Gab Kovacs1 and Paula Briggs2
(1)
Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
(2)
Sexual and Reproductive Health, Southport and Ormskirk Hospital, Southport, UK
Hormonal Control of Ovulation
Development of the Graafian Follicle
The Effect of Oestrogen and Progesterone on the Endometrium
Ovulation of the Follicle
The Corpus Luteum and Pregnancy
Basal Body Temperature
Cervical Mucous Changes and the Basis of the Billings Method of Natural Family Planning
Fertilisation
Early Embryonic Development and Implantation
Understanding menstrual physiology is the basis for understanding the whole concept of fertility including the mechanism of action of contraception. It is also the basis for natural family planning.
Hormonal Control of Ovulation
The menstrual cycle is controlled by the hypothalamo- pituitary axis. The pituitary is a small gland the size of a cherry that sits at the base of the brain, behind the bridge of the nose. It is stimulated by Gonadotrophin Releasing Hormone (GNRH), a deca-peptide (a hormone made up of ten amino acids). GNRH is secreted from the hypothalamus via venous channels in a pulsatile manner (Fig. 1.1). It is the frequency and the amplitude of these pulses which determines the response from the pituitary gland. Follicle Stimulating Hormone (FSH), is secreted by the anterior pituitary gland and stimulates the Graafian follicles. FSH levels are higher in the early follicular phase of the menstrual cycle (initiating follicular development) than in the luteal phase. It has a small peak, which accompanies the very important Luteinising Hormone (LH) peak, just prior to ovulation. The anterior pituitary also secretes LH, which remains at basal levels throughout the cycle with the exception of the LH peak. The LH peak commences about 36 h prior to ovulation, and it last for 24 h, with the peak occurring 24 h prior to ovulation.
Fig. 1.1
The hypothalamo-pituitary-ovarian axis
Development of the Graafian Follicle
As the follicles start to develop from Day 1 of the cycle, the granulosa cells of the follicles start to secrete the hormone oestrogen. Oestrogen has an effect on many parts of the body and also has the effect of regulating the release of gonadotrophins. As the oestrogen level rises, the FSH secretion is reduced, so that usually only one follicle matures. This is a negative feedback. Various follicles have different sensitivity to FSH, and it is the most sensitive follicle, which becomes dominant, the one destined to ovulate. The other developing follicles undergo atresia. The hormone Inhibin (type A and B) is also secreted from the ovary and it too has an inhibitory effect on the pituitary with respect to FSH secretion.
The Effect of Oestrogen and Progesterone on the Endometrium
Circulating oestrogen causes both the glands and the stroma of the endometrium to proliferate. Following ovulation progesterone, is released resulting in secretory changes in the endometrium with tortuous glands containing lots of glycogen able to provide a welcoming nutritional environment should an embryo arrive.
Ovulation of the Follicle
When the follicle is ready to ovulate, oestrogen primes the pituitary gland to release LH. in a peak. This is responsible for the release of the ovum from the follicle about 36 h after the start of the rise, and 24 h after the LH peak. The hormone would more accurately be called “Ovulating Hormone” and that is what Luteinising Hormone means (as it induces the Corpus Luteum – yellow body- after ovulation).
The Graafian follicle, as well as providing the gamete to form a new embryo, is also responsible for the secretion of the steroid hormones, oestrogen and progesterone. At the beginning of each menstrual cycle, several follicles start to develop, but usually only one matures, with the other follicles degenerating, a process called atresia.
As the leading follicle matures, it reaches a diameter of nearly 20 mm, and bulges out from the surface of the ovary. It is similar to a hen’s egg where the yolk corresponds to the ovum and the egg white the granulosa cells. The “egg shell” in the Graafian follicle is represented by the outer covering of theca interna and theca externa.
When the follicle reaches 16–18 mm in diameter, ovulation occurs in response to the LH peak. The shell of the egg is cracked and the yolk (the ovum) is released to find its way into the Fallopian tube where fertilization may occur if sperm are present.
During the development of the Graafian follicle, the female germ cell also has to mature and to reduce its chromosome compliment from 46 (diploid) to 23 (haploid).
When the mature oocyte is released from the ovary, it is about 135 μm (0.135 mm) in diameter and is surrounded by cells called the Cumulus Oophorus.
The tissue forming the theca interna and externa (the human equivalent to the egg shell) remain as the corpus luteum. The yellow colour comes from the deposition of carotene in the cytoplasm of the thecal cells. The corpus luteum is responsible for secretion of hormones essential for a pregnancy to be established (oestrogen and progesterone). These hormones stimulate the uterine lining (endometrium) to prepare, in anticipation of an embryo arriving in a few days time, if a sperm has fertilised the ovum.
It is the combined secretion of oestrogen and progesterone that induces the secretory changes in the endometrium.
The Corpus Luteum and Pregnancy
The corpus luteum has an inherent life span of about fourteen days, and as it succumbs, in the absence of a pregnancy, the levels of oestrogen and progesterone decline, resulting in an influx of inflammatory white blood cells (leucocytes) and the release of chemicals called prostaglandins and cytokines. This results in the endometrium sloughing off, and the commencement of the next menstrual period. The first day of bleeding is defined as “day one” of the next cycle. However if fertilisation occurs, the early embryo secretes beta Human Chorionic Gonadotrophin (bHCG), which has a stimulatory effect on the corpus luteum, rescues it, and maintains its hormonal function, so that the levels of oestrogen and progesterone no not decline, but continue to increase. This maintains the endometrium, and prevents the onset of the next menstrual period. It is the role of the corpus luteum to secrete adequate oestrogen and progesterone during the first three months of the pregnancy, a role then adopted by the placenta at about 3 months.
Basal Body Temperature
Progesterone is thermogenic, elevating body temperature by a small and sustained amount. Measuring a woman’s basal body temperature on waking on a daily basis will show an elevation of about half a degree centigrade once ovulation has taken place and progesterone is secreted. Whilst the pattern is not always clear, in many women it is a useful method of determining if and when ovulation has occurred. This phenomenon of luteal temperature rise is the basis of the “temperature method” of natural family planning, and can also be used for assessing whether, when and how well ovulation is taking place, in the assessment of a subfertile couple, and in the management of ovulation stimulation with clomiphene citrate (see Chapter 16).
Cervical Mucous Changes and the Basis of the Billings Method of Natural Family Planning
Another very important effect of oestrogen and progesterone is on the secretions of the cervical glands- the cervical mucous. Following the observations of the Billings, we can use the changes in cervical mucous as a bioassay of the menstrual cycle, thus pinpointing fertile and infertile days.
The quantity and quality of cervical mucous varies depending on the circulating levels of oestrogen and progesterone.
The effect of oestrogen is to stimulate the production of copious amounts of mucous from the cervical glands. The physical composition of cervical mucous depends on its water and salt concentration. Oestrogen encourages slippery mucous referred to in the Billings method of natural family planning (NFP) as “Basic Fertile Pattern (BFP)”. When progesterone is secreted and reaches the cervical glands, it changes the salt concentration to result in “Basic Infertile Pattern (BIP)” mucous. It is this defined change from BFP to BIP that defines the time of ovulation, and enables couples to use it for NFP.
These physiological changes are logical, as at the time just prior to ovulation, it is important that the mucous facilitates the passage of the sperm through the cervix and the Fallopian tubes. After ovulation the thickened BIP mucous is protective, not allowing sperm (which no longer have any physiological function), and maybe micro-organisms, from entering the uterus.
Fertilisation
The human ovum is released from the surface of the ovary at ovulation and finds its way into the Fallopian tube with the help of the finger like projections on the tubes called fimbriae. The ovum then progresses along the Fallopian tube with fertilisation taking place in the lateral one third (called the ampulla). The window of opportunity for fertilisation is of the order of a few hours. It is therefore important that the oocyte is exposed to fertile sperm early in its journey in the Fallopian tube. Sperm deposited in the vagina enter the cervical canal, where they are protected by the mucous from the acidic environment of the vagina. To maximize the chance of fertilisation, sperm need to be deposited into the vagina prior to ovulation. It is believed that sperm will survive for several days in the mucous environment, so couples who want to conceive are advised to have sexual intercourse at least every second day from when menstruation finishes until ovulation is thought have occurred.
Conversely, couples using NFP must abstain around the ovulatory period. The problem is that it is uncertain how long a sperm may survive, and pregnancy has been documented even when sexual intercourse did not occur for several days prior to ovulation.
Fertlisation commences with contact between the oocyte and sperm, and climaxes with the fusion of their two haploid pronuclei (each containing 23 chromosomes) resulting in a diploid embryo (with 23 pairs of chromosomes (46)). After the attachment of the sperm to the ovum, the acrosomal cap of the sperm releases the enzyme hyaluronidase, which helps to break through the zona pellucida membrane surrounding the oocyte. As the successful sperm enters the oocyte, it stimulates the zona pellucida to undergo the acrosome reaction, which prevents any further sperm from entering the oocyte.
Early Embryonic Development and Implantation
After fertilisation, the embryo undergoes repeated cell division known as cleavage and segmentation, which transforms it into a solid clump of cells. At the sixteen cell stage it is called the “morula”. Our understanding of this stage of human embryo formation is now much improved due to in vitro fertilisation and the ability to observe embryos in the laboratory. Division into two cells usually occurs by 24 h after fertilisation, with the embryo reaching four to eight cells by 48 h (Fig. 1.2).
Fig. 1.2
The menstrual cycle
As the embryo keeps dividing it is also travelling along the Fallopian tube towards the uterine cavity. This movement is accomplished by both the movement of the fine hairs (cilia) lining the tube as well as contractions of the muscles within the tubal walls. The clump of embryonic cells on about the fifth day undergoes cavitation, and accumulates fluid to become a blastocyst. This is around the same time that it reaches the uterine cavity. The cells then differentiate into the inner cell mass which will form the embryo, and the trophobalst which forms the placenta and membranes. Nutrition during this journey is provided by the tubal and uterine secretions. The trophobalst then burrows into the superficial layer of the endometrium, and starts to establish the placenta, which will provide nutrition to the embryo, as well as the source of oestrogen and progesterone during the pregnancy.