Infertility is regarded as an inability to conceive after 12 months of regular contraceptive-free sexual intercourse. Regular intercourse generally means two to three times a week. If a woman is older than 35 years old and has been trying for more than six months, a fertility specialist may regard her as having an infertility problem. Sometimes infertility not only refers to an inability to conceive but a recurring difficulty in delivering a livebirth.
Infertility is a medical definition and when a couple fulfills that definition, they should seek medical help. Infertility is better regarded as subfertility because many couples with infertility do actually conceive given enough time or with some help. Only a small number of people have true sterility – unable to conceive at all. Subfertility refers to couples with fertility rates that are less than the average rate for a given population. Couples who are subfertile usually take longer and in some cases many years before conceiving naturally. However, not every couple have years ahead of them to conceive. One thing we know for certain, fertility rate decreases with the advancing age of the woman, much more so than the man. Moreover, if a couple plans to have more than one child, they may not have years ahead of them.
If a couple has never been able to conceive they are said to have primary infertility. If they have conceived previously but the pregnancy ended in a miscarriage or birth of a non livebirth and that they experience trouble falling pregnant subsequently, they are said to have secondary infertility. As a rule, couples with secondary infertility generally carry a better chance of falling pregnant than couples with primary infertility.
The management of a couple with infertility generally starts with a thorough history taking from both partners. Hence it is important that couples attend all appointments together. This is particularly so for the very first appointment. The history taking process generally takes 15 to 20 minutes for both partners. Medical history, family history, social and fertility history are all obtained. It is important to bring along with you all previous investigations you might have had to the appointment. It is common for the woman and man to be examined. Routine pelvic swabs and pap smear are performed on the woman as well as an internal examination. The man may be examined if he has any problems or a significantly abnormal semen analysis result. Usually, a series of time sensitive hormone tests, blood borne infection screening, ovarian reserve test and ultrasound scan are ordered for the woman. The man will have a semen analysis from a credible andrology laboratory. In some situation, hormone and genetic screening blood tests may also be required for the man.
The couple is then reviewed a few weeks later with all the test results. The next step of management would depend on the duration the couple has tried to conceive, the age of the woman, the concern level of the couple, the test results and any relevant family or past medical history. Sometimes the couple just needs more time. They are counseled regarding timed intercourse, checking for ovulation and fertile period, keeping a menstrual diary or temperature charting. Sometimes the woman may need surgery or further imaging tests such as a specialized ultrasound scan to check for blockage of fallopian tubes. Laparoscopy is the preferred surgical method. It is key-hole surgery where small cuts are made on the abdomen and long slender instruments are passed via ports into the abdomen and pelvis to look for pathology such as endometriosis. Laparoscopy not only allows accurate diagnosis of disease but also allows treatment of many fertility related surgical diseases.
The woman with irregular menstrual cycles with no clear evidence of regular ovulation may need to take clomiphene, a ovulation induction medication. Sometimes the couple may need to undergo assisted reproduction technology (ART) to conceive. ART includes ovulation induction with intrauterine insemination, gamete intra-fallopian transfer (GIFT) or in-vitro fertilization (IVF).
Female Infertility
About 30% of couples with infertility are due to problems arising from the females. There are many known problems described in the scientific literature but I will only focus on a few common ones, mostly the surgically related diseases of female infertility.
Endometriosis
A condition due to the growth of endometrial type tissues outside the cavity of the uterus usually within the pelvis but sometimes found outside the pelvis (extra-pelvic sites). The tissue that lines the cavity of the uterus is called endometrial tissue. The common areas that are affected by endometriosis in the pelvis are on the ovaries, fallopian tubes or uterus, uterosacral ligaments and pouch of Douglas (space between the uterus and the rectum), pelvic sidewalls, surface of rectum, bladder and in the vagina. In rare situation endometriosis can be found in remote areas such as under the diaphragm, in the groin area, in the lungs, abdominal scars and others. The appearance of endometriosis varies to the naked eye. It can appear as patches of brown, white, red, yellow-brown and sometimes clear implants. Quite often these implants have a deeper component below the surface and these can only be felt by touch. Scar tissues can form around these implants over time giving that characteristic ‘nodule’ appearance. Tiny nerve fibres can be caught up in endometriosis lesions causing pain. When they are found as islands of endometrial tissues within the muscle wall of the uterus they are called adenomyosis. If significantly large areas of the muscle wall are affected, they give off the typical “Venetian blind” appearance seen on ultrasound scan. On ovaries the endometriosis first start off by growing on the surface giving the appearance of “gun-powder” patches. Over time, these superficial implants start to work their way into the ovary and then appear as chocolate cysts or endometrioma. The reason for the name is because the content of the cyst appears like liquid chocolate when the cyst is cut open. This is due to old altered blood.
How common is endometriosis? Quite frankly this is a difficult question to answer because it is difficult to measure. Various studies estimate endometriosis to affect 10-20% of women between the ages of 12 and 50. In women with significant period pains and infertility, the proportion of women affected by endometriosis can be as high as 50%. Having a family history of endometriosis amongst your first degree relatives will confer a 6 times increased risk on you for developing endometriosis. Women with endometriosis can have no symptoms at all. This may come as a surprise to some women. Often it is diagnosed serendipitously at the time of laparoscopy for the investigation of infertility. Furthermore the severity of endometriosis does not correlate well with the severity of symptoms. Some women with few and only small patches of endometriosis may have debilitating pain during their menses. Other women with very severe endometriosis may have no or few symptoms. Period pains felt in the lower abdominal area, low back pain, vagina pain, pain with intercourse, irritable bladder pain and sometimes passing blood in the urine, irritable bowel or constipation symptoms and sometimes irregular vaginal spotting may indicate endometriosis. Having difficulty conceiving may also be due to endometriosis, with or without any other symptoms.
The causes of endometriosis are not fully understood and are a matter of on-going research. It is only partially explained by the back-flow of menstrual blood into the pelvic cavity via the fallopian tubes. However a woman’s particular immune system or genetic background may have a great deal to explain why some women with retrograde menstrual flow develop endometriosis whilst others do not.
Endometriosis affects fertility in a number of ways. The presence of endometriotic lesions can affect sperm function in the female reproductive tract, affect quality of eggs and development of embryo and distort anatomical relationship between ovaries and fallopian tubes due to scarring around the ovary or tubes. This thereby affects egg capture from the ovary during ovulation. Occasionally endometriosis can affect the inside of the fallopian tube causing internal scarring and blocking the passage of sperm and egg. This prevents the meeting of sperm and egg thereby affecting fertilization.
The diagnosis of endometriosis can be difficult. It is made from a combination of the complaining symptoms, examination findings, ultrasound imaging result and surgical findings at laparoscopy. How one treats endometriosis depends on the age of the woman at the time of diagnosis, her desire to conceive, the severity of her complaints and the severity of the endometriosis discovered on ultrasound scan or at laparoscopy. For younger women (e.g. teenagers) with mild symptoms simply starting them on a trial of oral contraceptive pill may be appropriate. Laparoscopy may be indicated for the more severe cases and any implants, nodules, patches or visible lesions are resected or diathermied. Endometrioma often needs to be drained first and the cyst wall removed. Other medications such as zoladex, synarel or danazol may be used as first line treatment in a limited number of patients but often reserve for patients post laparoscopy with the more severe diseases. The oral contraceptive pill may also be suitable for some patients post surgery. Occasionally, surgery may be limited to alleviating pain and IVF is the only option for the woman to fall pregnant.
Endometriosis affecting ovaries, pouch of douglas and uterus. Note the corresponding scarring.
Endometriosis on left uterosacral ligament. Top nodule gun powder appearance. Bottom typical appearance.
Endometriosis. Note fairly extensive lesion in left uterosacral ligament. Its white, deep and raised a nodule.
Severe endometriosis with the pouch of douglas obliterated with scarring and endometriosis.
Spot of endometriosis on left ovary
Spot of endometriosis on left ovary diathermied
Typical appearance of endometriosis on pelvic sidewall. It is black in appearance because it contans old blood
Typical appearance of endometriosis on right uterosacral ligament.
Uterine fibroids
Also known as leiomyomas, are fairly common and affect up to 70% of the female population. Certain racial groups are more prone to them such as women of African descent. Many women with uterine fibroids are unaware that they have them. Fibroids arise from an abnormal growth of smooth muscle cells in the uterus and are quite capable of growing to quite a large size. They are a benign form of tumour. This means that they do not tend to invade or spread to surrounding tissue like cancers do. 99% of all uterine fibroids are benign. It is contentious whether fibroids will ever become cancerous but there exists a possibility that a cancerous growth within an otherwise benign fibroid may co-exist. There is an underlying genetic predisposition to developing uterine fibroids such that a woman with first degree relatives (mother or sisters) with uterine fibroids is at 2.5 times increased chances of developing fibroids. Fibroid uterus is one of the most common reasons why women require a hysterectomy.
As mentioned, women with small solitary uterine fibroid may not have any symptoms. Larger fibroid or multiple fibroids can cause problems with heavy painful periods or abnormal uterine bleeding. Fibroids can seldom present with acute pain especially when they undergo degeneration during pregnancy. Sometimes fibroids can grow to a size mimicking a twenty week pregnancy or larger. This can cause pressure symptoms and major discomfort. Fibroids can affect one’s prospect of conceiving depending on their size, location and number. Fibroids that grow just below the surface of the uterine cavity (submucosal fibroid) or large fibroid (> 5 cm diameter) within the wall of the uterus (intramural fibroid) are known to reduce your pregnancy chances by two thirds or a half respectively!
Not all women with uterine fibroids need any treatment. The need for treatment would depend on the symptoms, desire to fall pregnant, size and number of fibroids. The type of treatment would depend on the presenting problem, the age of the woman, the need to preserve fertility, the size and number of fibroids, the location of the fibroids and whether you have had previous abdominal surgery. There are many different methods available for the treatment of fibroids. The doctor may prescribe you certain medications e.g. zoladex, synarel, GnRH antagonist, antiprogesterone (Mifepristone) to shrink the fibroids to provide some temporary relief. Usually the fibroids will return to its original size once the medications are stopped after 3-4 months' time. Because of significant side effects e.g. menopausal symptoms and thinning of bone, these medications are rarely continued beyond 6 months. Hence they are used predominantly to shrink a very large fibroid uterus in order for surgery to be performed safely. One advantage of operating on a shrunken fibroid uterus is that it allows for a minimally invasive laparoscopic approach e.g. robotic assisted laparoscopic myomectomy or hysterectomy. The advantages of minimally invasive surgery vs open surgery will be covered in greater details in later text. Surgery is the only approach that allows all fibroids to be removed. The other procedural approaches are uterine artery embolisation and MRI guided focus ultrasound (MRgfUS) treatment. Uterine artery embolisation involves injecting polyvinyl particles into your artery in the groin under local anaesthetic to block off blood supply to the fibroid uterus. This effectively starves the tissue of blood supply resulting in cell death. Pain side-effects are considerable and can be prolonged lasting months. It is not suitable for large fibroids and women wishing to preserve their reproductive potential. MRgfUS involves using magnetic resonance imaging to map out the fibroids first and then with direct high energy ultrasound to destroy fibroids producing instant thermal cell death. It is a relatively new technology and long-term data are not available. Its safety and suitability for use in women wishing to fall pregnant in the future are not fully established. Various obstetrics and gynaecology bodies around the world have expressed caution in using MRgfUS for the treatment of young women with fibroids who wish to preserve their uterus for fertility reasons.
A large fibroid situated at the front of uterus. Note fibroid is bigger than uterus and blanched after injection with vasopressin.
Video on uterine fibroids
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Blocked tubes
Refers to blocked fallopian tubes. Fallopian tube is a long trumpet like structure that is attached to the top corner of the uterus. Each normal uterus has two fallopian tubes. At one end where it attaches to the uterus, its caliber is the smallest and it gradually opens up towards the other end like a flower in full bloom. It has fimbriae which resemble the petals of an orchid flower, opening towards the ovary situated adjacent to it. During ovulation, the fimbriae brush backwards and forwards over the ovary picking up the ovulated egg and sweeping it towards the opening of the tube. The egg meets the fittest and most motile of the ejaculated sperm lying in wait for the egg in the narrowest part of the fallopian tube called the isthmus. Once the egg is fertilized, the zygote (a newly fertilized egg) will divide and double its cell content every day and eventually enters the cavity of the womb around day five or six. It normally implants around day six or seven. Cilia are soft bristle like structure that line most of the inside of the fallopian tube. The cilia sweep and generate a current that carries the egg or embryo towards the uterus. This is important because the fallopian tube is a delicate structure and can be damaged quite easily either deliberately in the case of tubal ligation (tying your tubes) or destroyed by infections (sexually transmitted or after delivery or post curettage) or diseases such as endometriosis. The tubes can be damaged in numerous places singularly or at multiple sites along the tube including the fimbrial end. Occasionally if the fimbrial end is damaged with scarring either due to previous infections or endometriosis, careful dissection can sometimes free the adherent tube and one might see a return of function. Before the days of IVF, tubal surgeries to unblock tubes were routinely performed. A fine catheter was used to push through obstruction at the start of the tube or surgery to the fimbriae to open up the clubbed end were frequently attempted. Success rates were limited because there were often damages elsewhere within the tube which could destroy the tiny cilia. Even if the tubes were deemed open or patent, there is no guarantee that the delicate function of the cilia within the tube is not affected. IVF offers the best and highest chance of pregnancy for women with blocked tubes.
One possible exception is in young women after tubal ligation. Reversing the blockages by microsurgery or laparoscopic surgery can often return near normal function to the tubes. Hence if the tubes are patent after reversal surgery, there is a very good chance of pregnancy afterwards.
Right Tubal Inflamation
Pelvic adhesions surrounding swollen left tube. This tube must be removed or clipped prior to IVF
Alternatively blocked tubes filled with fluid - hydrosalpinges can be clipped
Pelvic adhesions divided and both swollen fallopian tubes removed at laparoscopy prior to IVF
Polycystic ovarian syndrome
PCOS is a disorder characterized by an imbalance in the sex hormone levels in your body resulting in higher levels of male hormones to female hormones. The imbalance in the sex hormone levels in the ovaries and bloodstream results in high blood levels of insulin, a hormone made by the pancreas to allow cells to take in sugar. The alteration in the normal hormone balance upsets the body’s metabolism resulting in weight gain or difficulty controlling your weight. The abnormally high insulin levels also cause insulin resistance where the cells in the body ‘dumb’ down their response to insulin. This increases the risk of developing diabetes. Moreover, the metabolic derangement also upsets fat and cholesterol profiles in the body. Higher levels of male hormones in the female body interfere with ovarian function and interrupt ovulation. Hence the ovary develops the characteristic polycystic appearance (multiple tiny cysts) seen on ultrasound scan or at laparoscopy. This is so because the follicles do not grow to maturity and their development are stunted. In addition, the menstrual cycles become irregular and ovulation unpredictable or if it happens at all! Needless to say, this causes problems if one is trying to conceive. Some women might also complain of increased acne or develop coarse facial hair.
The management of PCOS consists of a two-prong approach. Firstly, the short-term issue such as acne, hair growth, irregular cycles and infertility will need to be dealt with first. If there is no plan to start a family yet, commencing on the oral contraceptive pill is the best option. Otherwise, ovulation induction medication such as clomiphene is used to encourage regular and predictable ovulation. There are other second line medications that can be used to treat acne or facial hair. The long-term management consists of focusing on a healthy diet, exercise and lifestyle modification to manage one’s body weight. This helps to prevent diabetes, high cholesterol levels and cardiovascular diseases. Anti-diabetic medication can also be used in some patients to help reduce weight and decrease insulin resistance. Some women may not response to clomiphene and may benefit from laparoscopic ovarian drilling to re-address the hormonal imbalance in the ovaries and help to kick-start ovulation. Eight out of ten women ovulate after ovarian drilling. Only a few diathermy holes (about four to six) are drilled into each ovary. However the ovulation achieved after ovarian drilling is short lived though.
For other women with difficulty ovulating despite a trial of clomiphene or ovarian drilling, ovulation induction using gonadotropins with intrauterine insemination (if there is issue with intercourse timing or mild to moderate sperm abnormality) is the next step. IVF is rarely required unless there are also other underlying problems.
Other causes
There are many other causes of female factor infertility that are not covered here. Dr. Leong also cares for women with recurrent miscarriages, premature ovarian failure or early menopause, abnormalities of the uterus e.g. uterine septum or scarring and other hormonal causes of infertility e.g. high prolactin levels, low central or brain produced hormone levels e.g. hypogonadotropic hypogonadism.
Severe pelvic adhesions where omental fat pad is adherent to back of uterus
Severe pelvic adhesion at laparoscopy. Uterus attached to bowel at the back and cyst on the right.
Adhesions or scarring in the pelvis due to pelvic infection in the past. Note a scissor cutting a sheet of scar attached to the ovary
Pelvic adhesions behind uterus seen at laparoscopy
Male Infertility
Infertility secondary to a male problem is as common as from a female problem.
This may be a revelation to some people but it is important to set the record straight. Male factor infertility affects 30% of couples presenting with an infertility problem. It is estimated that in Australia, male infertility affects about one in every 20 men. Coping with male infertility can be very difficult. In more than half the cases, doctors can find no reason for the poor sperm quality. In the other 40% cases that do have an underlying reason, less than half have a treatable or reversible cause.
Sperm are made in the testes, in the tightly packed fine tubes known as seminiferous tubules. When fully stretched out, these tubules occupy the length of a football field. Inside the tubules, are sperm producing germ cells called spermatogonia. Between the tubules are Leydig cells which come under the influence of LH hormone and they produce the male sex hormone known as testosterone. It takes about 70 days to produce a mature sperm. Within a testis, sperm can be at different stages of development with some sperm at early stages and others at later stages. The testes (come in a pair) originate in the abdomen and migrate down along the back of the abdomen to reach the scrotum just before birth. This process is crucial because the cooler scrotum (about 3°C below normal body temperature) is important for sperm production and normal testicular function when puberty arrives! After a sperm is being produced, it is transported along the tubules to the epididymis. Mature sperm then gain their motile function by moving through the epididymis. This process takes about two weeks. The epididymis sits at the top of the testis and also functions as a temporary reservoir for sperm before ejaculation. From the epididymis a tube called the vas deferens transports the sperm pass the prostate to join the tube called the urethra that opens up on the glans (head) of the penis. A gland called seminal vesicle produces much of the fluid that forms the ejaculate (semen). Semen is a mixture of fluids from the different glands of the male reproductive tract with 90% coming from the prostate gland and seminal vesicles. The remaining arises from the epididymis and contains sperm. During ejaculation, semen is deposited in the upper vagina and around the cervix. When the timing is favourable such as around ovulation, the cervical mucous is thin and watery. This cervical consistency allows sperm to travel very quickly up into the uterus within minutes of ejaculation. Within hours, sperm is found in the fallopian tubes waiting for the egg.
The quality and quantity of a man’s sperm are important for fertility. If the number of sperm in an ejaculate is low or if the sperm are of poor quality, it can be difficult and sometimes impossible for a couple to become pregnant. In most cases, there are no obvious signs of infertility. The man is generally able to have an erection, intercourse and ejaculate normally. The quantity and appearance of the ejaculated semen usually appears no different whether it is normal or abnormal. A specialized semen analysis test is required to determine the quantity and quality of the sperm. Please note that semen analyses performed in a general commercial laboratory with non-dedicated andrology services usually does not provide a high enough quality of evaluation. Hence, Dr. Leong would repeat a semen analysis with the Monash IVF’s andrology laboratory to ensure the highest quality interpretation. In a semen analysis report, a number of different parameters are recorded. These include semen volume, sperm concentration, sperm motility, sperm morphology, presence of white blood cells, semen pH and sperm antibodies. Men normally produce 2 to 5 mls of semen in an ejaculate. Sperm concentration is another word for sperm count which is measured as the number of sperm in a given volume of ejaculate normally expressed as number of sperm per ml of semen. Normal concentration per WHO (World Health Organisation) definition is 20 million per ml. Sperm motility measures the ability of sperm to move and progressive motility measures the ability to swim forward. The number of motile sperm compared to non-motile sperm is reported as a percentage of the total number of sperm present. Sperm morphology refers to the sperm’s shape and physical features. The number of sperm that are abnormally shaped is compared with the number of normally shaped sperm. An abnormal sperm can have abnormally shaped heads or tails which can affect their motility and ability for fertilisation. In the human species, it is quite normal for fertile men to have large number of abnormally shaped sperm, up to 85%. If the abnormality is persistently higher than 85%, fertility will be affected. In rare circumstances, the sperm of some men have round heads (globozoospermia) and they will have difficulty achieving a pregnancy naturally. Small number of white blood cells can be found in normal semen and this does not pose any problem. However if large numbers are found, this may be a sign of an infection in the reproductive tract and should be treated. In addition, high white cell numbers can also happen for unknown reasons. The pH level is measured to determine if the semen is acidic or alkaline. Normal semen is slightly alkaline. If acidic and combined with low or no sperm count, this may suggest a possible blockage somewhere in the ejaculatory ducts. Sperm autoantibodies can be found in semen if sperm was previously exposed to the immune system. Normally the testes are screened off from the immune system. Hence if there are any events that would breach this barrier, the immune system will make antibodies against the sperm. This can happen after a vasectomy, infection, trauma or for no apparent reason. Antibodies attaching to sperm can reduce their motility and slowing their progress through the cervical mucous. A sperm surrounded by antibodies especially around its head will have difficulty binding to the egg via surface receptors. This will interfere with the fertilization process.
The causes of abnormal sperm analyses can be divided into problem due to a blockage somewhere in the male reproductive tract or abnormal sperm production. We can also look at it in another way by classifying whether the conditions are reversible or not reversible. Only one in eight infertile men has a reversible condition and after treatment couples can become pregnant naturally. Some of these treatable conditions are due to a derangement in hormonal pattern, vasectomy (can be reverse with surgery), sperm autoantibodies (if not severe), sexual problems (e.g. erection) and adverse effects of certain medications (e.g. salazopyrin and anabolic steroids). Conditions that are not reversible are due to problems intrinsic to the sperm production pathway e.g. absence of germs cells (Sertoli cell-only syndrome), maturation or germ cell arrest and unexplained hypospermatogenesis (lower number of sperm produced). Sometimes the sperm count is normal or near normal but high proportion of the sperm are abnormal looking or very sluggish. The good news is that Artificial Reproductive Technology can help men achieve a pregnancy even if they produce very few sperm. Provided they produce sperm even if none was observed in the ejaculate then sperm may be retrieved directly from the testes with a needle biopsy or sometimes open biopsy. However about one in nine infertile men have no sperm in their semen or in their testes and unfortunately these men are sterile and cannot be treated. Sperm producing cells in the testes either did not develop or have been irreversibly destroyed. Adoption and donor insemination are the only options available for these unfortunate men. A blockage in the reproductive tract can be induced surgically such as in the case of vasectomy, occur after an infection or sometimes due to a congenital problem (most commonly cause from congenital absence of the vas deferens seen in men who are carrier for the cystic fibrosis gene or have full-blown cystic fibrosis). Lifestyle factors such as smoking, excessive use of spas and saunas, certain recreational drugs and environmental or occupational toxins e.g. pesticides, heavy metals, toxic chemicals and radiation may affect the quality and quantity of sperm produced. A small number of men (1-2%) with abnormal sperm production may have an inheritable genetic condition that affects the Y chromosome or have abnormal chromosomes (Klinefelter’s syndrome or balanced translocation).
Dr. Leong will normally suggest that the male partner has a semen analysis with the Monash IVF laboratory and blood borne infection screening test after the first visit. Subsequent tests would depend on the finding of these initial results. These include hormone blood tests, testicular ultrasound scan, genetic screening and a urine test.
