9. Gonadotropin treatment can be used for ovulation induction in women with infertility due to a severe ovulatory disorder, or as empiric treatment in those who have no alternative but IVF. Gonadotropin treatment should only be used where there are ultrasound facilities to identify the number of maturing follicles in order to improve effectiveness and avoid excessive ovarian stimulation.
(a) Gonadotropin ovulation induction:
Amenorrhea or oligomenorrhea usually reflect anovulation or oligoovulation, respectively. Elevated FSH values imply ovarian failure or World Health Organization (WHO) Type III Ovulatory Disorder which cannot be treated with gonadotropins. If the FSH values are low to normal, however, gonadotropin treatment may be indicated. Anovulation may be due to hypothalamic amenorrhea, (WHO Type I), in which case FSH levels are low to low-normal, but the most common underlying disorder is polycystic ovarian syndrome (PCOS), which is included in the WHO Type II group and is usually treated initially with clomiphene citrate. (ASRM, 2008)
The indications to use gonadotropins for ovulation induction in the WHO Type II group with oligo-anovulation are (1) when clomiphene citrate treatment has failed to stimulate ovulation after 3 cycles and (2) when ovulation occurs with clomiphene citrate treatment, but there is no pregnancy after 3 to 6 cycles.
In clinical protocols in women without menses, gonadotropin treatment is usually started after a progestin-induced menses, at a fairly low dosage of 37.5 to 75 International Units (IU) of FSH per day, using the least costly approved preparation available. When ultrasound monitoring shows one or two mature follicles at around 16-18 mm diameter, release of the oocyte can be induced with human chorionic gonadotropin (hCG), recombinant luteinizing hormone (LH) or gonadotropin-releasing hormone (GnRH) agonist. With more than two mature follicles, the risk of multiple pregnancy is excessive. Ovulation will usually occur 24 to 48 hours after the hCG injection, and timely intercourse should be advised (ASRM,2008b; ASRM, 2008c).
There are no trials of the effectiveness of gonadotropin treatment for ovulation induction because, with untreated pregnancy rates around 2% (Brown, 2009), treatment-associated pregnancy rates above 10% with treatment are unlikely to be due to bias. In 13 studies involving 1269 cycles and 881 anovulatory infertile women who received gonadotropin treatment, the pregnancy rate was 15% per cycle and 41% per patient (Mulders, 2003). Pregnancy rates are higher in women with hypothalamic amenorrhea (25% per cycle) than in those with PCOS (8% per cycle) (Fluker, 1994).
Multiple pregnancy and ovarian hyperstimulation syndrome (OHSS) are the most frequent adverse events after ovulation induction treatment. Prevention of multiple births depends on cancelling the cycle if there are more than two mature follicles; OHSS frequency and severity can be minimized by using lower dosages of hCG or replacing hCG with recombinant LH or GnRH agonist (ASRM, 2008i; ASRM, 2012b). Multiple pregnancy can be especially risky in low resource environments where access to maternal and prenatal care if often severely limited.
- In women with infertility due to oligo-anovulation where treatment with clomiphene citrate or metformin is unsuccessful, fair evidence shows that gonadotropin treatment is effective.
- Fair evidence shows that the pregnancy rate is higher with hypothalamic amenorrhea than it is with polycystic ovarian syndrome.
- Protocols should attempt to minimize risk of multiple pregnancy and ovarian hyperstimulation syndrome.
- (b)Gonadotropin ovarian stimulation with IUI: ovarian stimulation with IUI can be used for oligo-anovulation after clomiphene treatment failure and as an empiric treatment (FSH/IUI) where IVF is not available.
When IVF is not accessible, gonadotropin ovarian stimulation followed by IUI is used as empiric therapy. This application is usually in couples with unexplained infertility after they have tried milder treatments without success or with other diagnoses after standard treatment has been tried without success. Since the aim is to increase the number of mature follicles, the added likelihood of pregnancy comes with an added risk of multiple pregnancy.
Two trials provide seemingly contradictory evidence about the effectiveness of gonadotropin ovarian stimulation with IUI. The treatment was effective in couples with prolonged infertility (Guzick, 1999) but not in couples who have a good prognosis and a duration of infertility which is less than three years (Steures, 2006). While there were differences in the control treatment and the gonadotropin dosages, the difference in duration of infertility is sufficient to explain the apparent contradiction (Table 2).
Two RCTs on gonadotropin and IUI treatment
|Authors||Guzick et al., 1999||Steures et al., 2006|
|Number of couples||231||127|
|Duration of infertility (yrs)||3.5||2.0|
|Pregnancy rate (%)|
The Guzick trial (1999), involved 4 cycles of gonadotropin IUI in the treatment group and four cycles of intracervical insemination (ICI) in the control group. The Steures trial (2006) involved 6 cycles of gonadotropin IUI or six months of expectant treatment. The objective of gonadotropin treatment was different in the trials: in the Guzick trial (1999), 150 IU of follicle-stimulating hormone daily until at least two follicles reached 18 mm; in the Steures trial (2006), 75 IU daily until at least one follicle reached 16 mm.
The gonadotropin regimen in the Steures trial (2006) achieved a 23% pregnancy rate per couple, compared with 33% with the more aggressive regimen used in the Guzick trial (1999). The aggressive gonadotropin regimen, however, yielded three sets of quadruplets, four sets of triplets and 18 twin births in the 80 pregnancies during gonadotropin/ICI or IUI cycles, a 32% multiple birth rate. There were only four multiple births (two triplet and two twin births) in the Steures trial (2006). The calculated singleton pregnancy rates for the trials are 23% and 20% for aggressive and non-aggressive gonadotropin regimens, respectively.
The main difference between the trials, however, is the pregnancy rate in the control groups: 10% in the Guzick trial (1999) versus 27% in the Steures trial (2006). This is associated with longer duration of infertility (3.5 versus 2.0 years) in the former trial. In a hypothetical scenario, the pregnancy rate with the Guzick regimen would not be significantly better than that in the Steures controls and the pregnancy rate with the Steures regimen would be significantly better than that in the Guzick controls.
In practice, it is critical to consider the clinical setting: the patients, the protocol and the monitoring facilities. With respect to the clinical setting, given that the risks of multiple pregnancy carry even more serious consequences in limited resource settings, non-aggressive regimens are essential. With respect to the patients, unless the duration of infertility is more than three years, expectant management is as effective as gonadotropin/IUI treatment. With respect to the facilities, careful monitoring with ultrasound is needed to minimize multiple birth. It is important to inform patients, however, that the pregnancy rates per cycle of moderate gonadotropin/IUI treatment are in the same range as those from CC/IUI treatment.
The optimal treatment often depends on the socioeconomic situation, clinical care setting, expertise of the providers and characteristics of the patients. One management trial (FASST) involved 503 couples of women and men with unexplained infertility that were randomly allocated to three cycles of CC/IUI and then up to six cycles of IVF or to three cycles of CC/IUI, then three cycles of gonadotropin/IUI before the IVF cycles. The group who did not have gonadotropin/IUI achieved more pregnancies sooner at lower cost than the group that was randomized to all three steps (Reindollar, 2010). Thus, where IVF is available, gonadotropin/IUI treatment has no added value.
In a further trial in patients with unexplained or mild male infertility, IVF with elective single embryo transfer was compared with IVF in a modified natural cycle and intrauterine insemination with controlled ovarian hyperstimulation. The healthy singleton live birth rates within 12 months were similar (43% to 52%) and multiple pregnancy rates were low with all three treatments (Bensdorp, 2015).
- Good evidence shows that gonadotropin-intrauterine insemination is not an effective empiric treatment if the duration of infertility is less than three years.
- Good evidence shows that, while gonadotropin-intrauterine insemination is an effective empiric treatment in patients with three or more years duration of infertility, the benefit is small.
- Gonadotropin-intrauterine insemination treatment can be associated with an unacceptable likelihood of multiple pregnancy. Protocols, which minimize this risk should be used.
- Good evidence shows that where in vitro fertilization treatment is available, there is no added value from having gonadotropin-intrauterine insemination treatment first.
- The best treatment approach depends on many clinical and nonclinical factors.
3. Infertility surgery: tubal surgery and/or surgery for fibroids, adhesions and endometriosis is sometimes indicated in highly selected patients. Laparoscopic ovarian drilling may be used for polycystic ovarian syndrome (PCOS). Hysteroscopic surgery may be indicated for polyps, myomas, intrauterine adhesions, cornual obstruction and uterine abnormalities, such as septum. It is important to treat co-existing endocrine conditions and other female and male infertility problems.
The value of infertility surgery depends on good diagnostic facilities for tubal disease, adhesions, endometriosis, fibroids and other anatomical abnormalities, on modern surgical facilities and on the availability of personnel trained in their use. (ASRM, 2014; ASRM, 2008f; ASRM, 2012a; ASRM and SRS, 2012a; ASRM and SRS, 2012b)
Surgery may be indicated for tubal obstruction, pelvic adhesions or severe endometriosis when the pathology clearly prevents access of spermatozoa to the oocyte or creates a barrier to the transport of the embryo. There are no randomized controlled trials, but RCTs are not necessary when the likelihood of pregnancy without treatment is near zero, as it is in the most severe stages of tubal disease and endometriosis. Surgery, however, does not restore normal pregnancy rates. Management of endometriosis is often complex because it can be associated with pain and ovarian cysts (endometriomas) as well as infertility. (Johnson, 2013) (Dunselman, 2014)
The basic requirements for a good infertility surgery service are adequate instrumentation and sterilizing procedures, experienced surgeons, good anaesthesia, continuous monitoring capabilities and good postoperative care.
With tubal obstruction, if IVF is available, it is a matter of judgment and severity of tubal disease whether to recommend surgical repair of the fallopian tubes (with the potential for future fertility) or IVF with the potential need for repeated costly cycles. While the cost of tubal surgery is similar to that of one or two IVF cycles, if tubal surgery is effective, it may be possible to have more than one pregnancy.
During the assessment for infertility, co-existing endocrine or other medical conditions may become apparent, which should be treated if possible. These include diminished ovarian reserve, obesity, anorexia, diabetes and thyroid disease. A history should also be taken for exposure to endocrine disruptors in the patient’s environment, even though commonly not much can be done to change the woman’s or man’s exposure.