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?

Reduced fertility

Whether or not a couple is fertile, depends on the answers to these four questions:
  • Are (sufficient, healthy) sperm available?
  • Is there an egg (at the correct moment)?
  • Can the sperm reach the egg?
  • Can the egg implant?

You are less fertile if you are unable to become pregnant after one year of having regular sexual intercourse. This would indicate that the answer to one of the above questions is negative.
For the majority of prospective parents, it is a matter of reduced fertility (sub fertility). A lesser number suffer absolute infertility (sterility or infertility).


With regard to the examinations the CRG is able to perform into the causes of reduced fertility, see causes in women and/or causes in men.

Figures

Ovulation problems   30%
Abnormal semen
22%
Fallopian tube problems (e.g. adhesions)
17%
Endometriosis
5%
Unexplained infertility
14%
Other (immunological, genetic, etc.)
12%
    According to the World Health Organisation (WHO), sub fertility /infertility problems affect about 10% of the world population.
    In real figures, this is approximately 80 million people, approximately 2 million additional cases per year.
    The table shows the results of studies over the years (in the western population) at establishing the precise roots of fertility problems, which produced the following statistics.
    The studies showed that one of the highest contributing factors of increased infertility is that many (western) women are delaying having children. See also: "A woman’s age and its influence on fertility".
          
    A worldwide WHO examination of 5,700 couples established that:
    • 41% of the cases were down to fertility problems in the woman,
    • 27% in the man and
    • i 32% in both the man and the woman.

    When considering the figures, it is important to keep in mind that the fertility of a couple depends on factors in both partners. For instance, a less fertile man (with less sperm than usual) can be able to have fathered children with his first fully fertile partner, whilst failing to conceive with his second, less fertile partner, because maybe her eggs are of a lesser quality, or she has a problem with her fallopian tubes.
    Just because one or the other partner has previously been able to have a child, does not automatically mean that they are perfectly fertile. During the first consultation at the CRG, the doctor will talk with the couple to establish which examinations will be necessary for which partner.

    Possible Causes

    Our knowledge of the human reproductive system and the hormonal processes has taught us what can go wrong:
    • defective hormone production in the brain;
    • efective hormone production in the reproductive organs;
    • nsufficient sperm production;
    • oor quality of sperm;
    • roblems related to the ripening process of eggs;
    • insufficient supply of eggs, or absence of eggs, poor quality of eggs;
    • obstructions in the path of the sperm within the male reproductive system;
    • obstructions in the path of the egg within the female reproductive system;
    • problems with the timing, location or interaction of the unity between sperm and egg;
    • implantation problems of the embryo.
    In the West, people - couples and individual women - often postpone having children for various reasons. This immediately explains the increasing subfertility in this part of the world. A woman's age is a crucial factor for human fertility.
    Why is that?
    Every woman is born with a specific number of eggs. Not only does this supply diminish over the years, but over time she is exposed to various negative influences such as environmental and stress factors, health problems, etc.
    In other words, the quality of the eggs diminishes too.
    In men, whose sperm are constantly renewed and produced throughout their lives from the stem cells, this problem, although present to a certain degree, is less pronounced

    Postpone motherhood?

    If you can feel the clock ticking but you want to postpone motherhood, AGE banking may be a solution. This is also known as social freezing

    More specifically, the quality of a woman's eggs diminishes due to the following factors:
    • the occurrence of ovulation, i.e. the selection and ripening of a normal egg that can be fertilised - can reduce.
    • The older the woman is, the higher the chances of an abnormal cycle without ovulation, even if she still menstruates;
      the eggs show more abnormalities.
      Indirectly this can de deduced from the increase of the risk of having a child with chromosomal defects, the older the mother is. At the age of 25, the chances of this are 1 in 500, at 35, 1 in 250 and at 45 as much as 1 in 25.
    • embryos resulting from poor quality eggs do not implant well; and
    • the chance of miscarriage increases greatly after the age of 37. This is also due to the fall in egg quality.

    Somehow, the fertility of a woman is not totally dependent on the function of the ovaries. This is apparent from the following: in the western world, the menopause (identified by the absence of menstruation for a period of one year), occurs around the age of 51.
    However, at the age of 38 (well before the menopause), 20% of women are already infertile. At the age of 42, it’s around 50% and at 45, 90%.

    Strictly speaking, the presence of one sperm and one egg is sufficient for successful fertilisation to take place. However, this is harder than it sounds.
    During the sperm's journey through the female reproductive system, the majority of sperm are lost.
    Ejaculate is primarily a viscous substance, but due to a protein acting enzyme from the prostate it becomes more fluid at room temperature after 10 to 30 minutes.
    The same thing happens in the vagina. And in a more liquid form, the majority of the sperm flows back out.
    The sperm's journey to the egg in the fallopian tube is a fight for survival.

    Therefore the total number of sperm introduced into the vagina during intercourse plays an important role when evaluating male fertility.
    A routine sperm analysis takes many more parameters into account. Explanation

    Ejaculate (semen) consists of two components:
    • sperm, produced in the testicles,
    • seminal fluid, a nutrient-rich plasma that is one third produced by the prostate and two thirds by the seminal vessels.
      Both prostate and seminal vessels add biochemical nutrients (resp. fructose and citric acid).
    Seminal fluid has two functions:
    • it transports the sperm in the male reproductive system to the outside, and into the female reproductive system, and
    • lcauses an increase in the pH value in the vagina.
      Good seminal fluid has a pH value of 7.2 to 7.8 and serves as a protective buffer for the sperm against the more acidic environment within the vagina. Sperm quickly becomes immobile in a pH environment lower than 6.2.
    Therefore, the composition of the ejaculate is important for a successful fertilisation:
    • the quantity and pH value of the semen;
    • number of sperm per ml and in total;
    • the quality of the sperm: the shape, motility and vitality
      Semen
      Volume 1,5 ml or more
      pH 7,2 – 7,8
      Sperm
      concentration 15 milion/ml or less
      total count 39 milion or more
      progressive motility (fast or slow forward movement) or > 34%
      fast progressive motility  
      normal formation > 4%
      vitaliteit > 58% live
      witte bloedcellen < 1 million/ml

      A semen analysis in the CRG's andrology lab takes place according to WHO guidelines (see table).
      The following applies for "normozoospermia" (a normal semen sample):
      • an ejaculate of at least one and a half ml,
      • containing a minimum of 15 million sperm per ml or a total of 39 million sperm, of which more than 58% are live sperm with good motility,
      • and more than 4% are of normal shape,
      • the pH value of the semen must be between 7.2 and 7.8.

      Nevertheless, we should not become too focused on the figures. . The figures alone do not allow us to diagnose a man as infertile. Male infertility is not an all or nothing diagnosis, but depends partly on factors concerning his partners' fertility

      The WHO norms do allow for a male factor fertility grade to be estimated. A serious male factor can be part of an acceptable level of fertility within a couple, provided that the woman is very fertile.





      Incorrect hormonal interaction   
      Premature menopause

      Ovulation problems (jointly) account for 30% of infertility. This type of problem usually arises from 'mistakes' in the woman' hormonal interaction. As a result, the egg ripening process is not initiated, or is incomplete.
      • If no ovulation occurs, it is called anovulation. In this case, no menstruation will take place either (amenorrhea).
      • If there is a regularity problem with ovulation, it is called dysovulation. You may have irregular menstruation (oligomenorrhea), but your menstrual cycle may also be normal.
      • Amenorrhea can also be caused by a premature exhaustion of the supply of eggs: this is known as premature menopause.

      Incorrect hormonal interaction    

      The normal process of egg ripening and ovulation is the result of a finely tuned interaction between the brain and the reproductive organs:
      • the hypothalamus excretes the hormone GnRH with clockwork regularity (every 60-90 minutes) depending on the stage of the menstrual cycle,
      • this stimulates the hypophysis to produce the sex hormones FSH and LH (slower or faster),
      • they stimulate the ovaries to start the ripening process of follicles (tiny fluid filled sacs, each containing an egg, and
      • during this ripening process, the follicles begin producing oestrogen through a transformation of testosterone in the surrounding cells.

      How do you know if you have PCOS?

      If you have at least two of the three following symptoms, you are probably suffering from PCOS:

      1. ovaries with a large number of fluid filled sacs (follicles),
      2. a menstrual cycle in excess of 35 days,
      3. an increased concentration of male hormone in your blood, or signs that point to this: acne, loss of hair (on your head), excess body hair.

      Polycystic Ovarian Syndrome (PCOS)   

      PCOS is the most common cause of ovulation problems in women of fertile age. Almost ten percent of all women have this syndrome, and one third of them (in part because of this syndrome) seek the help of reproductive medicine to have children.

      PCOS is characterised by a large number of follicular fluid filled sacs in the ovaries. These small follicles are sometimes wrongly called cysts, hence the term 'polycystic’.
      It is a heterogeneous disorder, the cause of which is not yet fully understood. We do know it involves an important genetic background.

      • Usually women with a polycystic structure of the ovaries have a bad hormone interaction, often as a result of an increased concentration of LH (the ripening hormone).
      • Often we also see an increased production of male hormones (androgens) and a reduced sensitivity for insulin (hyperinsulinism):
        • the first can result in acne and excess body hair,
        • the latter in an increased risk of diabetes, particularly if the person is overweight.
        Paying attention to healthy food and physical exercise is extra important for women with PCOS.

      PCOS can interrupt the normal progress of the menstrual cycle, causing less or sometimes no ovulations to occur. A spontaneous pregnancy becomes difficult to impossible.
      Women who find themselves in this situation have various options if they want to get pregnant:
      • controlled ovulation by administering hormones - see ovulation induction,
      • in-vitro maturation of eggs - see IVM, and even
      • hormonal stimulation followed by IVF/ICSI.

      And finally we want to mention that sometimes PCOS can be treated with an operation involving ‘drilling’. With a laser or another source of heat, holes are drilled in the ovary, causing part of it to shrivel. This allows the hormonal balance to (temporarily) restore itself.

      Disturbance in the brain   

      in the hypothalamus

      • If the hypothalamus fails to produce sufficient levels of GnRH hormone, there is no or an incomplete ripening process, resulting in anovulation.
        This rare condition can be treated by means of a GnRH-pump.
      • Stress and drastic or uncontrolled weight loss can also lead to disturbances in the production of GnRH, also resulting in an irregular or incomplete ripening process.
        Relaxation methods or controlled weight loss can rectify this.
        If that is not effective, hormonal clomiphene citrate or gonadotrophine treatment or a GnRH-pump may be required (see ovulation-induction).

      in the hypophysis

      Sometimes, the hormonal disturbance is the result of too much prolactine in the blood. Prolactine is produced in the hypophysis. High levels can lead to interference in the follicle ripening process and thus anovulation or dysovulation.
      • Quite often, an 'adenoma' or benign tumour in the tissue of the hypophysis is to blame. If it is a small tumour (a micro-adenoma, sometimes visible on a brain scan), it can be treated with medication.
      • In the rare case that it is a macro-adenoma (larger, visible also on an x-ray), surgery will be required to remove it.

      between the hypothalamus and the hypophysis

      Sometimes, blood tests reveal all hormonal levels to be normal, apart from progesterone, which would cause problems related to ovulation. This would indicate a disturbance in the interaction between the hypothalamus en hypophysis: something not right with the frequency and regularity of GnRH release, with unsynchronised production of FSH an LH as a result. This either leads to disturbances of follicle ripening, or in rarer cases, a failure of LH levels to peak, resulting in no ovulation.
      In cases where the follicle ripening process is affected, (detectable with ultrasound scan) the treatment of choice is to administer clomiphene citrate or gonadotrophins, often combined with hCG injections at the end of the ripening process.

      Premature menopause   

      The scientific term for this is 'Premature ovarian insufficiency' or POI and it indicates precisely what is wrong: the supply of primordial follicles (the follicles from which eggs ripen when prompted by the sex hormones) in the ovaries is prematurely exhausted. You have no periods anymore and frequently suffer hot flushes.
      Unfortunately, the condition itself is not reversible: the only chance of pregnancy is with donated eggs (egg donation) or adoption.
      The transportation of the egg to the womb can be hindered or prevented if the fallopian tubes do not function correctly. The most common causes of this are endometriosis and adhesions as a result of an infection (see STDs and infertility).

      The lining of the womb is called 'endometrium'. It develops and thickens during every cycle and is shed and expelled during menstruation (apart from a thin layer).
      • In the condition known as 'endometriosis', this mucous membrane lining occurs in other places too, such as on the ovaries, the fallopian tubes, the peritoneum the bladder and bowels. It can even grow too deep and too thick in the uterus itself. The areas of tissue located in these other places undergo the same changes during the cycle as the tissue in the uterus itself.
      • Endometriosis is not a dangerous condition. Approximately one in ten women have some degree of it without any significant symptoms. The most common complaint is pain, which increases during menstruation and during sexual intercourse.
      • Endometriosis is restricted only to certain areas and does not always lead to reduced fertility. Treatment is therefore not always necessary.

       

      However, it is true that the sooner a diagnosis is made, the higher the chances are of maintaining an effective level of fertility and avoiding procedures to treat it. Because given time, endometriosis will eventually lead to infertility. It causes adhesions in and around the fallopian tubes and ovaries which impede the transportation of eggs, and adhesions in the uterus itself, can prevent the embryo from implanting.
      The most effective method of determining the kind and extent of endometriosis, and treating it, is by performing a laparoscopy.


      Abnormalities of the uterus include:
      • horned or double horned uterus: sometimes a fallopian tube is attached to a horn, sometimes both are;
      • the presence of a division (septum) in the cavity of the uterus causing a double cavity if the septum is large enough;
      • the presence of fibroids, either on the inside or the outside of the uterus.
      Strictly speaking, these abnormalities do not interfere with fertilisation, but they do hinder or prevent implantation of the embryo and can cause miscarriage.

      For this reason, a gynaecological examination will be routinely performed by the doctor at the CRG, unless you have already had one recently at your own gynaecologist.
      Should the physical examination indicate any problems, further diagnostic investigations may be suggested (diagnostic hysteroscopy or laparoscopy).
      To optimise your chances of pregnancy, the abnormality can be remedied by either therapeutic hysteroscopy or laparoscopy, or in the case of large myomas, laparotomy.

      The list of gynaecological treatments gives more information concerning conditions and the treatments thereof.

      The transportation of the egg to the womb can be hindered or prevented if the fallopian tubes do not function correctly. The most common causes for this are adhesions or endometriosis.
      STDs can also result in adhesions in men (on the epididymis here) and thus hinder the normal transport of sperm.

      They are caused by infections, so-called sexually transmitted diseases or STDs.
      Chlamydia en gonorrhoea are two such diseases which can cause a PID (Pelvic Inflammatory Disease), an infection of the inner pelvic area. This is because the STDs spread upwards in a woman's body, i.e. after sexual intercourse in the sperm in the direction of the fallopian tubes.
      A PID can manifest itself in and around the fallopian tubes and ovaries, the uterus or the peritoneum.
      The greatest risk is from chlamydia, because this is the STD most common in the Benelux countries in men and women between the ages of 15 and 35. In addition, most people, especially women, don't even realise they are infected: 60% of cases do not have any clear symptoms. In the remaining 40%, symptoms only begin to manifest one to three weeks after exposure to the disease. They can consist of a burning sensation during urination, pain in the lower abdomen, vaginal discharge and sometimes fever.
      In men a chlamydia infection is usually easier to identify, also one to three weeks after infection, as pain or a burning sensation during urination and discharge from the penis.

      Implications for fertility

      Chlamydia en gonorrhoea are treatable using antibiotics if the diagnosis is made on time. However, if left untreated (e.g. because the complaints are very vague or are not taken seriously) the infection can cause serious damage in woman. The longer chlamydia is left untreated, the greater the chances of serious consequences for your fertility.
      Chlamydia can spread from the vagina, up through the cervix and uterus and into the fallopian tubes. This causes adhesions and scarring, and possible a narrowing or blocking of the fallopian tubes. This prevents the transport of eggs and may result in infertility.
      Chlamydia can also infect the abdominal cavity, and infect other organs. This is known as a Pelvic inflammatory disease or PID.

      And finally, gonorrhoea can cause PID too, but this disease is less common than chlamydia.