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OVULATION INDUCTION & INTRAUTERINE INSEMINATION By S. Nasseri ANOVULATORY DISORDERS The clinical approach to ovulation induction requires an understanding of the causes of anovulation. The World Health Organization (WHO) classified different categories of anovulation into three categories: ●WHO class1: Hypogonadotropic hypogonadal anovulation (hypothalamic amenorrhea [HA]) ●WHO class2: Normogonadotropic normoestrogenic anovulation (almost all women in this category have polycystic ovary syndrome [PCOS]), when using the Rotterdam criteria for the diagnosis of PCOS ●WHO class3: Hypergonadotropic hypoestrogenic anovulation (primary ovarian insufficiency [POI; premature ovarian failure]) However, most experts have moved away from this terminology and assign women to one of the four most common ovulatory disorders: hypogonadotropic hypogonadism (HA), PCOS, POI, or hyperprolactinemia. The use of serum anti-müllerian hormone (AMH) concentrations may help to further define various patient categories Anti-Mullerian Hormone • AMH is expressed by the small (<8 mm) preantral and small antral follicles. • Serum concentrations (ELISA) reflect the number of the primordial follicles & the size of P.F pool • It is the best biochemical marker of ovarian function. • Low levels correlate with reduced ovarian reserve and less than three follicles. • High levels correlate with a vigorous response to ovarian stimulation and a higher risk of OHSS. • AMH is also a predictor of ovulation induction success (N0 of retrieved oocytes ) & therefore individualizing treatment protocols. • AMH is also a predictor of IVF success. GOALS OF OVULATION INDUCTION The overarching goals of ovulation induction in women with anovulatory infertility are: ●Induce monofollicular rather than multifollicular development and subsequent ovulation and ultimately pregnancy and birth of a healthy newborn . ●Start with the least invasive and simplest treatment option subsequent options should depend upon ovarian response (ovulation and number of follicles) . ●Maximize the rate of singleton pregnancies, minimize multiple gestation rates. ●Minimize the risk of ovarian hyperstimulation syndrome (OHSS) in women undergoing gonadotropin therapy, particularly those with polycystic ovary syndrome (PCOS), who are at higher risk. GENERAL PRINCIPLES ●The method of ovulation induction selected by the clinician should be based upon the underlying cause of anovulation and the efficacy, costs, risks, and potential complications associated with each method as they apply to the individual woman. ●Women with ovulatory disorders should undergo conventional ovulation induction strategies before considering assisted reproductive techniques, because success rates are good, and if monitored by an experienced clinician, complication rates are low ●Induction of ovulation should be differentiated from stimulation of multiple follicle development in ovulatory women (usually referred to as controlled ovarian hyperstimulation), as is done with assisted conception techniques. ●PCOS represents a risk factor for developing OHSS following ovarian stimulation with gonadotropins in any setting. HYPOTHALAMIC AMENORRHEA • Patients are hypoestrogenemic and are therefore unlikely to respond to CC, an antiestrogen. However, because CC is easy to administer, it may seem reasonable to give one course of clomiphene prior to initiating pulsatile gonadotropin-releasing hormone (GnRH) or gonadotropin therapy. • For those who ovulate, CC can then be continued. • For those who do not ovulate, we suggest pulsatile GnRH as first-line therapy in countries where it is available. If pulsatile GnRH is unavailable, gonadotropin therapy should be initiated, with both luteinizing hormone (LH) and folliclestimulating hormone (FSH) (these women do not respond to FSH alone). PCOS • The approach to women with PCOS starts with weight loss, if indicated, followed by ovulation induction with either CC or letrozole depending upon the patient’s body mass index (BMI). • Gonadotropins • Metformin • Ovarian Diathermy PRIMARY OVARIAN FAILURE • All ovulation induction strategies for women with primary ovarian insufficiency (POI) are unsuccessful and we suggest against their use. • Women with POI should be offered the option of in vitro fertilization with donor oocytes. HYPERPROLACTINEMIA • The treatment of choice for anovulatory women with hyperprolactinemia is dopamine agonists. ORAL AGENTS • • • • Clomiphene citrate Aromatase Inhibitors Metformin Dopamine agonists CLOMIPHENE CITRATE • Clomiphene, like tamoxifen and raloxifene, belongs to the category of compounds known as selective estrogen receptor modulators (SERMs). These drugs are competitive inhibitors of estrogen binding to estrogen receptors and have mixed agonist and antagonist activity, depending upon the target tissue. • CC has been the most widely used agent for ovulation induction for over 40 years. • It is most effective in women with polycystic ovary syndrome (PCOS). While they could be used for ovulation induction, tamoxifen and raloxifene appear to be less effective than clomiphene so are not typically used for this purpose. SITES OF ACTION • Primary site of action: hypothalamus • Pituitary (direct effect): gonadotropin release • Ovaries (direct effect): in the absence of estrogen estrogen agonist FSH stimulation on LH receptors in granulosa cells • Uterus-Cervix-Vagina antiestrogenic effect Clinical Outcome of Normogonadotrophic Anovulatory Women Treated with Clomiphene Dose of clomiphene (mg) Ovulation rate (%) Pregnancy rate (%) 50 100 150 200 250 52.1 21.9 12.3 6.9 4.9 52.8 20.7 9.8 8.8 6.2 • 60 to 85 percent of anovulatory women, typically with PCOS, ovulate in response to CC. • Of those who ovulate, 30 to 40 percent conceive. • Predictors of pregnancy with CC are: younger age low BMI low FAI Oligomenorrhea rather than amenorrhea COMPLICATIONS • • • • • • • • • • • • • Vasomotor flushes (10%) Abdominal distension, bloating, pain or soreness (5.5%) Breast discomfort (2%) Nausea & vomiting (2.2%) Visual symptoms (1.5%) blurring vision, scotoma, abnormal perception Headache (1.3%) Dryness or loss of hair (0.3%) Significant ovarian enlargement (5%) ( mild OHSS) Severe OHSS is rare ( < 1% ) Abortion rates & teratogenicity Incidence of multiple follicular recruitments = 35- 60% Multiple gestation ( twin = 5-10% Triplet = 0. 3% ) Ectopic pregnancy probably not increased TREATMENT OF CLOMIPHENE RESISTANT PATIENTS • A-Medical Treatment: • • • • • • 123456- Extended clomiphene treatment Dexamethasone Pretreatment suppression (GnRH agonist- OCP) Bromocriptine Gonadotropins Insulin sensitizers • B- Surgical Treatment METFORMIN • Biguanide → NIDDM • Mechanism of action: 1- inhibition of gluconeogenesis in liver 2- ↑ uptake of glucose in periphery • Treatment for 12 weeks: → ↓ fasting insulin, total testosterone, free testosterone index, BMI, waist/hip, hirsutism, acne • Response: 1- Obese PCOS→ 89% ovulation rate (CC + Met) versus 12% (CC + pla) 2- Lean PCOS→↓ hyperandrogenemia Typical regimen using metformin with or without clomiphene in PCOS patients • Start metformin : - Metformin, 500 mg/day with breakfast for 4 days - Metformin, 500 mg /BD with breakfast and dinner for 4 days - Metformin, 500 mg with breakfast and 1000 mg with dinner for 4 days - Metformin, 1000 mg /BD at breakfast and dinner • • If a trial of metformin alone is chosen→ single serum progesterone weekly (it may take up to 2 months before spontaneous ovulation) If no spontaneous ovulation when the full dose of metformin has been reached : - Met + CC (50mg/day) → LH kits & time intercourse - ↑ CC dosage until ovulation occurs • • Continue ovulatory dosage of CC+ Metformin up to 3-6 cycles → LH kits & time intercourse If no response→ Review the diagnosis→ Gonadotropins or Ovarian diathermy Laparoscopic Ovarian Drilling • • • • Unipolar or bipolar cautery (Ovarian diathermy) Laser ↓ LH, testosterone, DHEAS, LH/FSH Further 73% spontaneous ovulation, 24% ovulation with CC, 1.8% ovulation only with Gonadotropins • Median time to conception = 10.2 months • Cumulative pregnancy rate: - After 12 months about 50% - After 24 months about 80% LETROZOLE • It is an aromatase inhibitor. • It blocks the conversion of testosterone and androstenedione to estradiol and estrone, respectively. • Letrozole reduce negative estrogenic feedback at the pituitary and increase FSH output . • In contrast to CC, letrozole appears to be free of the adverse effects on endometrial and cervical mucus . • A large randomized trial and a meta-analysis of nine trials in anovulatory women with PCOS now suggest that letrozole therapy results in higher live-birth and ovulation rates when compared with clomiphene therapy. The effect appears to be most pronounced in obese women with PCOS (BMI >30 kg/m2). • Therefore, some experts now suggest letrozole as a first-line drug for obese women with PCOS. In general , from the available data there is no convincing evidence that letrozole is superior to clomiphene and therefore the cost should be taken into account when using anti-estrogens DOPAMINE AGONISTS • Bromocriptine, the first dopamine agonist drug to prove effective in the treatment of hyperprolactinemia, remains in widespread use. • Drugs that bind more specifically to dopamine D2 receptors on the lactotroph cells, such as cabergoline, are associated with fewer side effects. • The safety of bromocriptine with regard to teratogenesis is much better established than that of cabergoline, so many clinicians and patients prefer bromocriptine to attempt pregnancy, but patients who have severe side effects from bromocriptine prefer cabergoline. • We suggest either bromocriptine or cabergoline for ovulation induction, depending upon the patient’s preferences. • Treatment should be stopped once pregnancy has been diagnosed. GONADOTROPINS • • G.T were first introduced into clinical practice in 1961 Gonadotropins extracted from the urine of postmenopausal women (human menopausal gonadotropins [hMG]), in which the ratio of luteinizing hormone (LH) to follicle-stimulating hormone (FSH) bioactivity is 1:1. • Refinement of the initially crude preparation resulted in the availability of purified and highly purified urinary FSH (uFSH). • Since 1996, recombinant human FSH (rhFSH, >99 percent purity) has been available. • Recombinant preparations are appealing due to their ease of administration (SC rather than IM), purity, and batch-to-batch consistency. DIFFERENT TYPES OF GONADOTROPIN PREPARATIONS GONADOTROPINS • • • • • • • HMG( Pergonal) (1961) Purified Urinary FSH (Metrodin) Recombinant FSH (Gonal F- Puregon )(1996) Recombinant LH (Luveris –Lutropin alfa) rFSH + rLH ((2:1) (Pergoveris) HCG Recombinant HCG (Ovitrelle) COMPARISION OF DIFFERENT G.T PREPARATIONS • hMG and FSH — The degree to which the type of FSH compound employed may influence outcome of ovulation induction remains the subject of controversy. • HMG & uFSH: Two meta-analyses comparing the effectiveness of daily uFSH to daily hMG for inducing ovulation in PCOS women demonstrated no difference in pregnancy rate per treatment cycle . However, the women given FSH were less likely to have OHSS. • rFSH &uFSH: In a meta-analysis of randomized controlled trials comparing rhFSH with uFSH for ovulation induction in PCOS, no significant differences were demonstrated for the ovulation rate . Furthermore, the ORs for pregnancy rate , miscarriage rate , multiple pregnancy rate , and OHSS showed no significant difference between rhFSH and uFSH. CANDIDATES Of GONADOTROPINS ●Women with polycystic ovary syndrome (PCOS) who have not ovulated or conceived with weight loss, clomiphene, or letrozole therapy . ●Hypogonadotropic anovulatory women with hypopituitarism or women with hypothalamic amenorrhea (HA) who do not have access to pulsatile gonadotropin-releasing hormone (GnRH) therapy. WHICH GONADOTROPIN ? • In PCOS patients FSH is better because of elevated LH • no differences in PR using rFSH or uFSH • In Hypothalamic Amenorrhea: HMG rFSH +rLH PROTOCOLS • The aim of ovulation induction with gonadotropins, as with CC, is the formation of a single dominant follicle. • In spontaneous cycles, this is achieved at the beginning of the cycle by a transient increase in serum FSH concentrations above the threshold value . The concentrations then decrease due to negative feedback, preventing more than one follicle from undergoing preovulatory development . • Because ovarian sensitivity to FSH stimulation varies among individual women, specific treatment and monitoring protocols are needed to achieve development of a single follicle when exogenous gonadotropin is administered. • Low-dose step-up protocol which is the preferred method since 1990 in PCOS patients. • Step-down protocol (OHSS) • Sequential Protocol which combines an initial step-up followed by a step-down regimen after leading follicle >or= 14 mm (OHSS) Chronic low dose Step up protocol Cycle day3 75IUFSH/day 7days Foll<10mm Maintain dose Foll>10mm 7days Maintaindose Until foll>18mm Foll<10mm Increase by37.5 IU/d Foll>10mm 7days Foll<10mm Increase dose 37.5IU/w Max=225iu/d Foll<10mm Cancel cycle Increasing starting dose By37.5IU/d Foll>10mm Foll>10mm hCG injection Step down protocol Cycle day 3 150-250IU FSH/d/5d Ultrasonography (every2-3 days) foll>9mm Foll<9mm Decrease 37.5 IU/day Every 3 days Increase 37.5IU/d Maintain 10days Maintain 75IU/day Until hCG injection foll>9mm Foll<9mm Cancel cycle DOSES OF GONADOTROPINS • In the conventional gonadotropin protocol, the starting dose of FSH is 150 u/day. However, this regimen is associated with a multiple PR of up to 36 percent and OHSS occurs in up to 14 percent of treatment cycles . • In patients with PCOS, who are at particular risk for complications, this approach has been abandoned in favor of a low-dose, step-up protocol designed to allow the FSH threshold to be reached gradually, minimizing excessive stimulation and development of multiple follicles. LOW – DOSE STEP- UP • In this protocol, the initial subcutaneous or intramuscular dose of FSH is 37.5 to 75 u/day. • It is recommended that the dose be increased only if, after 14 days, no response is documented on ultrasonography and serum estradiol monitoring. • Increments of 37.5 u then are given at weekly intervals up to a maximum of 225 u/day . • The detection of an ovarian response is an indication to continue the current dose until hCG can be given to trigger ovulation. LOW-DOSE STEP-DOWN • This protocol mimics more closely the physiology of normal cycles . • Therapy with 150 unit FSH/day is started and continued until a dominant follicle (>10 mm) is seen on TVS. • The dose is then decreased to 112.5 int. units/day followed by a further decrease to 75 i.U/day three days later, which is continued until hCG is administered to induce ovulation. • The appropriate starting dose can be determined by using the low-dose step-up regimen for the first treatment cycle . MONITORING • • • • • The ovarian response to gonadotropin therapy is monitored using transvaginal ultrasonography to measure follicular diameter. The scans during the late follicular phase, usually performed every two or three days, should be focused on identifying follicles of intermediate size. hCG is given as an ovulatory trigger on the day that at least one follicle appears to be mature. The criteria for follicle maturity are a follicle diameter of 18 mm and/or a serum estradiol concentration of 200 pg/mL (734 pmol/L) per dominant follicle. Ovulatory triggers : hCG ; rhCG; GnRH ago If three or more follicles larger than 15 mm are present, stimulation should be stopped, hCG withheld, and use of a barrier contraceptive advised in order to prevent multiple pregnancies and OHSS. RESULTS WITH GONADOTROPIN TREATMENT • • • • • CPR after 6 treatment cycles→ 90% Pregnancy rate in obese PCO (40%) is less than lean PCO Spontaneous abortion rate → about 25% Spontaneous abortion is more frequent in obese PCO ↑Risk of EP because of multiple oocytes & high hormone level • Multiple pregnancy rate → 30% (triplet or more 5%) • Ovarian Hyperstimulation Syndrome (severe ,1-2%) • Normal incidence of congenital malformations PREGNANCY RATES IN DIFFERENT PROTOCOLS • • • • • A series of 225 women with PCOS treated over a 10-year period in one center found rates of ovulation and pregnancy of 72 percent and 45 percent, respectively, after use of the lowdose step-up protocol . Multiple folliculogenesis and ovarian hyperstimulation are less common than that seen with the standard protocol, and pregnancy rates appear similar. However, the results of the low-dose step-up protocol are negatively influenced by age and obesity. In single-center studies, the step-down protocol appeared to be accompanied by a lower incidence of ovarian hyperstimulation and a higher incidence of monofollicular growth, thereby reducing the risk of multiple pregnancy. In contrast, a multicenter study reported that the step-up protocol was more efficient in inducing monofollicular development and was associated with less ovarian hyperstimulation Experience to-date has indicated that the major drawback of the step-down regimen is that the initial starting dose is too high for some patients. In an effort to overcome this problem, sequential low-dose step-up and step-down regimens have been proposed . This approach requires further evaluation Gonadotropin therapy after CC treatment has failed has been the "classical" approach to ovulation induction for anovulatory infertility. Using this sequential approach, cumulative singleton live birth rates of 71 percent (only 7 percent multiples) over 24 months have been reported These results suggest that conventional approaches offer an effective means of treating the majority of women with anovulatory infertility before proceeding to more aggressive treatments such as IVF. OHSS • OHSS is a potentially life-threatening complication of ovulation induction. • Its most severe manifestations include massive ovarian enlargement and multiple cysts, hemoconcentration, and third-space accumulation of fluid • these changes may be complicated by renal failure, hypovolemic shock, thromboembolic episodes, acute respiratory distress syndrome, and death. ADJUVANT TREATMENT • GnRH agonists (Buserelin –first used in 1984)or antagonists( Cetrorelix – early 2000s) are commonly used for women with ovulatory infertility undergoing “controlled ovarian hyperstimulation” with gonadotropins in the setting of IVF. • The goal is to suppress pituitary gonadotropins to optimize control of the cycle and prevent a surge of endogenous LH prior to full maturation of the cohort of ovarian follicles. SUMMARY AND RECOMMENDATIONS The method of ovulation induction selected by the clinician should be based upon these factors: • 1-underlying cause of anovulation • 2-efficacy • 3- costs • 4- risks & potential complications INTRAUTERINE INSEMINATION • Intrauterine insemination (IUI) is a procedure in which processed and concentrated motile sperm are placed directly into the uterine cavity. Goal is to Maximize the Chance of Fertilization • Increase Number of Eggs • Position Sperm Closer to Eggs INDICATIONS • The impossibility of vaginal ejaculation: - Impotence - Severe hypospadias, - Retrograde ejaculation - Cryopreservation of sperm (cancer treatment) • Abnormal male factor - oligospermia - asthenospermia - teratospermia • Unexplained infertility • Cervical factor infertility • • (mucus, anatomy, immunologic factors) Mild to moderate endomertiosis Chronic anovulatory cycles Which ovarian stimulation to chose before intra-uterine insemination? Drug Cost; Drug availability and Patient acceptability CC is an effective alternative for young women with good prognosis, whereas in the remaining cases hMG or FSH would be the preferable drug. rFSH Vs Urinary preparations : No difference in clinical pregnancy rate. There is no advantage in routinely using GnRh-ago in conjunction with gonadotrophins for ovulation stimulation At the moment one should use the least expensive medication. IUI • • • • • • • • The minimum requirements : patency of at least one fallopian tube adequate number of motile sperm absence of active cervical, intrauterine & pelvic infection. The pregnancy rate after IUI : Male factors Female factors Technical factors MALE FACTOR • The minimum post-wash total motile sperm count for IUI is controversial . • Although pregnancies from IUI have occurred with a post-wash total motile sperm count less than 5 million, a count greater than 5 to 10 million is associated with higher pregnancy rates . A count less than this warrants further evaluation and possible treatment by a urologist. • If samples consistently have less than 3 to 5 million motile sperm, PR will be < 1 % per cycle. ( IVF or ICSI ) SPERM COLLECTION AND PROCESSING • We ask men to produce a semen specimen in the morning after two or three days of sexual abstinence . • The specimen is produced by masturbation, ideally in a private room designated for this purpose in the laboratory/office. • The entire ejaculate is collected in a sterile cup to minimize the risk of uterine infection from contaminants. • We advise avoidance of lubricants, as most are toxic to sperm SPERM PROCESSING • • • • • • Goals 1- separate sperm in the ejaculate from prostaglandin-rich prostatic secretions and seminal fluid, which can cause uterine cramping and, rarely, anaphylaxis, when placed directly into the uterine cavity. 2- sperm preparation maximizes the number of motile sperm for insemination, removes cellular debris, and concentrates the specimen. TECHNIQUES Swim up method and Density Gradient Centrifugation. A systematic review of randomized trials comparing these two techniques did not find a statistically significant difference in pregnancy rates . However, the percentage of motile sperm is generally higher with density gradient centrifugation than with the swim up technique . Therefore, we prefer this method in men with oligo- or asthenospermia. TIMING THE INSEMINATION • The luteinizing hormone (LH) surge can be detected in serum 36 hours before ovulation and in urine 24 hours before ovulation. • The oocyte can be fertilized up to 24 hours after ovulation; • Sperms are most capable of fertilization up to 48 hours after entering the female genital tract. • Timing the intrauterine insemination (IUI) is based on these relationships. However, the optimum time for IUI is controversial . NUMBERS Of IUI IN ONE CYCLE • Whether to perform one or two IUIs is also controversial. • In the two most recent RCTS, and a 2010 meta-analysis , the PR per cycle was similar whether one IUI to two IUIs were performed. • For this reason, a single IUI the day after a urinary LH surge is recommended. TYPES Of IUI • Unstimulated Cycles (Natural ): Natural cycle IUI are most appropriate for patients with ejaculatory dysfunction, vaginismus, or cervical factor infertility. Once the LH surge is documented in first morning urine, IUI is performed the next day • Stimulated Cycles STIMULATED CYCLES • Clomiphene citrate : For most patients, is the first-line approach (50 to 150 mg for 5 days), depending on ovulatory status. • letrozole : yields equivalent pregnancy rates as CC in combination with IUI . • Gonadotropins: • older women • younger women with diminished ovarian reserve (or IVF ) GnRH Agonists & Antagonists • It may improve pregnancy rates by reducing the incidence of premature luteinization in women with some types of ovulatory dysfunction . • Alternatively, a GnRH antagonist can be added to the controlled ovarian stimulation cycle when the lead follicle is 14 mm in size. • This delays luteinization, thus allowing development of additional follicles, which is particularly useful if only one follicle has developed. • Use of GnRH antagonists may also be beneficial in preventing luteinization when IUI is delayed over a weekend or holiday in practices with staffing restrictions IUI PROCEDURE Equipment • Prepared sperm specimen • Speculum • 1 cc sterile syringe with blunt cannula • Disposable polyethylene insemination catheter Patient preparation — Proper identification of both the patient and sperm sample in the laboratory and the clinic is essential. Antibiotic prophylaxis is unnecessary. Povidone iodine should not be used to cleanse the cervix because it is toxic to sperm. Technique • Aspirate the processed sperm and its suspension media into the syringe. Ideally, the sperm is suspended in a small volume of media, no more than 0.5 mL, to prevent expulsion or reflux from the cervix and uterine contractions after it is inseminated into the uterus. IUI CATHETERS • Attach the syringe to an 18 cm polyethylene insemination catheter. Two types of catheters are available: (1) relatively rigid single sheath catheters (straight or with a preformed curve) that cannot be bent and (2) double sheath catheters with an external flexible sheath that will maintain a curve and a very soft internal catheter. In a 2010 meta-analysis of six randomized trials, pregnancy and live birth rates were the same for flexible and rigid catheters INSERTION of CATHETER • Without touching the end of the catheter that will enter the sterile uterine cavity, insert the catheter through the cervical os, through the endocervical canal, and into the uterus to a depth of approximately 6 to 6.5 cm. • Try not to let the catheter touch the fundus, as this will cause cramping and, in some cases, disruption of the endometrium and bleeding, which is toxic to embryo development. • If difficulty is encountered with insertion of the catheter, use of a rigid stylet or abdominal ultrasound guidance may be helpful. • Inject slowly the sperm and then slowly withdraw the catheter. • Sperm are present in the tubes as early as five minutes after insemination . • Patients will rest in supine position for 10 minutes after sperm injection. • Although only limited data are available on whether rest is of any value in enhancing pregnancy fertilization rates, one randomized trial reported higher pregnancy rates in rested patients compared with those who were immediately mobile post-IUI • Psychologically, patients are often reassured by a period of rest following the procedure Postprocedure Care • The patient may resume her normal activities after insemination. • Increased wetness after the procedure is due to loosened and watery cervical mucus, it does not mean the sperm specimen has flowed out. • Abdominal cramping or discomfort • Light bleeding or spotting • Patients may have intercourse after IUI if they wish to do so. • Pregnancy test : two weeks after IUI. NUMBER OF IUI CYCLES • Pregnancy rates are significantly lower after the third IUI cycle, irrespective of the ovulation induction method .( Then move on to more aggressive treatment). • European guidelines (Denmark, England, Wales, France, the Netherlands) suggest three to six IUIs, depending on the cause of infertility . COMPLICATIONS • Upper genital tract infection (rare ) • OHSS (Gonadotropin cycles) • Multiple Gestations Thank You for Your Attention