What is subfertility? Is it common?

Subfertility (sometimes called infertility) is defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse (and there is no other reason, such as breastfeeding or postpartum amenorrhoea). In a woman over 35 the relevant time changes to 6 months.

Primary infertility is infertility in a couple who have never had a successful conception in the current or previous relationships. Secondary infertility is failure to conceive following a previous pregnancy.

Subfertility is quite common and statistics estimate the percentage of couple having some degree of diffculty to conceive from 12 to 28%

What is the physiological mechanism of conception?

It is true that the human reproductive process is complex. For purposes of evaluation only, we can break it down into its most important and basic component parts.

• Sperm must be deposited at or near the cervix at or near the time of ovulation, ascend into the fallopian tubes, and have the capacity to fertilize the oocyte (male factor).

• Ovulation of a mature oocyte must occur, ideally on a regular, predictable, cyclic basis (ovarian factor).

• The cervix must capture, filter, nurture, and release sperm into the uterus and fallopian tubes (cervical factor).

• The fallopian tubes must capture ovulated ova and effectively transport sperm and embryos (tubal factor).

• The uterus must be receptive to embryo implantation and capable of supporting subsequent normal growth and development (uterine factor)

The coordination of these factors is critical in successfully conceiving. Sometimes, some factors overlap (for example in endometriosis) and therefore the approach should evaluate all the factors involved and manage accordingly.

What are the causes of subfertility?

In general, the causes can be either from the woman, the man, both and, in some circumstances, no possible cause can be identified. When we break down reasons why subfertility happens, the major causes include ovulatory dysfunction (15%), tubal and peritoneal pathology (30- 40%), and male factors (30- 40%); uterine pathology is generally uncommon, and the rest is largely unexplained. To some extent, the prevalence of each varies with age. Ovulatory dysfunction is more common in younger than in older couples, tubal and peritoneal factors have a similar prevalence. Male factors and unexplained infertility are more common diagnoses in older couples. A detailed list of all the possible causes cannot be presented here due to space restrictions.

What is the psychological impact of subfertility on a couple?

Infertility may have profound psychological effects. Partners may become more anxious to conceive, increasing sexual dysfunction. Marital discord often develops in infertile couples, especially when they are under pressure to make medical decisions. Women trying to conceive often have clinical depression rates similar to women who have heart disease or cancer. Even couples undertaking IVF face considerable stress.

The emotional losses created by infertility include the denial of motherhood as a rite of passage; the loss of one’s anticipated and imagined life; feeling a loss of control over one’s life; doubting one’s womanhood; changed and sometimes lost friendships; and, for many, the loss of one’s religious environment as a support system.

Emotional stress and marital difficulties are greater in couples where the infertility cause lies with the man.

In every case, extensive discussion with each other and good communication skill are needed by the couple in order to overcome the emotional stress. We are here to provide you with any help needed by discussing with you about your feelings, providing scientific data and referring you to specialists for further assistance.

What is the indicated workup?

This is the initial assessment to an infertile couple. We advise that the assessment is done simultaneously for both partners.

For the woman

History (medical, sexual, social)

A detailed history is crucial in identifying causes that may inhibit normal conception. Questions will involve:

• Duration of infertility and results of any previous evaluation and treatment
• Menstrual history (age of first period, cycle length and characteristics, premenstrual symptoms, and onset/ severity of any severe period pain.
• Pregnancy history (number of conceptions and live births, pregnancy outcome, and associated complications)
• Previous methods of contraception
• Intercourse frequency and sexual dysfunction
• Past surgery (procedures, indications, and outcomes), previous hospitalisations, serious illnesses or injuries, pelvic inflammatory disease, or exposure to sexually transmitted infections
• Thyroid disease, nipple leakage, hirsutism, pelvic or abdominal pain, and pain during intercourse
• Previous abnormal pap smears (smear tests) and any subsequent treatment
• Current medications and allergies
• Family history of birth defects, developmental delay, early menopause, or reproductive problems
• Occupation and exposure to known environmental hazards
• Use of tobacco, alcohol, and recreational or illicit drugs

Physical and gynecological examination

A complete examination is performed to document the following:

• Weight, body mass index (BMI), blood pressure, and pulse
• Thyroid enlargement and presence of any nodules or tenderness
• Breast characteristics and evaluation for secretions
• Signs of androgen excess (acne, hirsutism, oily skin etc)
• Vaginal or cervical abnormality, secretions, or discharge
• Pelvic or abdominal tenderness, organ enlargement, or masses
• Uterine size, shape, position, and mobility
• Adnexal masses or tenderness

Gynecological ultrasound

Transvaginal ultrasound is useful in order to check the condition of the uterus and ovaries. We will also determine the appearance and number of the follicles in the ovaries. Thus, the ultrasound is often performed 15 days before a woman’s expected menstrual period. Sometimes, serial scans starting from day 8- 10 and repeated everey other day may be indicated to follow up the follicular growth.

Hysterosalpinogram

A hysterosalpingogram (HSG) is an X-ray test that looks at the inside of the uterus and fallopian tubes and the area around them.

During a hysterosalpingogram, a dye (contrast material) is put through a thin tube that is put through the vagina and into the uterus. Because the uterus and the fallopian tubes are hooked together, the dye will flow into the fallopian tubes. Pictures are taken using a steady beam of X-ray as the dye passes through the uterus and fallopian tubes. The pictures can show problems such as an injury or abnormal structure of the uterus or fallopian tubes, or a blockage that would prevent an egg moving through a fallopian tube to the uterus. A blockage also could prevent sperm from moving into a fallopian tube and joining (fertilizing) an egg. A hysterosalpingogram also may find problems on the inside of the uterus that prevent a fertilized egg from attaching (implanting) to the uterine wall. An HSG is usually scheduled between days six and 13 of your cycle.

Hormonal tests

• FSH, LH, estradiol, TSH, fT4, PRL on days 2- 3 of your cycle (day 1 is the first day you notice period blood). An abnormally high FSH can be indicative of ovarian reserves depletion. Increased LH can be indicative of PCOS or androgen excess environment. Thyroid function (TSH, fT4) can interfere with the normal ovulation process and increased prolactin (PRL) can be the cause of anovulatory cycles.
• AMH on any day of your cycle. Anti Mullerian Hormone (AMH) is a hormone produced by the remaining ovarian follicles. It is, therefore, a means of assessing ovarian reserve. A level above 1.0 ng/ ml is suggestive of adequate ovarian reserves.
• Progesterone. This hormone needs to be measured seven days before the onset of your next period. If you have a 28 days cycle then progesterone should be measured on day 21. In case you are unsure, then measure on day 21 and every seven days until your periods come. Levels of progesterone above 3 ng/ ml provide adequate evidence that ovulation has occured.
• In case evidence or signs are suggestive of excessive androgen levels (acne, hirsutism, elevated LH, polycystic ovaries appearance etc) then assessment of the “male” hormones total and free Testosterone, SHBG, 17-OH progesterone, DHEA-S. These hormones (if out of range) can inhibit normal ovulation.

For the man

History (medical, sexual, social)

Urological examination for evaluation of:

• your testicles – to look for any lumps or deformities
• your penis – to look at its shape and structure, and for any obvious abnormalities
• the presence or absence of a varicocele
• secondary sex characteristics, including body habitus, hair distribution, and breast development

Spermodiagram (Semen analysis)

Your semen will be tested to determine whether you have a low sperm count, low sperm mobility or abnormal sperm

The table illustrates the consensus of normal semen parameters. Semen should be collected after 2- 5 days of abstinence and evaluation should rely on at least two occasions. Semen can be collected by means of masturbation into a specimen cup or by intercourse with the use of special semen collection condoms that do not contain substances toxic to sperm. Ideally, the specimen should be collected at the laboratory. If collected at home, the specimen should be kept at room or body temperature during transport and examined in the laboratory within 1 hour of collection. It is best to discuss this with the lab that will analyse the sample.

Semen volume	Normal:	2–5 mL per ejaculation. According to WHO criteria, minimum volume 1.5 ml
Abnormal:	An abnormally low or high semen volume is present. This may sometimes cause fertility problems.
Liquefaction time	Normal:	20- 30 minutes after collection
Abnormal:	An abnormally long liquefaction time is present. This may be a sign of an infection.
Sperm count	Normal:	Concentration of 15 (in older references 20) million spermatozoa per milliliter (mL) or more. Total sperm count of 40 million spermatozoa.
Abnormal:	A very low sperm count is present. Men with sperm counts below 1 million have fathered children.
Sperm shape (morphology)	Normal:	According to WHO: 4% of the sperm with normal morphology.According to Kruger criteria: More than 14% of the sperm have a normal shape.
Abnormal:	Sperm may have two heads or two tails, a short tail, a tiny head (pinhead), or a round (rather than oval) head. Abnormal sperm may not be able to move normally or to penetrate an egg. Some sperm that aren’t normal are usually found in every normal semen sample. But a high percentage of abnormal sperm may make it harder for a man to father a child.
Sperm movement (motility)	Normal:	Percentage motility 40% with forward progression 32%More than 50% of the sperm show normal forward movement after 1 hour.
Abnormal:	Sperm must be able to move forward (or “swim”) through cervical mucus to reach an egg. A high percentage of sperm that can’t swim well may make it harder for a man to father a child.
Semen pH	Normal:	Semen pH of 7.1- 8.0. According to WHO: 7.2- 7.8
Abnormal:	An abnormally high or low semen pH can kill sperm or affect how well they can move or can penetrate an egg.
White blood cells	Normal:	No white blood cells or bacteria are found.
Abnormal:	Bacteria or a large number of white blood cells are present. This may be a sign of an infection.
Fructose		Regarding the level of fructose in the semen, WebMD lists normal as at least 3 mg/mL.WHO specifies a normal level of 13 μmol per sample. Absence of fructose may indicate a problem with the seminal vesicles

Out of all these parameters, concentration and progressive motility are the most important sperm parameters in predicting the likelihood of pregnancy via intercourse or intrauterine insemination. For example, when sperm concentration is < 10 million/ml and/ or progressive motility < 20%, the chance of pregnancy using the conventional methods is very low. In vitro fertilization would provide the best chance of pregnancy in this case.

Which are my fertile days? How can I calculate them?

Conception happens when an ovum (egg) meets one sperm and the fertilised egg implants in a well- prepared endometrium (the inner lining of the womb). A woman cannot conceive every day of the month. In fact, the so called “fertile window” is quite narrow. That is because the egg is released on a specific day of the cycle and the life span of both the egg and the sperm is limited. Additionally, hormonal changes affect the endometrium making its surface hostile to implantation outside this fertile window.

There are several methods to calculate when your fertile days are. For women with regular cycles, subtracting 14 days before the onset of the next period will give you your ovulation (release of the egg) day. So if your next period will come on the 29th of the month and your cycle is 27 days long, your ovulation day is 29th- 14 days= 15th of the month. This is day (27- 14=) 13 of your cycle. The most fertile days then are two days before the ovulation day, the day of the ovulation and the day after. These does not exclude conception to happen in the few days adjacent to the most fertile ones as this estimation of the ovulation day relies on the next period which we do not know when will actually happen. Notice that unless the cycle is 28 days long, ovulation does not happen halfway your cycle!

In order to help you calculate those days, we have launched an app that informs you about your fertile days and also lets you know about the probable ovulation day. This app is available for devices running Android (mobiles and tablets) and can be downloaded for free by clicking >HERE<.

Your basal body temperature (BBT) is your temperature first thing in the morning. Just after you ovulate, it rises slightly. sometimes by less than a degree, and stays higher until your period starts. If you record your temperature every day, you can detect the subtle changes that mean one of your ovaries has released an egg.

How to take your BBT:

• Use a basal body thermometer. Has to be a sensitive one in orders to show small changes in temperature but you can still get a cheap one.
• Take your temperature at the same time each morning, always before you get out of bed. (Try keeping the thermometer on your nightstand.) Even getting up to go to the bathroom can affect your body temperature, as can smoking, drinking, or getting a bad night’s sleep.
• Remember, your BBT won’t tell you exactly when you’ve ovulated, and it may take a couple of months before you start to see a pattern. You’re most likely to get pregnant 2 or 3 days before your ovary releases an egg, and then another 12 to 24 hours after that. When your temperature has spiked for 3 days, your chances of conceiving drop

There are other methods that rely on commercial kits measuring hormone level (LH) in your blood or in your urine or by serial ultrasound scans that observe the growth of your ovarian follicles but these are more expensive and less convenient so they should not be your first choice unless indicated. We are more than happy to discuss with you and choose together the method that best suits you.

What is the treatment?

The treatment you are offered will depend on what is causing your fertility problems. Before we proceed with any treatment we have to make sure that the initial workup has been completed. Sometimes, simple instructions and proper education about the correct time of ovulation and about the frequency of intercourses are enough for a successful conception.

Treatment options

There are three main types of fertility treatment:

• medicines to assist fertility
• surgical procedures
• assisted conception

Medicines to assist fertility

Medicines often used to assist fertility are listed below. These are usually prescribed for women, although in some cases they may also be prescribed for men.

• Clomifene helps to encourage ovulation (the monthly release of an egg) in women who do not ovulate regularly or who cannot ovulate at all.
• Tamoxifen is an alternative to clomifene that may be offered to women with ovulation problems.
• Metformin is particularly beneficial for women with polycystic ovary syndrome (PCOS).
• Gonadotrophins can help stimulate ovulation in women, and may also improve fertility in men.
• Gonadotrophin-releasing hormone and dopamine agonists are other types of medication prescribed to encourage ovulation in women.

However, medication that stimulates the ovaries should not be given to women with unexplained infertility, as it is not thought to be an effective treatment in these circumstances.

Surgical procedures

Surgical procedures that may be used to investigate fertility problems and assist with fertility are listed below.

• Fallopian tube surgery

If your fallopian tubes have become blocked or scarred, perhaps as a result of pelvic inflammatory disease (PID), you may need surgery to repair the tubes. Surgery can be used to break up the scar tissue in your fallopian tubes, making it easier for eggs to pass along them.

The success of surgery will depend on how damaged your fallopian tubes are. One study found that 69% of women with the least damaged tubes had a live birth after surgery. Other estimates for live births in women following surgery are 20–50%.

Possible complications from tubal surgery include an ectopic pregnancy (when the fertilised egg implants outside of your womb). Between 8% and 23% of women may experience an ectopic pregnancy after having surgery on their fallopian tubes.

• Laparoscopic surgery

Laparoscopy is often used for women who have endometriosis (when parts of the womb lining start growing outside of the womb), to destroy or remove cysts (fluid-filled sacs). It may also be used to remove fibroids (small growths in the womb).

In women with PCOS, laparoscopic ovarian drilling can be used if ovulation medication has not worked. This involves using either heat or a laser to destroy part of the ovary. This type of procedure is quite rare nowadays.

• Correction of an epididymal blockage and surgical extraction of sperm

The epididymis is a coil- like structure in the testicles that helps to store and transport sperm. Sometimes the epididymis becomes blocked, preventing sperm from being ejaculated normally. If this is causing infertility, surgery to correct the blockage can be performed.

Surgical extraction of sperm may be an option for men with:

an obstruction that prevents the release of sperm, such as an injury or infection

a congenital absence of the vas deferens (men born without the tube that drains the sperm from the testicle)

a vasectomy or a failed vasectomy reversal

Both procedures only take a few hours and are carried out as outpatient procedures under local anaesthetic. You will be advised on the same day about the quality of the material collected and if there are any sperm present.

Any material with sperm will be frozen and placed in storage for use at a later stage. If surgical retrieval of sperm is successful, enough sperm is usually obtained for several cycles of treatment (if required).

Assisted conception

• Intrauterine insemination (IUI)

Indications for insemination include the cervical factor, the male factor, stage I and II endometriosis as well as infertility of an unknown cause.Intrauterine insemination (IUI) involves sperm being placed into the womb through a fine plastic tube. Sperm is collected and washed in a fluid. The best quality specimens (the fastest moving) are selected.

The sperm are passed through a tube that enters the cervix and extends into the womb. This procedure is performed to coincide with ovulation, to increase the chance of conception. The woman may also be given a low dose of ovary stimulating hormones to increase the likelihood of conception.

Some women may experience temporary cramps, similar to period cramps, after or during IUI, but other than that, the procedure should be painless.

Availability and success

The National Institute for Health and Care Excellence (NICE) recommends that you should be offered up to six cycles of IUI if:

you are unable (or would find it very difficult) to have vaginal intercourse – for example, due to a physical disability

you have a condition (such as a viral infection that can be sexually transmitted) that means you need specific help to conceive

as a first- step treatment to increase the chances of conception in couples failing to conceive

Provided that the man’s sperm and the woman’s tubes are healthy, the success rate for IUI in women under 35 is around 15% for each cycle of treatment.

Intrauterine insemination is a service offered in our Practice.

• In-vitro fertilisation (IVF)

During in-vitro fertilisation (IVF), the fertilisation of the egg occurs outside the body. The woman takes fertility medication to encourage her ovaries to produce more eggs than normal. Eggs are then removed from her ovaries and fertilised with sperm in a laboratory dish. A fertilised embryo is then put back inside the woman’s body.

There are several different methods that can be used during IVF and intracytoplasmic sperm injection (ICSI). We wpuld be more than happy to discuss with you any concerns, doubts and questions.

Availability and success

The Greek law 3305/ 2005 for human reproduction states that all medically induced reproduction methods should be applied to adults until the age of normal reproduction capacity which, for women, is defined as 50 years of age, which is the mean age of menopause.

The success rate for a cycle of IVF is about 32% for women under 35 years of age. The success rate decreases as the woman’s age increases.

We work closely with major Greek IVF centres and we can offer arrangements for your assisted conception attempts.

• Egg and sperm donatioN

If you or your partner has an infertility problem, you may be able to receive eggs or sperm from a donor to help you conceive. Treatment with donor eggs is usually carried out using IVF.