Ebook Textbook of clinical embryology: Part 2 - Cambridge medicine

Chapter Treatment of male and female infertility Tim Child Once a couple experiencing fertility problems have undergone appropriate and timely investigations then, in the majority of cases, a diagnosis can be made. A minority will have the rather unsatisfactory diagnosis of exclusion, ‘unexplained infertility’. A treatment plan can then be made. The patients should attend the consultation together. Pre-pregnancy counselling Women who are trying to become pregnant should be informed that drinking no more than one or two units of alcohol once or twice a week, and avoiding episodes of intoxication, reduce the risk of harming a develop-ing fetus. Men who drink up to three or four units of alcohol per day are unlikely to affect their fertility. Excessive alcohol intake can affect semen quality. Womenwhosmokeshouldbeinformedthatthisis likely to reduce their fertility and should be offered referral to a smoking cessation programme. Passive smoking may also affect female fertility. While there is an association between male smoking and reduced semen quality, the impact of this on fertility is unclear. Dietary supplementation with folic acid before conception and up to 12 weeks’ gestation reduces the risk of having a child with a neural tube defect. The recommended dose is 0.4mg per day, though for women with diabetes, on anti-epileptic medication or who have previously had a child with a neural tube defect, a dose of 5mg per day is recommended. A female body mass index (BMI) over 29 is asso-ciated with a longer time to conception and a higher rate of miscarriage. Women who are not ovulating, and who have a BMI over 29, are likely to improve their chances of conception by losing weight. Similarly there is a correlation between male obesity and reduced fertility. Women with low BMI of less than 19 and who have irregular or absent menstruations are likely to improve their fertility by increasing their weight. While there is an association between elevated scrotal temperature and reduced semen quality, it is not clear whether wearing loose-fitting underwear improves fertility. Someoccupationsinvolveexposuretohazardsthat can reduce male or female fertility, and appropriate advice offered. A number of prescription, over-the-counter and recreational drugs interfere with male and female fer-tility and so should be enquired about, and appropri-ate advice given. Vaginal sexual intercourse every 2–3 days through the cycle optimizes the chance of conception. For couples with a diagnosed cause of infertility, the treatment will depend on the cause. Ovulation disorders Following investigation, the cause of ovulatory dys-function should be classified (see Chapter 20): WHO Group I Ovulation disorders (hypogonadotrophic hypogonadism) Women with WHO Group I anovulatory infertility can improve their chances of conception and an uncomplicated pregnancy by moderating high exer-cise levels and increasing the body weight if the BMI is less than 19. Pulsatile subcutaneous administration of gonadotrophin releasing hormone via a pump is a physiological and successful way of inducing mono-ovulatory cycles. However, the need to wear the pump constantly limits the use of this technique. Ovulation induction with once daily sub-cutaneous gonadotro-phin injections for two weeks or so is more commonly used. The absence of endogenous LH pituitary Textbook of Clinical Embryology, ed. Kevin Coward and Dagan Wells. Published by Cambridge University Press. 161 © Cambridge University Press 2013. Section 2: Infertility 162 production means that a gonadotrophin with LH activity should be used in addition to FSH. The ovar-ian response needs to be closely monitored with ultra-sound to reduce the risk of hyperstimulation and multiplepregnancy.AnhCGinjectionwillberequired to induce ovulation, followed by timed intercourse. WHO Group II Ovulation disorders (PCOS) Women with WHO Group II ovulation disorders who are overweight should be encouraged to normalize their BMI. This may promote spontaneous ovulation or increase the response to ovulation induction drugs and also reduce risks during pregnancy. Clomifene citrate The anti-estrogen clomifene citrate has for decades been the first-line ovulation induction drug for PCOS. Clomifene blocks the estrogen feedback from the ovaries to the pituitary and hypothalamus, ‘trick-ing’ the pituitary into releasing more FSH which may be sufficient to result in follicular development. Clomifene is taken as a tablet, usually at an initial dose of 50mg once daily for 5 days from day 2 of the menstrual cycle. Side effects include headaches and visual disturbances. If these occur then clomifene must be stopped and an alternative treatment used. The most important side effect is a 10% multiple pregnancyrate,nearlyalwaystwins,thoughtheauthor has seen two sets of quadruplets following clomifene treatment. It is good practice to offer ultrasound mon-itoring in the first cycle to recognize the development of too many dominant follicles, cycle cancellation and dose reduction in the next cycle. Failure to respond at all to clomifene (‘clomifene resistance’) leads to a step increase in the clomifene dose each cycle to a maxi-mum of 150mg daily. If still clomifene resistant even at the maximum dose then second-line treatments as discussed below are used. Clomifene is licensed for a maximum of six cycles of treatment. Very prolonged use (over 12 months) has been linked with a possible increase in the risk of developing ovarian cancer. Metformin As discussed in Chapter 20, PCOS appears to be a condition of insulin resistance. Obese women with anovulatory PCOS, who reduce their weight by 5% or more, will also reduce their insulin resistance and may begin to ovulate spontaneously. If not then the insulin sensitizing agent metformin can be used. Metformin is taken in multiple doses every day, unlike clomifene which is only taken for 5 days per cycle. Metformin’s side effects include nausea, vomiting and other gastrointestinal disturbances. It does not pro-mote weight loss. A number of RCTs have compared clomifene against metformin against combined clomifene and metformin for first-line ovulation induction in women with PCOS. A recent NICE (National Institute for Health and Clinical Excellence) meta-analysis suggests similar cumulative live birth rates with the different treatments. An advantage of metformin is that it pro-motes mono-ovulation so there’s no need for ultra-sound follicular tracking. In addition, metformin may normalize testosterone levels and consequently reduce hirsutism, thus having additional non-fertility benefits. The need for daily multiple doses and the gastrointesti-nal side effects are disadvantages. The main disadvan-tage ofclomifeneisthemultiplepregnancy rate. Hence, the options should be discussed with women to enable them to make an informed choice. Women who are clomifene resistant can undergo one of the following second-line treatments: laparo-scopic ovarian drilling, gonadotrophin therapy, or combined treatment with clomifene and metformin if not already used first line. Success rates appear similar between the options. Laparoscopic ovarian drilling (LOD) During a laparoscopy the ovaries are each ‘drilled’ using a diathermy electrical current for a few seconds in multiple places. This technique has replaced the now obsolete ‘wedge-resection’ procedure. An advan-tage of LOD is that other pathology such as endome-triosis or adhesions can be diagnosed and treated during the same procedure. Tubal patency can also be tested (‘lap and dye’). Also, if successful, then the resulting mono-ovulation is consequently not associ-ated with an increased risk of multiple pregnancy or the need for ultrasound follicular tracking. Furthermore, if successful, the effect can last for many years after a single procedure. Disadvantages include the need for surgery and the associated risks of anesthesia and intra-abdominal organ damage. Thereisariskofcausingtheformationofperi-ovarian adhesions which could reduce fertility. Rarely, prema-ture ovarian failure has been reported secondaryto the ovarian trauma. It is not clear how LOD has its effect. The ‘drilling’ disrupts the ovarian stroma and appears to reset the milieu allowing folliculogenesis to commence. Chapter 17: Treatment of male and female infertility Gonadotrophin therapy Gonadotrophins are administered by daily subcutane-ous injection and are either recombinant or urinary derived. Disadvantages of gonadotrophin treatment include the need for frequent ultrasound follicular tracking and the risk of multiple pregnancy, which occurs with rates of up to 20% or more. The multiple rate depends on the threshold maximum ‘safe’ follicle number set by the doctor for inducing ovulation. For instance, some clinics will cancel the treatment cycle if there are four or more mature follicles, which will clearly mean there is a triplet risk if all three dominant follicles ovulate. The use of ‘low-dose step-up’ gonadotrophin regimes for ovulation induction in PCOS patients results in multiple pregnancy rates of < 10% (i.e. sim-ilar to clomifene). The gonadotrophins are started at a lowdoseofbetween25to75iuandheldatthatdosefor 10 days before the first ultrasound monitoring scan. If a dominant follicle >10mm diameter has developed, then the same dose is continued for a few days. A further scan is arranged to confirm the presence of a preovulatory follicle, at which time an hCG trigger is given to induce ovulation followed by timed inter-course.Ifontheinitialday10scanthereisnofollicular response, then the gonadotrophin dose is increased by a small amount and the scan repeated every seven days and the dose increased until a follicular response is achieved and ovulation can be induced. Meta-analysis suggests that patient satisfaction and cumulative success rates are similar between LOD and gonadotrophintherapy.The‘one-stop’natureofLOD, the avoidance of ultrasound monitoring, daily injec-tionsandmultiplepregnancyriskareclearadvantages. However, many women prefer to avoid surgery and to move on to more immediate treatment using gonado-trophins rather than wait and see whether ovulation results after LOD. Assisted conception The third-line treatment for infertility due to PCOS is assisted conception, the standard method being IVF. In summary, IVF involves gonadotrophin ovarian stimulation followed by transvaginal oocyte retrieval, in vitro oocyte fertilization and culture, and trans-cervical embryo transfer. In long-protocol IVF, the hypothalamo-pituitary axis is suppressed by adminis-tration of a GnRH-agonist for a few weeks before commencing gonadotrophins. In short-antagonist protocol IVF, a GnRH-antagonist is commenced around day 5 to 7 of gonadotrophin stimulation with-out prior suppression. Live birth rates are similar between long- and short-antagonist protocol IVF for women with PCOS. However, the risk of developing ovarianhyperstimulationsyndrome(OHSS),themain health risk to women undergoing IVF, is significantly lower with the short-antagonist protocol. If long-protocol IVF is used, then co-treatment with metfor-min tablets will also significantly reduce the risk of developing OHSS. It is not known whether the use of metformin co-treatment during short-antagonist IVF is of additional benefit. Risk factors for developing OHSS during IVF include younger age (< 33 years), previous OHSS and the presence of ovaries of polycystic morphology. OHSS can be mild, moderate or severe. Mild or mod-erate OHSS may cause ‘only’ discomfort, nausea and diarrhea. However, severe OHSS is potentially, though rarely, fatal and requires hospital admission for intra-venous rehydration and thromboprophylaxis, along with close monitoring of fluid balance and blood haematology, clotting and biochemistry factors. The rate of severe OHSS is about 1% of all IVF cycles. Women with PCOS undergoing long-protocol IVF have a severe OHSS rate of 2–10%; this is reduced to 1–3% with the use of metformin co-treatment or by using a short-antagonist protocol. A number of other strategies are also available to reduce the risk of devel-oping OHSS and are reviewed elsewhere. The only way of absolutely avoiding the risk of developing OHSS is to not stimulate the ovaries. Oocyte in vitro maturation (IVM) involves the trans-vaginal aspiration of immature oocytesfrom unstimu-latedovaries,followed bytheirinvitromaturationand fertilization. Embryos are then cultured in vitro and transferred trans-cervically. IVM is fully reviewed in another chapter. IVM is most successful for younger womenwithovariesofpolycysticmorphology(i.e.two of the main risk factors for OHSS). While clearly there is zero risk of developing OHSS in a woman under-goingIVM,andthetreatmentisvery‘easy’andaccept-able from a patient perspective, the success rate is currently significantly less than IVF, which limits its desirability. WHO Group III Ovulation disorders (ovarian failure) Anovulation due to ovarian failure is detected by high levels of FSH, or low levels of AMH or a low AFC. The 163 Section 2: Infertility woman may have a family history of premature ovar-ian failure, a personal history of chemo-radiotherapy orremovalofovariantissue,forexamplewhileremov-ing endometriotic cysts, or have a genetic disorder such as Turner syndrome. There are no drugs that can be given to boost fertility in cases of ovarian failure. The treatment is oocyte donation or moving on from fertility treat-ments to other options such as adoption or accepting childlessness. Potential recipients of donor oocytes are offeredcounselling regardingthephysical andpsycho-logical implications of treatment for themselves and theirpotential children.IntheUK,childrenbornfrom gamete (oocyte and sperm) or embryo donation are abletotracethedonorfromtheageof18years.Oocyte donors are screened for both infectious and genetic diseasesand undergo afull stimulated IVF cycle. Their oocytes are collected and fertilized in vitro with the recipient’s partner’s sperm. The recipient’s endome-trium is prepared with exogenous oestrogen and pro-gesterone in coordination with the donor’s cycle and embryo transfer then takes place. The success rate is related to the age of the donor. Thismust be taken into account when deciding how many embryos to trans-fer. Pregnancy rates of around 50% per cycle are common. WHO Group IV (hyperprolactinaemia) Women with ovulatory disorders due to hyperprolac-tinaemia should be offered treatment with adopamine agonist such as bromocriptine under the care of an endocrinologist. hydrosalpinx is present. Even if tubal patency results, the patient must be warned that the blockage may recur and that, if she conceives, she is at significantly increased risk of developing atubal ectopic pregnancy. Early ultrasound in pregnancy is required to confirm an intrauterine position. If the disease is more severe or involves the whole tube, then surgery is unlikely to be of benefit. IVF was developed as a treatment for tubal disease and remains the most successful form of therapy. The presenceofanultrasound-visiblehydrosalpinxisasso-ciated with a halving of the IVF success rate due to leakage of the fluid into the uterine cavity. Removal of the affected tube(s) restores the IVF success rate to what it would have been if there were no hydrosalpinx (Figure17.1).Somewomenwithahydrosalpinx notea watery brown vaginal loss off and on throughout the menstrual cycle. Ultrasound can often demonstrate the fluid within the endometrial cavity. The hydro-salpinx fluid contains embryo-toxic substances. There is also the purely mechanical effect of the fluid flushing the embryo. Some women may, however, be resistant to the suggestion, particularly with bilateral hydrosalpinges, that their fallopian tubes are removed, leaving thempermanently sterile.If there areextensive adhesions in the pelvis, then removal of the tubes can be difficult, so sometimes a clip is applied laparoscopi-cally at the cornu, where the tube enters the uterus, to prevent fluid leakage into the endometrial cavity. A newer hysteroscopic technique involves insertion, via the uterine cavity, of an implant through the tubal ostia into the proximal part of the tube (‘Essure’). The product was developed as a form of contraception and is unlicensed for this indication. 164 Tubal and uterine disease Tubal damage Hysterosalpingogram, HyCoSy or laparoscopy may demonstrate the presence of tubal disease. If one fal-lopian tube is patent then the cumulative chance of conception is satisfactory and no particular treatment is required. If both tubes are blocked then treatment options depend on the position of the block (proximal vs. distal) and severity of the disease. Mild distal (at the fimbrial end) tubal disease can be treated by laparoscopic fimbrioplasty in which the blocked (‘clubbed’) tubal ends are surgically opened and ‘flowered-back’. There is little role for this if the rest of the tube is damaged, particularly if a Figure 17.1 Laparoscopic view of bilateral hydrosalpinges. Chapter 17: Treatment of male and female infertility Treatments such as ovulation induction or IUI are inappropriate for women with tubal disease. Intrauterine adhesions An uncommon cause of amenorrhea is extensive intrauterine adhesions (‘Asherman’s syndrome’) usu-ally due to endometrial curettage for a miscarriage or retainedplacentaltissueafterdelivery.Thebasalendo-metrial layer is damaged to the extent that prolifera-tionandendometrialthickeningdoesnotoccurandso neither does menstruation, despite there being ovula-tory cycles. Sometimes less extensive intrauterine adhesions are found in women who are menstruating but who have fertility or recurrent miscarriage prob-lems. The presence of intrauterine adhesions can be suspected on ultrasound scan but is confirmed on HSG or hysteroscopy. Hysteroscopic resection of the adhesions is undertaken and an intrauterine coil left in place for a month to try to reduce adhesion reforma-tion. Often, since the basal endometrial layer is dam-aged, the result is relatively poor. Under these circumstances surrogacy may be required. Fibroids (leiomyomas) Fibroids which are distorting the endometrial cavity may be removed, a procedure called myomectomy. The method of removal depends on the site and size of the fibroid(s). Fibroids within the endometrial cav-ity are removed using a hysteroscope inserted through the cervix under general anaesthesia (Transcervical Resection of Fibroid, TCRF). The cavity is irrigated with glycine and electrical current passed through a semi-circular loop which is used to cut away the fi-broid in strips for removal through the cervix. The same method is used for sub-mucosal fibroids of up to 3cm diameter. Risks of TCRF include perforation of the uterine wall and intrauterine adhesion formation. Larger fibroids distorting the endometrial cavity are removed abdominally, preferably by laparoscopy rather than open surgery. Risks of myomectomy, by any route, also include bleeding requiring blood trans-fusion or further surgery, and rarely, to save a life, hysterectomy. While it is generally accepted that myomectomy is appropriate for fibroids distorting the endometrial cavity, the situation for intramural fibroids that are not distorting the cavity is not so clear. It is accepted that such fibroids do reduce the implantation rate; however, whether removal of the fibroids improves the rate is not known since sufficiently powered RCTs have not been undertaken. Certainly if the woman has symptoms attributable to her fibroids, such as heavy menstrual bleeding or bladder-bowel pressure symptoms, then surgery is probably indicated. Endometriosis Laparoscopic removal of minimal to mild endome-triosis is associated with a statistically significant increase in the rate of natural conception and so should be offered. The endometriosis is removed by cutting away using scissors or laser, or is ablated using electric diathermy. Laparoscopic removal of endometriotic ovarian cysts (cystectomy) is associated with an increase in the subsequent rate of natural conception. There are two methods of treating cysts. The first step is to open and drain away the ‘chocolate’ cyst fluid within the cyst. The wall can then either be stripped away or an attempt made to ablate it. Stripping has the advantage of allowing the tissue to be sent for histopathological analysis. Occasionally cysts thought to be endometri-otic are found to be malignant or borderline in char-acter. Strippingof the cyst wallis also associated witha higher natural cumulative conception rate and a lower chance of cyst recurrence. However, cystectomy can cause further damage to the ovary, which may reduce the response to ovarian stimulation during IVF. It is unclear whether endometriomas should be removed prior to IVF. No sufficiently powered RCTs have been undertaken. Cystectomy does not improve the ovarian response to stimulation (and, if the ovary is further damaged, may have the opposite effect) (Figs 17.2 and 17.3). It may improve ovarian accessi-bility for transvaginal oocyte recovery. Certainly dur-ingoocyterecoveryitisimportanttoavoid passing the needle into anendometrioma, as this can lead to pelvic infection and possible ovarian abscess formation. Surgery may be required to treat a pelvic abscess and the ovary may be permanently damaged. If an endo-metrioma is entered during oocyte recovery, intrave-nous antibiotics are given. Women with moderate to severe endometriosis may benefit from surgical removal of disease and adhesions to improve their fertility and/or pain symptoms, though no randomized studies have been undertaken to test this hypothesis. However, very often the most appropriate treatment is IVF. Prolonged GnRH-analogue down-regulation for two 165 ... - tailieumienphi.vn