Research into infertility

In this part of the site we outline the wider context of assisted fertilisation:

  • how does a person become pregnant in a natural reproductive cycle?
  • what exactly is reduced fertility?
  • what research can we do at the CRG to find possible causes?

Reproductive cycle in people

Our reproductive system is governed and controlled by hormones.
In fertility medicine, we use this knowledge to improve the chances of fertilisation of prospective parents who have problems getting pregnant.

Hormones are substances produced by certain glands and cells in our bodies which are released into the bloodstream to reach an organ to deliver a signal. The organ in turn performs a particular function.
Both in males and females, the production and maturation of reproductive cells (sperm and eggs) are controlled by gonadotrophins, i.e. hormones which act specifically upon the reproductive organs (gonads).
  • GnRH (gonadotrophine releasing hormone) activates the production of LH and FSH.
  • FSH (follicle stimulating hormone) stimulates the ovaries to produce follicles and the testicles to produce sperm.
  • LH (luteinising hormone) stimulates ovulation and the production of male hormone (testosterone) in both the ovaries and testicles.

In both males and females, the presence of gonadotrophins results in the production of hormones in the reproductive organs:
  • oestrogens and progesterone: female sex hormones;
  • testosterone: male sex hormone.

During pregnancy, an additional hormone is produced by the placenta: hCG.
hCG (human chorionic gonadotrophine or pregnancy hormone) indirectly supports the evolution of the pregnancy.

How does a man's body function hormonally and how does the male reproductive system work?
This is known as Andrology, the area of medical science which specialises in male (in)fertility.

Male hormones
Sperm production

Male hormones   

Sperm production and maturation is controlled by the gonadotrophins FSH and LH.
  • FSH (follicle stimulating hormone, so named because it is identical to the hormone which stimulates the maturation of follicles) indirectly stimulates the production of sperm cells.
  • LH (luteinising hormone) is indirectly responsible for the ripening of sperm cells.
FSH and LH are secreted by the hypophysis, a small gland in the brain which is controlled by the hypothalamus, part of the midbrain just above it.
The hypothalamus regularly secretes a hormone called GnRH or gonadotrophin releasing hormone, which stimulates the release of LH and FSH.
In short, FSH an LH stimulate the reproductive organs to function and in turn, to produce sex hormones. In the male, this is primarily testosterone.

This is the hormone which turns a boy into a man. Production begins at puberty and starts the development of secondary sexual characteristics (beard growth, deepening of voice, muscle development, etc.). From puberty, testosterone controls the sexual function and libido of the man and is responsible for the maturation of sperm cells.
Production of testosterone peaks around the age of 30-35, then gradually begins to decline.
In the male 'cycle', testosterone levels are monitored in the brain and if sufficient levels are present, the secretion of GnRH reduces, resulting in the production of less gonadotrophins. Similarly, if testosterone levels are low, e.g. because the testicles are not producing enough testosterone, the brains receive the message to produce more FSH en LH.

Central heating principle  

    This hormonal regulation can be likened to a central heating system, with the testicles as the water boiler and the hypophysis the thermostat.

    • If it is cold in the room (i.e. too little male hormone present) the thermostat activates the heating system (production of gonadotrophins).
    • As soon as the room reaches the desired temperature (sufficient testosterone levels), the heating shuts off (no more gonadotrophins produced).
    The male pill is developed with this principle in mind.
    It also explains why taking testosterone (e.g. bodybuilders) can lead to infertility. Men who take testosterone to increase their muscle mass are in principle adding additional heating to the room where the thermostat is located. This gives an incorrect signal to the hypophysis, i.e. that sufficient male hormone is present in the body, which in turn leads to a halt in gonadotrophin production.
    However, gonadotrophins are necessary for the production and maturation of sperm cells. In other words, the unnatural presence of testosterone causes a drop in the natural impulse to produce gonadotrophins, leading to no (or a significant reduction in) sperm production.

    Sperm production   

    Sperm cells are produced in very tiny canals (tubules) in the testicles. Production starts at puberty and continues a man's entire life.
    The production itself is a complicated process of cell division and cell differentiation which takes about three months in total But of course the process occurs in thousands of tubules and at different stages constantly, so that there is always a constant supply of mature sperm available, i.e. a man does not have to wait 3 months for his next ejaculation.
    After its production in the testicle, the sperm travels to the epididymis, which contains a single tightly coiled tubule. The sperm remains here for about a week, during which time it continues to mature and become more motile.
    The epididymis also serves as a reservoir of sperm. During an orgasm, sperm cells are expelled from the epididymis and begin their journey to the outside world via the vas deferens, through the prostate to the penis.
    The vas deferens and the accompanying nerves and blood vessels constitute the spermatic cord. Before they enter the prostate there is a widening which forms the connection with the seminal vesicles. Both the seminal vesicles and the prostate secrete a liquid which forms a nutrient-rich plasma, in which the sperm are ultimately transported via the urethra of the penis into the outside world.


    From less than 2 million (and less) motile sperm per ml the man has a serious fertility problem. From less than 20 million sperm per millilitre reduced fertility is possible.

    A fertile man usually ejaculates 1.5 to 4ml of semen containing 20-200 million sperm per ml. Any less than 2 million (and less) motile sperm per ml would indicate a significant fertility problem (see also the sperm quality).

    This production and ejaculation process forms a crucial examination ground in the treatment of couples with reduced infertility. Ejaculation problems can sometimes be bypassed using surgery or techniques for sperm extraction.
    Menstrual cycle

    To understand why a woman cannot become or remain pregnant, we first need to know how her body functions hormonally and how her reproductive system is constructed and if there are any abnormalities present.
    This area of medicine is the domain of the gynaecologist. However, it is primarily due to reproductive medicine and its manipulation of hormones and their effects, that women who at one time would never have been able to conceive, are able to have children today.

    Female hormones
    Supply of eggs 
    Menstrual cycle 
    Natural fertilisation 

    Female hormones   

    A woman's fertility is controlled by the same hormones as those required for sperm production in men:
    • The hypothalamus regularly secretes (every 60-90 minutes) the hormone GnRH (gonadotrophin releasing hormone).
    • This releases the gonadotrophins FSH and LH.
    • This is regulated by the hypophysis, a small gland located just below the hypothalamus,
    • if the sex organs have signalled that this is necessary (low oestrogen level, see below).
    The big difference between the male and female systems is the fact that the hormonal process in women follows a pre-determined cycle pattern. Unlike a man, the woman does not need to constantly manufacture reproductive cells. One of her supply of eggs has to ripen and be released every month so that it can be fertilised.

    Supply of eggs   

    A woman is usually born with a lifetime supply of approximately 300,000 to 400,000 eggs. They are distributed over the two ovaries, in so-called 'sleeping follicles'. The egg is enclosed in feeding cells called granular cells.
    A woman's body does not manufacture any new eggs at any point in her lifetime. On the contrary, a natural degeneration process of eggs results in a reduction of eggs to a mere 100,000-200,000 by the time of puberty. Around the age of fifty, no viable eggs remain and menopause sets in.
    In a woman's fertile years one egg is ripened and released from one of the ovaries (ovulation) every four weeks. Several eggs begin to ripen, but only one reaches maturity.


    Even before puberty and during the fertile years, eggs naturally degenerate and die. This even happens during pregnancy and whilst taking a contraceptive pill!
    Contrary to what many people think, no more eggs are lost during fertility treatment than during a natural cycle.
    In fact, quite the opposite is true. The hormonal stimulation restricts the number of eggs which would otherwise be lost during the natural ripening process, so that more eggs survive the cycle.

    Menstrual cycle  

    In theory, the menstrual cycle has a duration of 4 weeks. In reality however, the length of the cycle varies from woman to woman and indeed from cycle to cycle.
    • It begins with the ripening of one egg and ends either in menstruation or pregnancy.
    • The ripe egg is picked up by the feathery finger-like ends of the fallopian tubes where it can be fertilised by a sperm.
    • Tiny hairs on the inside of the fallopian tube fan the as yet unfertilised egg in the direction of the uterus.
    • The lining of the uterus has been prepared to receive an embryo, which can implant and develop into a baby.
    • If the egg is not fertilized, or if implantation does not occur, menstruation takes place. The mucous membrane lining of the womb, which formed with a view to a potential pregnancy, is shed and expelled via the vagina.
    The chart below shows the progression of the monthly cycle from the ripening of the egg (at the top), the evolution in the hormonal values (middle) and the forming of the endometrium (at the bottom). There are two phases.

    From day 1 to ovulation (follicular phase)   
    • The menstrual cycle is set in motion as a result of low oestrogen levels. The diminished levels of female sex hormones in the woman's bloodstream trigger the hypothalamus to produce GnRH (faster).
    • This stimulates the hypophysis to produce FSH and LH.
    • FSH (follicle stimulating hormone) causes several follicles in the ovaries to develop. Follicles are tiny fluid filled sacs in which the egg is located.
    • Follicles secrete oestrogen, which stimulates the lining of the womb to thicken in preparation of the potential implantation of an embryo.
    • The rise in oestrogen stimulates the hypothalamus to reduce the levels of GnRH.
    • The levels of FSH drop, causing a halt in the development of the follicles.
    • However, there is always one dominant follicle which is able to adjust to the lower levels of FSH and continues to grow. Under the influence of FSH and LH (luteinising or ripening hormone) the egg in the dominant follicle matures.
    • When oestrogen levels reach sufficient levels, the production of LH reaches its peak. The egg is now ripe can ovulation takes place. 32 to 48 hours elapse between the LH peak and the ovulation itself. The LH peak occurs around day 12 of the cycle and ovulation around day 14, based on a normal menstrual cycle.
        From ovulation to day 28 (luteal phase)   
        • After ovulation of the ripe egg, the journey towards the uterus begins.
        • During this time, the empty follicle in the ovary where ovulation occurred, begins to alter into a yellowish structure called the Corpus Luteum.
        • This structure continues to produce oestrogen just like the follicle did, but additionally begins to produce progesterone.
        • Together, these hormones stimulate the development and thickening of the lining within the uterus and suppress the production of FSH and LH in the hypophysis

          Day one?

          To time an ART (assisted reproductive treatment) cycle, the first day on which the woman gets up in the morning with bright menstrual blood loss is referred to as day 1.
          If your period starts during the day or the blood only turns bright red over the course of the day, the next day applies as day 1.

          • If the egg does not become fertilised (or the fertilised egg does not implant in the uterus), the corpus luteum begins to degenerate about 10 days after ovulation.
          • Oestrogen and progesterone levels sink considerably, causing the lining of the womb to begin breaking down around day 28 of the menstrual cycle. The woman menstruates and the production of FSH and LH triggered by the hypophysis begins again.
          • The first day of menstruation is the first day of the new cycle.

          Natural fertilisation   

          At 0.2mm, the egg is the largest cell found in the body, sperm cells are amongst the smallest. One sperm cell needs to find its way to an egg cell at just the right moment and penetrate it to speak of new life.
          • After ovulation, the egg remains viable for about one day. Sperm remains viable for about two days after ejaculation.
          • Fertilisation occurs in the fallopian tube. During the eggs' journey towards the uterus, after intercourse millions of sperm swim up in the other direction from the vagina.
          • Semen constitution changes drastically once it arrives in the vagina: it goes from thick and viscous to thin and liquid. The vast majority of sperm flows back out through the vagina, or does not make it through the mucous plug of the cervix.
          • At most, a few hundred sperm - very motile and good shape - complete the journey via the uterus all the way to the fallopian tubes. If there is an egg in either of the tubes, the chances are it will be fertilised by one single sperm. It can be compared to climbing Everest: Only the fittest and strongest make it to the summit.
          • The embryo that is created divides many times and becomes a blastocyst (an embryo consisting of many cells, with a liquid hollow). Over a period of five to six days, the embryo is transported to the uterus.


          Within the uterus, a recognition process must take place between the embryo and the lining of the womb. Once this happens, the embryo implants and hCG is produced. The hCG ensures that the corpus luteum remains intact and that it continues to release oestrogen and progesterone. During early pregnancy, delicate hormonal balances are crucial in the continuing development of the embryo.

          Quite soon, the main source of hCG is produced by the placenta, the part of the embryo which ensures a nutritional exchange between the mother and embryo. Presence of hCG can then be detected in the mothers' blood (or urine) and a positive pregnancy test can be performed. The placenta produces oestrogen and progesterone as well. By this time (the end of the first trimester), the development of the pregnancy is completely autonomous in its progression