differentiated into two layers, forming the theca interna and the theca externa .
As the follicle enlarges, it bulges towards the surface of the ovary and the area under the germinal epithelium thins out. Finally, the ovum with its surrounding investment of granulosa cells escapes through this area at the time of ovulation.
The cavity of the follicle often fills with blood but, at the same time, the granulosa cells and the theca interna cells undergo the changes of luteinization to become filled with yellow carotenoid material. The corpus luteum in its mature form shows intense vascularization and pronounced vacuolization of the theca and granulosa cells with evidence of hormonal activity. This development reaches its peak approximately seven days after ovulation and thereafter the corpus luteum regresses unless implantation occurs, when β-human chorionic gonadotropin (β-hCG) production by the implanting embryo prolongs corpus luteum function until the placenta takes over this role at about 10 weeks of gestation. The corpus luteum degeneration is characterized by increasing vacuolization of the granulosa cells and the appearance of increased quantities of fibrous tissue in the centre of the corpus luteum. This finally develops into a white scar known as the corpus albicans ( Fig. 2.4 ).
Hormonal events associated with ovulation
The maturation of oocytes, ovulation and the endometrial and tubal changes of the menstrual cycle are all regulated by a series of interactive hormonal changes ( Fig. 2.5 ).
The process is initiated by the release of the gonadotrophin-releasing hormone (GnRH), a major neurosecretion produced in the median eminence of the hypothalamus. This hormone is a decapeptide and is released from axon terminals into the pituitary portal capillaries. It results in the release of both follicle-stimulating hormone (FSH) and LH from the pituitary.
GnRH is released in episodic fluctuations with an increase in the number of surges being associated with the higher levels of plasma LH commencing just before mid-cycle and continued ongoing GnRH action being required to initiate the huge oestrogen-induced LH surge.
The three major hormones involved in reproduction are produced by the anterior lobe of the pituitary gland or adenohypophysis, and include FSH, LH and prolactin. Blood levels of FSH are slightly higher during menses and subsequently decline due to the negative feedback effect of the oestrogen production by the dominant follicle. LH levels appear to remain at a relatively constant level in the first half of the cycle, however there is a marked surge of LH 35–42 hours before ovulation and a smaller coincidental FSH peak ( Fig. 2.5 ). The LH surge is, in fact, made up of two proximate surges and a peak in plasma oestradiol precedes the LH surge. Plasma LH and FSH levels are slightly lower in the second half of the cycle than in the pre-ovulatory phase, but continued LH release by the pituitary is necessary for normal corpus luteum function. Pituitary gonadotrophins influence the activity of the hypothalamus by a short-loop feedback system between the gonadotrophins themselves and the effect of the ovarian hormones produced due to FSH and LH action on the ovaries.
Oestrogen production increases in the first half of the cycle, falls to about 60% of its follicular phase peak following ovulation and a second peak occurs in the luteal phase. Progesterone levels are low prior to ovulation but then become elevated throughout most of the luteal phase. These features are shown in Figure 2.5 .
There are feedback mechanisms that regulate the release of FSH and LH by the pituitary. This is principally achieved by the oestrogens and progesterone produced by the ovaries. In the presence of ovarian failure, as seen in the menopause, the gonadotrophin levels become markedly elevated because of the lack of ovarian oestrogen and progesterone production.
Prolactin is secreted by lactotrophs in the anterior lobe of the pituitary gland. Prolactin levels rise slightly at mid-cycle, but are still within the normal range, and remain at similar levels during the luteal phase and tend to follow the changes in plasma oestradiol-17β levels. Prolactin tends to control its own secretion predominantly through a short-loop feedback on the hypothalamus, which produces the prolactin-inhibiting factor, dopamine. Oestrogen appears to stimulate prolactin release, in addition to the release of various neurotransmitters, such as serotonin, noradrenaline (norepinephrine), morphine and enkephalins, by a central action on the brain. Antagonists to dopamine such as phenothiazine, reserpine and methyltyrosine also stimulate the release of prolactin, whereas dopamine agonists such as bromocriptine and cabergoline have the opposite effect.
Hyperprolactinaemia inhibits ovulation by an inhibitory effect on hypothalamic GnRH production and release and is an important cause of secondary amenorrhoea and infertility.
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