THE MENSTRUAL CYCLE

The menstrual cycle is the term given to the period from the first day if a menstrual bleeding (menstruation, menses, period) up to the last day before the next menstrual bleeding (average 28 days).

The changes occurring at the genital organs within this period of the time are regulated for the greater part by the sex hormones of the ovary. For this reason, the menstrual cycle is divided in accordance with the ovarian development into:

• The follicular phase
• The luteal phase.

When these two are present, the menstrual cycle is said to be BIPHASIC.

The function of the ovaries is subject to hormonal regulation. A few general principles of the hormone system are explained here for a better understanding of the hormonal processes. This will be followed by an explanation of the endocrine regulation of the menstrual cycle.

Functions of the hormones

Hormones are endogenous substances. They serve to transfer information between cells or between the compartments (functional units) of a cell.

Hormones regulate metabolic processes mediated enzymatically in the target cells In this connection, hormones can activate of inactivate by, for example, changing the concentration or activity of the enzymes.

In this way, the hormones fulfil the following tasks:

• Regulation of the function of certain organs or organ cysts, e.g. the reproductive function of the genital organs.
• Maintenance of the homeostasis (the internal environment of the organism), e.g. by keeping the blood sugar level constant
• Adaptation of the body's response to increased physical or mental stress
• Promotion of physical and mental development and maturity

Hormones are produced primarily in endocrine glands such as the pituitary. Endocrine glands are structures with internal secretion, i.e. the hormones produced there are released into the blood stream. In addition, there are accumulations of endocrine cells which do not exist as independent organs, but are hormone-producing parts of an organ (e.g. the theca and granulosa cell layer of the follicles). Certain nerve cells (e.g. so-called nuclear areas in he hypothalamus) also produce hormones.

There are various hormonal information pathways in the body:

• Hormonal information is exchanged mainly via the blood stream. Considerable distances can be covered in the body in this way. In many cases, this system can be covered in the body in this way. In many cases, this system of hormonal communication is regulated by the hypothalamus and the pituitary. The hypothalamo-pituitary system is, for example, the superordinate regulatory centre of the sexual glands (ovaries and testes).
• Transmission of information may also be confined locally. The hormonal message is exchanged directly between cells lying spatially close together. The structures within a particular can also communicate with each other, i.e. Certain cells and self-regulating.

Hormones display greatly varying chemical structures. Their effect is therefore selective, i.e. a hormone acts only on quite particular target cells. to do this, the hormone binds to a specific binding sties (receptors) of the target cells in accordance with the lock and key principle.

Endogenous sex hormones

Sex hormones in the narrower sense are represented by a number of STEROID HORMONES. Among other things, they are responsible for the regulation of reproduction and the development of the male and female sexual characteristics. they are produced in various organs of the body. The sexual glands (gonads) produce:

• Oestrogens
• Progestogens
• Androgens

Oestrogens and progesterone's are FEMALE SEX HORMONES, while androgens are MALE SEX HORMONES.

Male and female sex hormones can be produced both by the man and by the woman. For example, small amount of male sex hormones are always present in the female body as well.

The most important endogenous estrogens are ESTRADIOL, ESTRONE and ESTRIOL. Their biological activity decreases in this order.

The most potent endogenous progestogen is PROGESTERONE, another name for which is the LUTEOHORMONE or PROGESATATIONAL HORMONE.

The most important naturally occurring androgens include TESTOSTERONE, ANDROSTENEDIONE and ANDROSTERONE. Androstenedione is the quantitatively most important androgen on the women. Androgens are the precursors of estrogen biosynthesis.

For a better understanding of the following sections, they are prefaced by a recapitulation of some general basic terms of organic chemistry. This is followed by an explanation of the biosynthesis, cellular mechanism if action and degradation of the sex hormones.

Basic terms of organic chemistry

Sex hormones (steroids) are ORGANIC COMPOUNDS. Organic chemistry is the chemistry of carbon compounds.

Carbon atoms (C) combine both with each other and with atoms of other elements, particularly with hydrogen (H). Apart from carbon and hydrogen, only relatively few other elements are involved in the construction of organix compounds. They include oxygen (O), nitrogen (N), fluorine (F), chlorine (Cl) and phosphorus (P).

Carbon is tetravalent, i.e., every carbon atom forms four bonds. Carbon can form single, double and also triple bonds, which are denoted by one, two or three lines between the symbols of the elements.

A simplified way to write down the structure of organic compounds has been devised in which the carbon atoms and the hydrogen atoms bound to them are left out. To denote the position od individual C atoms in a compound, the C atoms are numbered consecutively.

Compounds made up exclusively of carbon and hydrogen are called HYDROCARBONS. They form the basic structure of all organic compounds.

The uniqueness and multiplicity of organic compounds stem form the fact that carbon atoms can be combined with each other in various ways. The result is a variety of carbon structures which can be in the shape of chains or rings. Carbon chains linked to a ring system are known as SIDE CHAINS.

Another reason for the multiplicity of organic compounds are the FUNCTIONAL GROUPS in the hydrocarbon structures. In this case, one or more hydrogen atoms are replaced by atoms of other elements. Chemical reactions such as construction, conversion or degradation of the various compounds are attributable to the responsiveness of the functional groups.

The nature of the bond (single, double or triple bond) between the individual atoms is also important as regards the responsiveness of organic compound.

Sex hormones and cholesterol

The basic structure of all sex steroids is derived from sterane (synonym: gonane). Compounds derived from sterane are known quite generally as STEROIDS. Sterane is a ring system made up of 17 C atoms;, it consists of four in connected rings - three cyclohexane rings (six side) and a cyclopentane ring (five sides). This compound, which does not occur in nature, is also known as cyclopentanopherhydrpenthrene.

Distinguishing features of the individual steroids are:

• The number of carbon atoms
• The functional groups of the steroid structure
• The type of bond between the carbon atoms
• The spatial arrangement of the rings among each other

All four parameters have an influence on the biological effect of the different steroids.

Cholesterol, the parent substance for the production of sex steroid, is a C27 steroid. It carries a methyl group (CH3 group, indicated in the simplified structure as single lines) at each of the positions C10 and C13. The side chain in C17 is formed from eight C atoms. Ring A carries a hydroxyl group (OH group) in position C3 while a C-C double bond is shifted from ring B to ring A.

Androgens belong to the group of C19 steroids. Instead of the side chain, they have a functional group, a keto function or a hydroxyl group in position C17. In the case of androsteneidone and testosterone, ring A displays a keto function and a double bond; the latter is absent from the structure of androsterone.

The estrogens produced in the body are C18 steroids. They lack a methyl group on position C10. Common to all natural estrogens is the aromatic A ring with the hydroxyl group. Estrone (E1) and estradiol (E2) have a keto function or a hydroxyl group in position C17. Estradiol (E3) has a further hydroxyl group in position C16.

Biosynthesis of sex hormones

Cholesterol is the parent compound for all steroid hormones regardless of their site of production, the synthetic pathway differs in the different phases of the cycle.

In the follicular phase, progesterone is primarily an intermediate product in the synthesis of androgens.

In the female organism, the androgens androstenedione and testosterone are the precursors of estrogen production. The process follows two main synthetic pathways:

• Oestradiol is produced from androstenedione via testosterone.
• In addition, estrone can be produced from androstenedione. The double arrow between estrone and estradiol shown in the illustration symbolises that the two compounds can be converted to each other.

The conversion of androgens to estrogens is done enzymatically. The most important enzyme in this chain of reactions is the AROMATASE. Aromatisation of ring A in the case of estrone and estradiol takes place under separation of the methyl group in position C10.

During the luteal phase, biosynthesis of the sex hormones stops for the greater part at the stage of progesterone. The blood concentration of progesterone os correspondingly high in this phase of the cycle. Only a small fraction of progesterone is converted to estrogen in the second half of the cycle.

Binding proteins

In the blood, steroid hormones are bound overwhelmingly to binding proteins (carrier proteins) and are transported in this way from their site of production to their site of action. The portion bound to protein can be as high as 99% with the different sex hormones. Only the non-protein-bound (free) portion of the hormone is regarded as biologically active.

The most important binding proteins for sex hormones are:

• Sex hormone binding globulin (SHBG)
• Transcortin
• Albumin

It is believed that the hormone-binding proteins have the following functions:

• Protection from metabolism (degradation or conversion)
• Regulation of the biological activity

Oestrogens are bound mainly to SHBG, but also to albumin and transcortin.

Progesterone is bound in blood to transcortin and albumin.

Testosterone is bound primarily to SHBG. It is thought that androsenedione and other androgens are bound mainly to albumin and transcortin.

Cellulat mechanism of action of the sex hormones

The cellular mechanism of action of the sex hormones has not yet been clarified in all detail and for every type of hormone. In general, however, the principle of the RECEPTOR-MEDIATED effect is accepted; this principle can be explained in simplified terms as follows:
The sex hormone enters the cell through the cell membrane. Once there, the hormone is bound to a specific protein, the receptor. Whether binding takes place in the cytoplasm or after translocation into the cell nucleus has not yet been clarified.

The classical model assumes that binding to the receptor takes place in the cytoplasm. The hormone receptor complex reaches the cell nucleus through the nuclear membrane and binds there to DNA.

The synthesis of a messenger molecule (messenger RNA, m-RNA) is induced by the binding of the hormone-receptor complex to a certain section of DNA which is specific to this complex. During this process, the "blue-print" for certain proteins is "rewritten" (transcribed) to the M-RNA.

The m-RNA leaves the cell nucleus. Ribosome's accumulate in the cytoplasm. The blue-print transferred with the m-RNA now serves as the basis for the synthesis of the proteins (translation).

The resulting proteins are the actual cellular response to the sex hormones:

• As enzymes, they prompt further reactions, e.g. the synthesis of hormones such as progesterone.
• As receptors, they serve as the binding site for further steroids. Estrogens, for example, can induce the production of progesterone receptors.

Metabolism and elimination of sex hormones

The metabolism, i.e. the inactivation, of the sex hormones takes place mainly in the liver. Because the steroid hormones and their degradation products are hardly soluble in water, they are converted primarily with glucuronic and sulphuric acid to readily water-soluble compounds (glucuronides, sulphates), which can easily be excreted from the body. Excretion takes place mainly via the kidneys (with the urine). Another excretory pathway for the sex hormones is via the biliary tract into the intestine.

Metabolism and elimination of oestrogen

The main metabolite of progesterone is pregnanediol. It is produced in the liver through the uptake of hydrogen atoms and is then conjugated (combined) with glucuronic acid. Other metabolites include 17-hydroxyprogesterone and pregnanetriol.

Metabolism and elimination of androgens

Androgens are converted in the liver to numerous degradation products. Testosterone is broken down primarily into the only slightly androgenic metabolites androsterone and isoandrosterone. The degradation products of the androgens are conjugated with glucuronic acid or sulphuric acid and excreted with the urine.

The regulatory system hypothalamus-pituitary-ovaries

The function of the ovaries is subject to hormonal regulation by the HYPOTHALAMUS (part of the mid-brain) and the PITUITARY. The hypothalamus, pituitary and ovaries form a system for the regulation of the female reproductive functions. This regulatory system is organised hierarchially. They hypothalamus and the pituitary together represent the control centre (hypothalamo-pituitary system), with the hypothalamus being superordinate regulatory organ. The pituitary fulfils a mediator function between the hypothalamus and the ovaries.

The exchange of information between these organs is carried out by different hormones.

Certain nerve cells of the hypothalamus produce RELEASING HORMONES. The releasing hormone GnRH (gonadotropin-releasing hormone) induces the synthesis and release of the GONADOTROPINS FSH and LH in the pituitary.

FSH (follicle-stimulating hormone) together with LH (luteinising hormone) stimulates follicular maturation in one of the two ovaries. The granulosa and theca cell layers, which are able to synthesise sex hormones, develop in the maturing follicle. LH induces ovulation and gives rise to conversion of the ruptured follicle to the hormone-producing corpus luteum.

At the same time, the gonadotropins stimulate the production of the female sex hormones in the ovary. In the first phase of the cycle, mainly estrogens are produced in the follicle under the influence of FSH. In the luteal phase, mainly progesterone is produced in the corpus luteum under the influence of LH.

The concentrations of the hormones produced in the hypothalamus, pituitary and ovary are adapted to the respective physiological situation during the cycle. (1) An important role in this is played by the sex hormones, which influence the superordinate hypothalamo-pituitary system by means of what is called a FEED-BACK mechanism.

Feed-back mechanisms can be negative or positive, A feed-back is NEGATIVE if the sex hormones reduce the secretion of hormones by the hypothalamus and pituitary. A feed-back is said to be POSITIVE if the endocrine activity of the hypothalamus and pituitary is increased.

The hypothalamus, pituitary and ovary form a self-regulating system by means of these feed-back mechanisms.

Hypothalamus and pituitary

The hypothalamus and the pituitary are closely associated both anatomically and functionally.

Anatomical relationship between hypothalamus and pituitary.

The HYPOTHALAMUS is a region in the lower part of the mid-brain.

The hypothalamus is divided into distinguishable nuclear areas (collections of nerve cells). A region of importance in the regulation of the female cycle lies within the accurate nucleus (synonym: infundibular nucleus) - an arch-shaped nuclear area. The hypothalamus connects with other regions of the brain via nervous communications. (1)

(1) Nervous stimuli from superordinate regions of the brain (e.g. the cortex and the limbic system) also reach the hypothalamus. Consequently, mental factors can also affect the functions regulated by the hypothalamus (e.g. stress-induced disturbances of the menstrual cycle).

The pituitary is a cherry-sized endocrine gland situated directly underneath the hypothalamus in a small recess in the base of the cranial cavity. The gland is divided into anterior and posterior lobes. The gonadotropin-producing glandular cells are situated in the ANTERIOR LOBE.

The hypothalamus and the pituitary are connected to each other via the funnel-shaped PITUITARY STALK ( INFUNDIBULUM).

A direct vascular connection exists between the hypothalamus and the anterior pituitary via the PITUITARY PORTAL SYSTEM. The portal system forms a dense network of capillaries (extremely fine vessels) at the entrance to the pituitary stalk. The system continues into the anterior lobe via long portal vessels in the infundibulum,. It then ramifies again into a capillary network which surrounds the glandular cells of the anterior pituitary. The capillary network allows intensive exchange of substances.

Functional relationship between hypothalamus and pituitary

GnRH is produced by special nerve cells, the ENDOCRINE NEURONES, in the hypothalamus. Endocrine neurones are able to produce hormones in response to a nervous stimulus. The nervous stimuli are carried by neurotransmitters from neurones of other cerebral regions to the endocrine neurones.

IN THIS WAY, THE HYPOTHALAMUS BECOMES A SWITCHPOINT FOR NERVOUS AND ENDOCRINE PROCESSES.

The axons of the GnRH-producing neurones pass to the vicinity of the pituitary stalk. GnRH is released at the axon endings after nervous stimulation. It then reaches the anterior pituitary directly via the portal system.

GnRH is released in pulses. In the follicular phase, GnRH is released at relatively constant intervals of about 90 minutes distributed over the day. In the luteal phase, the interval between the pulses is prolonged to several hours. The regularity of the pulses if highly important. Longer intervals possibly caused by illness of medicines lead to a disturbance of gonadotropin secretion. The consequences is impairment of ovarian function.

GnRH stimulates the production of the gonadotropins FSH and LH in the anterior pituitary. The gonadotropins can be released immediately. In keeping with the pulsatile GnRH stimulation, FSH and LH likewise display a pulsatile pattern of secretion., However, the anterior pituitary can also store gonadotropins, making use of vesicles (small blisters with store fluid) as the storage containers.

INFLUENCE OF OVARIAN SEX HORMONES ON THE HYPOTHALAMO-PITUITARY SYSTEM (FEED-BACK)

The sex hormones regulate the secretion of hormones by the hypothalamus and pituitary in the following way:

Hypothalamus

The effect of estrogens on the hypothalamus has not yet been fully clarified.

Progesterone reduces the pulse frequency of GnRH secretion in the luteal phase (negative feed-back).

Pituitary

Estrogens can exert inhibitory or stimulating effects on the pituitary. The effect exerted is concentrated-dependent:
As the follicle ripens in the ovary, the initially low estrogen concentration increases continuously. As a result, the release of FSH is increasingly inhibited, while LH release increase slightly. At the same time, estrogens stimulate pituitary storage of the gonadotropins, particularly of LH.

The estrogen concentration reaches a maximum towards the end of the follicular phase. The sharp increase of estrogen provokes a massive release of both gonadotropins in the pituitary once a certain threshold concentration (about 150 ug/ml) is exceeded over a certain period of time (about 36 hours) positive feed-back). Progesterone also increases slightly at this time, supporting the positive feed-back mechanism of the estrogens.

The increase of the LH concentration in blood is particularly marked. The LH surge triggers ovulation. (1) This positive feed-back mechanism of the estrogens os called the HOHLWEG EFFECT.

The high progesterone levels in the luteal phase inhibit the release of the gonadotropin.

The ovary

The follicle cells capable of synthesising sex hormones and the corpus luteum develop in the ovary under the influence of the gonadotropins. At the same time, FSH and LH stimulate the production of sex hormones.

However, the ovary is not only the site of hormonal production, but also a target organ for the sex hormones. This means that sex hormones are involved in the development of follicle and corpus luteum.

The production of sex hormones in the follicular phase

The production of sex hormones in the follicular phase is described by the TWO GONADOTROPIN/TWO-CELL CONCEPT:
FSH and LH ("two gonadotropins") regulate the production of sex hormones in the theca and granulosa cells ("two cells"). The process involves the LH-dependent production of androgens in the theca cells which are converted FSH-dependently to estrogens in the granulosa cells.

(1) Oestrogens are able to trigger the LH surge only at low progesterone concentrations. Otherwise, ovulation would likewise occur during pregnancy (when very high estrogen levels are present). However, the high progesterone concentrations during the pregnancy prevent the positive feed-back of estrogens.

The syntheses of sex hormones is described in the following for the individual stages of follicular maturation. The hormone concentrations in the blood display a characteristic picture during the various phases of the menstrual cycle.

Primary follicle

It is thought that follicular maturation is triggered not by gonadotropins, but by estrogens. The hormonal function of primary follicles in unimportant.

Secondary follicle

FSH stimulates the growth of the granulosa cell layer. LH initiates proliferation of the theca cells. The cells of the theca interna contain LH receptors. Androgens are produced in the theca under the influence of LH, which binds to its receptors. Androgens are the precursors of all estrogens synthesised in the ovary.

The androgens migrate into the granulosa cell layer from the theca cells. The granulosa cells contain FSH receptors. FSH induces the production of the enzyme AROMATASE via FSH- receptor binding, thus initiating the conversion of androgens to estrogens (aromatisation).

The granulosa cells secrete estrogens into the intercellular space. Stimulated by the estrogens , the oocyte grows markedly. At the same time, estrogens are released into the bloodstream, with which they reach the hypothalamo-pituitary system and the tubes, uterus, vagina and extragenital target organs.

Tertiary follicle

Estrogens and FSH together promote further growth of the granulosa cell layer. In addition, they induce not only the formation of L receptors, but also the increased formation of FSH receptors. Because of the large number if FSH receptors, the follicle becomes increasingly FSH-sensitive and increases the production of estrogens. Estrogens and FSH are stored in large amounts in the antrum which has developed in the meantime.

At the same time, the concentration of estrogens in the blood increase and reduces the release of FSH. LH is stored in the pituitary and also released in increased amounts under the influence of the estrogens.

The further developmental pathway of the follicles is decided around the seventh day of the menstrual cycle. The falling concentration of FSH in the blood is no longer sufficient for further follicular maturation. In response to the increasing concentration of LH i the blood, increased amounts of androgen are produced in the theca cells which increasingly inhibit development of the follicles or induce atresia. The ratio of the concentration of FSH to LH in the follicle itself now decides whether a follicle will develop further or undergo atresia. The rules are:
IF FSH IS GREATER THAN LH, THE FOLLICLE WILL CONTINUE TO GROW.

The large number of FSH receptors and the massive accumulation of estrogen and FSH in the antrum permit further development of the follicle. As a result, the development of the follicle becomes independent of central regulation. The increased amounts of androgen produced can continue to be aromatised to estrogens because of the high concentration of FSH.

IF FSH IS LESS THAN LH, THE FOLLICLE WILL BECOME ATRETIC.

If the FSH concentration is too low, the androgens cannot be aromatised ion sufficient quantity. The concentration of androgens in the follicular fluid therefore increase, with the result that the follicle finally becomes atretic.

In general, only one follicle reaches maturity in each cycle. The ratio of LH ato FSH on the follicular environment is, however, only an indicator of the fate of the follicles. The mechanisms which ultimately lead to selection of the dominant follicle have not yet been adequately clarified.

Graafian follicle

In the last phase of the follicular maturation, constantly high blood estrogen levels are produced which lead to the massive release of FSH and LH towards the end of the follicular phase (towards mid-cycle). FSH induces the increased formation of LH receptors in the granulosa cells. This permits the LH-induced production of progesterone in the luteal phase.

The granulosa cells begin to luteinise under the increasing influence of LH so that slight amounts of progesterone are produced even in the Graafian follicle. The production of relatively small amounts of progesterone at this point in time activates enzymes and tissue hormones, which lead to softening and rupture of the follicular wall prior to ovulation.

The LH surge towards mid-cycle is a pre-requisite for ovulation, which takes place about 20 hours later. Because the pituitary stores empty, the concentration of LH ad FSH fall after ovulation. The estrogen levels in the blood also fall.

The production of sex hormones in the luteal phase

The concentrations of FSH and LH fall after ovulation and remain relatively low during the luteal phase. In the transitional phase of the next cycle, FSH increase again slightly, inducing maturation of the next generation of follicles in the new cycle as well as the selection of a dominant follicle.

The concentration of progesterone, which is produced under the influence of LH, increases distinctly despite falling LH levels. This is due to the fact that sufficient LH receptors were produced in the granulosa cells even in the follicular phase to respond even relatively low LH concentrations. The estrogen concentration likewise increases again slightly after ovulation.

Progesterone suppresses all further follicular growth in the ovary. In addition, it exerts an inhibitory effect on the pituitary and hypothalamus (prolongation of the GnRH pulse intervals). This explains the decrease in the levels of FSH and LH.

If conception fails to occur, the corpus luteum perishes towards the end of the luteal phase - it regresses. The progesterone concentration then decreases again continuously up to menstruation.

Genital effects of sex hormones

The cyclical changes of the genital organs are brought about by estrogens and progesterone. Because the ovary s simultaneously both the site of hormone production and a target organ for sex hormones, the ovarian cyclical changes were explained under the aspect of the hormonal regulatory system.

The fallopian tubes

The speed with which the egg is transported through he tubes is of crucial importance. Any unphysiological inhibition or acceleration makes fertilisation to nidation of the egg in the uterus impossible.

Estrogens stimulate the motility (capacity for spontaneous movement) of the tubes and increase secretion by the glandular cells:
The infundibulum with its fimbria becomes amazingly motile at the time of ovulation, allowing the egg to be gathered up at the ovary. At the same time, the frequency of contraction of the tube wall increases. The egg is then transported to the site of fertilisation by the waves of contraction and the flow of secretion in the direction of the uterus.

Contractility of the tubal muscles and the flow of secretion are greatest two- three days after ovulation. At this point in time, the possibly fertilised egg is forced through the isthmus and transported into the uterus.

Progesterone causes the tubal muscles to quiesce and the production of secretion to regress just three - four days after ovulation.

The cilia of the tubes are subject to the influence of hormones in two respects. Estrogens stimulate growth f the cilia ad increase the rate with which they beat in the direction of the uterus. It is possible that, in this way, the cilia support the flow of grandular secretion and transport the egg.

The Uterus
Endometrium

In synchrony with the development of follicle and corpus luteum in the ovary, characteristic cyclical changes also occur at the endometrium. Three phases are distinguished:

• The DESQUAMATION PHASE ("menstruation"; day 1-4)
• The PROLIFERATION (GROWTH) PHASE (day 5 - 15) and
• The SECRETORY PHASE (day 15-28)

Desquamation phase

The day from which the menstrual cycle is calculated is the first day of menstrual bleeding. However, preparation for desquamation (shedding) of the functional layer takes place during the last few days of the luteal phase of the proceeding cycle.

If the egg has not been fertilised, the corpus luteum slowly ceases its endocrine function. As a consequence of the decrease in progesterone (reduced supply), the mucosa is shed in minute particles with the menstrual blood, Regeneration of the mucosa from the intact basal layer begins on the third - fourth day after the start of menstruation. This is the time at which the follicle begins to secrete estrogens.

Proliferative phase

In the proliferative phase, the estrogens of the ripening follicles induce growth of a new functional layer. Epithelial cells shoot out of the basal layer and form narrow, elongated gland tubes with secretory cells. Spiral arteries begin tog row at the same time. Their job is to supply the functional layer with blood.

In the middle of the proliferative phase, the gland tubes begin to convolute and grow wider. Increased numbers of spiral arteries grow from the myometrium into the functional layer. In addition, estrogens induce the formation of progesterone receptors in preparation for the progesterone-induced processes at the endometrium in the luteal phase.

In the late proliferative phase, the secretory activity of the glandular cells begins with the onset of ovarian progesterone production. Vacuoles begin to develop in the glandular cells. The vacuoles produces a glycogen-containing secretion, which serves the fertilised egg as a source of energy. Progesterone inhibits further proliferation at the same time. The functional layer is about 6 - 8 mm high at the time of ovulation.

Secretory phase

The increased production of progesterone by the ripening corpus luteum stimulates secretory transformation of the endometrium. The spiral arteries assume a corkscrew-like appearance. The glands are now wound in a spiral, and they display a sawblade-like appearance in the histological section.

At the same time, the production of highly nutritive secretion and the number of vacuoles increase. The secretion reaches its maximum between the 19th and 21st day of the cycle, which is the anticipated time of arrival of the fertilised egg. The endometrium is ready to accept the fertile egg at this time.

Complete transformation is a pre-requisite for nidation

If fertilisation has not taken place, the production of progesterone in the now regressive corpus luteum decreases. Reduced perfusion of the functional layer takes place ad a result of the progesterone deficit. This leads to atrophy and degeneration of all tissue components. The functional layer is shed as a result. The next menstrual cycle begins with this desquamation.

Uterine cervix

The changes are aimed at enabling the spermatozoa to ascend to the tubes at the time of ovulation. Estrogens induce dilation of the cervical canal and enlargement of the crypts. At the same time, they stimulate the production of mucus by the cervical glands and reduce the viscosity (thickness) of the cervical mucus.

The typical change in the consistency of the mucus can be used to determine the approximate time of ovulation:
THE SPINNBARKEIT TEST: Because of the reduction of the viscosity, the clear cervical mucus around the time of ovulation can be drawn into a thread with a length of 6 - 8 cm - the measure of its "spinnbarkeit".

FERNING TEST: The altered consistency of the mucus is also characterised by an increase of its mineral content. The crystallisation picture of the secretion changes in relation to the estrogen level. If a drop of mucus is placed on glass slide, a fern-like crystallisation pattern will drop as it dries if ovulation is imminent (ferning phenomenon).

These estrogen effects are reversed again in the luteal phase by the influence of progesterone. Owing to the presence of progesterone, both tests are negative just 3-4 days after ovulation.

Vagina

The vaginal epithelium is a highly sensitive indicator of the effect of sex hormones. Its structure and strength are subject to cyclical changes. The multilayered vaginal epithelium thickens and matures under the influence of estrogens. Progesterone, on the other hand, leads to marked desquamation of the cellular layers.

Cytological examinations reveal the degree of proliferation of the epithelium. A follicular and a luteal cell picture can be clearly distinguishable under the microscope.

This allows conclusions to be drawn indirectly about a woman's hormonal status (e.g. for the diagnosis of cycle disturbances).

The hormonal effect is also reflected in the environment of the vaginal secretion. Under physiological conditions, certain bacteria (Doderlein's bacteria) produce a protective acid environment. The starting product for Doderlein's bacteria is glycogen. This carbohydrate is deposited in the middle cell layers of the vagina around the date of ovulation under the influence of progesterone.

The protective function of the vaginal secretion is therefore dependent on the cyclical estrogen-progesterone effect. Consequently, any unphysiological shift of the hormone balance may impair the protective mechanism of the vagina and lead to the colonisation with pathogenic organisms.

These processes are of secondary importance as regards the reproductive process. This is because, during sexual intercourse, the spermatozoa are normally deposited directly infront of the portio and are therefore mainly within the alkaline environment of the cervical mucus.

Extragenital effects of sex hormones
Nervous sustem

In the follicular phase, the AUTONOMIC NERVOUS SYSTEM is primarily under the influence of the parasympathetic system because of the presence of estrogens. A s an example, the first phase of the cycle is characterised by increased motility of the gastrointestinal tract. In the luteal phase, progesterone leads to marked stimulation of the sympathetic system, Accordingly, digestive disturbances (constipation, gastric upsets) often occur in this phase.

Progesterone also affects the thermal centre of the mid-brain. Continuous measurement of the waking temperature (basal body temperature) over the entire menstrual cycle produces a typical biphasic pattern. In the follicular phase, the body temperature is at a low level of about 36.5 oC. With the start of progesterone production, the temperature increase to about 37 oC (thermogenic effect of progestogens). This temperature increase is sustained throughout the luteal phase. The temperature falls below 37 oC again with the start of menstruation.

Careful measurements of the making temperature after at least six - eight hours bed rest allow conclusions about the phases of a woman's cycle. This fact can be exploited in several ways:

• Measuring her temperature shows the woman her fertile and infertile days. It can be used as a method of natural contraception ( the temperature method), but it is susceptible to unusual events (e.g. fever).
• Failure of the temperature to fall after the luteal phase together with the absence of a menstrual period can be taken as the first sign of pregnancy.
• Measuring the temperature over several cycles also serves the doctor as a diagnostic measure, e.g. in the case of sterility. If the temperature fails to increase in the luteal phase, it can be assumed that ovulation has not taken place (i.e. no progesterone was produced). Such cycles are monophasic and usually short. The woman is sterile in monophasic cycles.

The mental behaviour of the woman is also influenced by sex hormones. In general, a woman's mental state is better in the estrogen phase. Libido is also more pronounced. A certain instability of moods which is ascribed to the effect of progesterone is often seen before menstruation.

Cardiovascular system

The blood pressure and pulse rate increases before menstruation.

Blood coagulation

Oestrogens increase the tendency of the blood to coagulate (clot). Progesterone, on the other hand, activates certain anticoagulatory factors. The ability of the blood to coagulate is therefore particularly low before menstruation.

Water balance

Estrogens cause increased accumulation of water in tissues, meaning that oedema can develop.

Pre-menstrual syndrome

The pre-menstrual syndrome develops in about 35% of all women after the age of 30. Characteristic general and local complaints occur during the luteal phase (particularly in the last six - eight days before menstruation). The symptoms of this pre-menstrual syndrome are many and various.

Particularly frequent complaints are breast tenderness, nervousness, depressive sates and irritability, lower abdominal pain , headache , constipation and nausea. Pre-menstrual storage of liquid in tissue, which can amount to 1-5 - 4 litre and which expresses itself as an increased tendency oedema, plays a special role.

The causes of this syndrome have to been adequately clarified. Luteal insufficiency is often observed in the women affected. The resulting reduced production of progesterone led to the assumption that estrogens then predominate over progesterone (theory of relative estrogen dominance). This would explain the apparent contradiction that the estrogen-induced accumulation of water in tissue occurs in the luteal phase.

Apart from hormonal causes, mental factors are also under discussion.