Obstetrics and Gynecology Infertility Dr. Layla Zaghal Definition The term infertility is no more used and has been replaced by the term subfertility ; when you tell a couple that they are infertile, it s like telling them they can never have babies, but this is not true, because, in fact, they just have a problem and you will do your best to treat it. Infertility is defined as the involuntary failure of a couple to conceive after 12 months of unprotected intercourse. However, previous old definitions considered 24 months of unprotected intercourse. Now, if you took 100 hundred couples and asked them to try to conceive, 75 couples of them would conceive within one year of marriage, another 10 of them would conceive after 2 years, and then, after 3 years of marriage you re left with 15 couples, and here the curve would reach to what-so-called a steady state plateau, where the curve remains in a steady rate without changes, which means that these couples need help! They have problems, and you need to investigate and interfere. Causes There are many causes of infertility. But the latest studies of WHO reported that 40% of the cases are due to 1 male factor. Less common is the 2 female factor (problems of ovulation). In other cases it s a 3 combined cause between both the male & the female. And the least common cause is 4 unexplained. 1 / 13
Unexplained infertility means that all the routine investigations done to the couple in the primary health care clinic are of normal results (semen fluid analysis, ovulation test, female hormonal tests and tubal patency test). But once you refer this couple to the fertility clinic and do all the specific investigations or start them on assisted conception techniques like IVF (in vitro fertilization) and IUI (intrauterine insemination), you can identify the cause, and only then you can explain the unexplained infertility. Why can t these causes be detected by routine investigations? Some causes may be cellular that can t be detected by routine investigations, like faint fertilization (where the sperm fails to fertilize the egg); how can this be detected without doing IVF and watch the sperm and the egg in the same dish waiting for a fertilization? So assisted conception techniques are both diagnostic and therapeutic techniques. Steps of Management A. Management always starts by taking a detailed history of the couple together. For the female; you have to ask about every single detail from menarche until the time of her visit. Ask about menarche, the regularity of her cycles, any change in the pattern of her period, the duration of the period and about any associated pain. One of the typical scenarios, that you may see quite often, is meeting a 24- year-old couple who has been trying to conceive for 3 years, and the female has regular painful cycles. Here, the most probable and the most common diagnosis would be endometriosis. Dr. Laila: Endometriosis is an important subject, and I m the one who writes its questions in your exam. And then she talked briefly about it [see the box]. Endometriosis is the implantation of the endometrium outside the uterine cavity. It responds to the hormonal stimulation and the cyclical changes which leads to bleeding in the ovaries and the abdomen cavity affecting the fertility. Patients present with severe painful regular cycles that may lead eventually to subfertility. It s quite common, and more common in Caucasians. It s classified into four stages. Mild endometriosis is treated by ovulation induction, while moderate and sever endometriosis sometimes require surgery for the resection of the disease before doing IVF cycles. 2 / 13
Also, you have to ask about all endocrine symptoms from hypothalamus down to the ovary and the testicles. [Hypothalamus pituitary ovarian axis/testicular axis]. Any problem from top to bottom may be the cause of infertility, such as tumors, trauma or infections. Hormones of the anterior pituitary gland that affect the ovulation: LH, FSH, TSH, prolactin, ACTH, melanocyte-stimulating hormone. Weight change, exercise, chronic illnesses, stress, radiotherapy and chemotherapy can all affect the glands and affect the cycle, so you have to ask about them in the female. Thyroid hormones are also important; both hypo- and hyperthyroidism can affect the menstrual cycle. In Jordan, about 5% of women above the age of 40 have thyroid disorders, meaning that such disorders are quite common, as well as subclinical hypothyroidism, which is common among menopausal women. You also have to rule out polycystic ovarian syndrome in subfertile women (PCOS not PCO appearance). Most women with problems of ovulation have underlying PCOS, and this can delay the conception. According to the latest Rotterdam criteria, PCOS stands for polycystic ovarian syndrome, and to diagnose it you have to have 2 out of 3: 1. Irregular evidence of anovulation. This can be detected by either oligomenorrhea, cycles lasting for more than 6 weeks apart or if there is no ovulation detected in the tests done for the patient. 2. Biochemical or clinical evidence of hyperandrogenism. Clinical hyperandrogenism means having the symptoms of hirsutism or acnes. Biochemical hyperandrogenism is detected by measuring the hormones levels; testosterone and DHEAS (dehydroepiandrosterone sulfate), and you calculate the free testosterone to find it higher than the normal female range. 3. Polycystic appearance of the ovaries on US scanning. The ovaries of these women appear on the ultrasound as pearl-necklace appearance. The underlying cause in PCOS is the peripheral insulin resistance and hyperinsulinemia, so women with PCOS are more prone to put on weight, 3 / 13
leading to a thick ovarian stromal and higher levels of androgens which again leads to gaining weight, more insulin resistance and increased insulin insensitivity leading to a thicker ovarian stromal,.. etc, making it a vicious circle. And once androgen levels increase, this leads to irregular cycles and delayed ovulation. So in these patients, instead of recruiting one follicle per month to release an oocyte, more than one follicle grow at the same time every month, but none of them succeeds in releasing an oocyte, which explains the pearlnecklace appearance seen on US. For the male history; you have to ask about: Puberty Secondary sexual characteristics Any previous surgeries, chronic illnesses Varicoceles, hernia repairs, undescended testis Problems with erection, ejaculation or intercourse Mumps orchitis; which is quite common in our area. In childhood it can affect the testicular development and can affect spermatogenesis later on. Other questions related to the couple together are also important, like if they have problems with the intercourse, and about the frequency of intercourse. B. Examination; you have to examine both the male and the female from head to toe. Female examination: head and neck (for signs of thyroid disorders), breast examination (looking for signs of galactorrhea; galactorrhea indicates high levels of prolactin, and increased levels of prolactin lower the FSH level which affects the ovulation), general look for female hair distribution and acnes, pelvic examination (palpation to look for masses). Male examination: you always check for hair distribution, secondary sexual characteristics and testicular size by palpation. 4 / 13
C. Investigations: Routine investigations include: In females: - Day 2 hormonal profile (FSH, LH, prolactin, TSH, testosterone, estradiol). If PCOS is suspected, you might also order DHEAS level. - Tubal patency; once the oocyte is released it passes through the fallopian tube to be fertilized in the ampulla of the tube, so tubal patency is necessary for the fertilization. The patency is usually checked by hysterosalpingogram (x-ray and dye test). Which is done at the end of the cycle, usually on the 10 th or the 11 th day, and by using the speculum, a dye is injected through the cervix. Then many x-rays are taken following its course into the tubes to see the filling and spilling phases. Sometimes you can check the tubal patency by saline ultasonography in the clinic, but it needs an experienced operative. But what s actually used worldwide is laparoscopy and dye test. Dr. Laila: You re not required to know when to use laparoscopy for tubal patency. But here are two examples: you do laparoscopy and dye test for a patient with previous surgeries, because it may be the adhesions that caused the impotency of her tubes. And for a patient with recurrent painful cycles, you also do laparoscopy because endometriosis is suspected here. So usually the history will guide you. In males: semen fluid analysis. Semen analysis should be done after abstinence from masturbation or intercourse for 5 days. If it was done for more or less than 5 days this may affect the count and the motility of the sperms. Rubella should be screened in both. Latest WHO criteria for normal semen analysis values have changed 6 months ago, and here are the new ones: The count should be > 15 million 5 / 13
Motility; sperms are classified due to their motility into 4 grades (a,b,c and d): A: rapid progressing sperms (fast swimmers) B: slow progressing sperms C: immotile sperms D: dead sperms So for normal semen motility a and b must be > 32% Morphology; it depends on the lab you are using and the results you get. If you get normal count and normal motility then you don t need to look at the morphology. However, if you question your lab abilities then you need a morphology which is > 50 % Liquefaction ;(اللزوجة) should be within 20 minutes. Volume should be > 2 ml. [HSG] - You can notice the uterus filled with dye, and there s a bilateral spillage, meaning it s a normal HSG. 6 / 13
[Laparoscopy] [Laparascopy and dye test] when you do dye test you can see bilateral spillage from the tubes. 7 / 13
D. Treatment: Treatment starts with 1 ovulation induction, either by drugs or by injectables. Of course you have to treat the underlying cause if it was a problem with ovulation. Metformin is not widely used for infertility, it s mainly used for lowering insulin insensitivity, so it s more preferable for obese patients as it helps in weight reduction and regulating the ovulation. The other important use of metformin is in IVF cycles to lower the risk of ovarian hyperstimulation syndrome. Clomid is a non-steroidal cyclical estrogen with an anti-estrogenic activity. It blocks the receptors in the hypothalamus, leading to false impression of lack of estrogen, which increases the release of FSH & LH from the pituitary gland, and this stimulates the ovaries and you end up having more than one follicle Typical MCQ Which is wrong: a. Clomid is a steroidal cyclical estrogen b. It has an anti-estrogenic activity on the hypothalamus and the pituitary gland c. It acts as estrogen on ovaries & uterus growing at the same time and ovulation eventually occurs. For example, a woman with polycystic ovaries with irregular cycles you can give her Clomid. Letrozole is an aromatase inhibitor. It s not yet FDA-approved for ovulation induction. It s rather used in cases of metastasis of breast cancer, it almost acts as tamoxifen. It was found that one of the side effects of letrozole is ovulation stimulation. What s good about letrozole that it reduces the rate of multiple pregnancies, because it stimulates monofollicular growth in each ovary. Injectables are composed of physiological female hormones, they are available in different injection forms (LH or FSH or combined). Nowadays these injectables are prepared in the lab without the use of postmenopausal women urine. The ovulation stimulation starts with injections, either IM or SC - depends on the injection form and the aim is to stimulate ovulation in irregular cycles. 8 / 13
2 Intrauterine insemination (IUI) simply stands for just taking the sperms, washing them then injecting them into the uterus. And in this case, normal semen analysis is necessary. We tend to reserve IUI for women with problems of intercourse like vaginismus, women who had previous cervical surgeries as in a case of cervical stenosis and women with any mechanical obstruction that prevents the sperm from swimming up in the tube. In those cases, the success rate of IUI is higher. There are different protocols for IUI. Some just wash the sperm and inject it, some others do ovulation induction then inject the sperm at the time of ovulation 3 In Vitro Fertilization (IVF). First baby delivered by IVF was Louise Brown in 1978. Steptoe & Edwards were the ones who made it happen, one was an embryologist and the other was a surgeon. They used a laparoscope to retrieve the eggs and return them. This old method had surly been modified since that time, and now, we retrieve eggs transavaginally using ultrasound scanning. IVF technique had been modulated in different ways: GIFT (gamete intrafallopian tube transfer) is another name for IVF where you take the oocyte and the sperm, combine them in the same syringe as gametes then transfer them back to the tube by laparoscope. But this method is no more used nowadays. ZIFT (zygote intrafallopian tube transfer) is another method, where you wait for the sperm and the oocyte to form a zygote before inserting them back to the tube. All these methods have been modified. Transvaginal ultrasound scanning is now used to collect the eggs. Then fertilization happens in the lab, and once the embryo is formed it s transferred back to the uterine cavity through the cervix. And this is called conventional IVF. The other form of this technique is IVF + ICSI (intracytoplasmic sperm injection). First you do IVF, you mix sperms and oocytes in one dish and wait for 18 hours for a sperm to fertilize an egg, and for every oocyte to be fertilized you have to have at least 200 sperms (so the count of sperms would be in millions). So after 18 hours, if no fertilization occurred, there must be a problem with the egg or the sperm itself. And here you can start with an 9 / 13
emergency ICSI, where you inject the head of the sperm (where the genetic material is contained) directly to the cytoplasm of the oocyte to increase the chance of fertilization. But still the success rate with ICSI is no more than 70%. Because there may be an abnormality with the shape of the head or the nuclear material. For a couple who s trying to conceive - if the semen analysis, the tubes and the ovulation are all normal - their chance of success per month is not more than 20%. Now, with Clomid the chance increases by 45% as a total of 65% success chance. While in IUI, it only increases by 8%-11%. In IVF, it s usually higher but depends on the female age; in young females it can reach up to 40%-50%. IVF protocols [ NOT REQUIRED] There are three different protocols: Short protocol, Ultra Short protocol and Long protocol. Basically, what you do is suppressing the female physiological hypothalamic pituitary ovarian axis, and then you take control over her ovaries. 1- To suppress, you start by giving her a GnRH agonist injection continuously, which will suppress the pulsatile release of GnRH from the pituitary. You keep giving the patient these injections for around 2 to 3 weeks until she goes into a state of menopause (called: down regulation state) where the pituitary is suppressed and there is no endogenous secretion of LH and FSH. Here, the patient may complain of headache, irritability, hot flushes.. etc (symptoms of menopause). You do a regular blood test to make sure that estrogen level is low (which indicates low FSH and LH levels). 2- After that, you start to stimulate the ovaries with synthetic FSH and LH injections according to your protocol in order to induce follicular growth. On average, the patient will need around 12 injections of FSH and LH before she has a proper response. During the period of FSH and LH injection, you should do regular transvaginal ultrasound scan every other day, in order to detect the follicular growth. 10 / 13
3- Once the patient is ready, you give her an injection to release the eggs and then you do an egg collection (under US guidance) through transvaginal access. On the same day, you ask the male partner to give his semen analysis, you mix the sperms with the eggs and then you wait for fertilization. A cycle of IVF in a long protocol can last around 6 to 8 weeks, and in a short protocol it lasts around 3 to 4 weeks. There is an indication for each protocol, but you are not required to know them. [Now back to the required material] After fertilization, we wait for the embryos to grow in the lab. As you took in the embryology course, the embryo will undergo changes as follows: - at day 1 it consists of 2 cells - at day 2 it consists of 4 cells - at day 3 it consists of 8 cells - at day 4 it will enter the morula stage (here it consists of cluster of cells that (قطف العنب cannot be differentiated from each other, appear like grapes or - at day 5 it will be called a blastocyst. Your transfer will be done either 2, 3 or 5 days after the egg collection and then you name your embryo accordingly as day 2 embryo, day 3 embryo or day 5 embryo. Day 5 (blastocyst) transplant has the highest clinical pregnancy rate; it can reach to 50% for females below 30 years of age. This is because during these 5 days, many of the embryos will die and only the strongest ones will survive (natural selection), so in day 5 transplant we are using the strongest and the most mature embryo, which has the highest chance to survive inside the uterus. Here in KAUH no one did blastocyst transplant before, except me! and I m still waiting for the results now Dr.Laila said. 11 / 13
Complications Complications of all those assisted reproductive techniques are many. You have to keep in mind that you are doing them to solve a problem, so if you want to have a child, you have to accept these minor complications. As any other drugs, clomide has its own side effects: - Headaches - Blurring of vision - Nausea and vomiting (rare) - Cysts - Hot flushes - A small risk of having multiple pregnancy (because it will stimulate the growth of more than one follicle at the same time). - Ovarian hyperstimulation syndrome: here the ovaries have an exaggerated response to stimulation so they will make load of follicles at the same time. In these patients, the ovaries will leak fluids and toxins to the systemic circulation, and this will induce vasodilatation and leakage from the vessels (shifting of fluids from intravascular to extravascular), so the patient becomes toxic and accumulates fluid all over her body (ascites, hydrothorax, pulmonary edema, pleural effusion ) This syndrome is divided into mild, moderate, severe and critical (You do not have to know more details about this classification). Complications related to IVF: - Side effects of the drugs used: for example if we give the patient GnRH agonist, she will be in a state of menopause and may develop headache, hot flushes, irritability In addition, injectable drugs may cause hyperstimulation of LH and FSH, and of course, locally it may cause bruises, hematoma or anaphylactic allergic reaction. - Complications of the procedures done in IVF: o Egg collection: here the physician inserts a needle (under US guidance) through the vagina to reach the ovary and aspirate the fluids from it. 12 / 13
Therefore, this will put the patient under many risks like organ injury (bladder, bowel ), infection (5 per 1000) or bleeding from the ovary. o Embryo transfer related complications. - Risk of miscarriages and ectopic pregnancies in IVF pregnancies is quite higher than in spontaneous pregnancies by 1-2%. - Ovarian hyperstimulation syndrome (mentioned above) - Psychological sequelae: you always need to tell your patient that IVF is expensive, its success rate in most of the scenarios is not more than 50%, and its cycle takes around 8 weeks (and after that, it is very disappointing if pregnancy test came negative). The End 13 / 13