Ovulation Induction

Induction of Ovulation Definition of ovulatory deficiencies by WHO Group 1: Hypothalamic-Pituitary Failure – this classification includes patient diagnosed as hypothalamic amenorrhea (stress-related amenorrhea, anorexia nervosa, Kallmann’s syndrome and isolated gonadotropin deficiency). These patients display hypogonadotropic hypogonadism with low gonadotropin (FSH, LH) and oestrogen levels, normal prolactin concentrations, and a failure to bleed after administration of a progestational agent (the progesterone challenge). Group II: Hypothalamic-Pituitary dysfunction – this classification includes normal gonadotropic, normoestrogenic, anovulatory, oligoamenorrheic women. Example include the classic anovulatory polycystic ovary syndrome. Group III: Ovarian failure – this classification includes those with hypergonadotropic hypogonadism, with low oestrogen levels. Example includes all variants of ovarian failure and ovarian resistance. Ovulation induction with Clomiphene citrate: Clomiphene citrate was first synthesized in 1956. Clomiphene citrate is an orally active nonsteroidal agent. It is similar structurally to oestrogen, but exerts a very weak biologic oestrogenic effect. Clomiphene binds to oestrogen receptors – it has prolonged binding to nuclear oestrogenic receptors (for weeks rather than hours), clomiphene modifies hypothalamic activity by affecting the concentration of the intracellular oestrogen receptors – specifically, the concentration of oestrogen receptors is reduced by inhibition of the process of receptor replenishment. When exposed to clomiphene, the hypothalamic-pituitary axis is blind to the endogenous oestrogen level in the circulation. Because the oestrogen receptors are reduced, the true oestrogen signal is falsely lowered, negative feedback is diminished and the 1

neuroendocrine mechanism for GnRH secretion is activated, resulting in increased FSH and LH. When clomiphene is administered to normally cycling women, FSH and LH pulse frequency (but not the amplitude) is increased, suggesting an increase in GnRH pulse frequency. Anovulatory women, respond differently with clomiphene, which stimulates an increase in gonadotropin pulse amplitude, presumably because GnRH pulses are already operating at maximal frequency in anovulatory women with polycystic ovaries. The subsequent ovulation that occurs after clomiphene therapy is a manifestation of the hormone and morphologic changes produced by the growing follicles. Clomiphene therapy does not directly stimulate ovulation, but it retrieves and magnifies the sequence of events that are physiologic features of a normal cycle. In animal models, clomiphene exerts an oestrogenic effect on the pituitary and directly stimulates gonadotropin release, independent of its action on GnRH. In the presence of oestrogen, clomiphene influences pituitary response to GnRH in women, preferentially promoting FSH secretion. In addition, clomiphene exerts a direct ovarian effect. In the absence of oestrogen, clomiphene is an oestrogen agonist, directly enhancing FSH stimulation of LH receptors in granulosa cells. Whereas in the uterus, cervix, and vagina, clomiphene acts primarily as an antioestrogen. Thus vaginal cornification (thickening of epithelium) is attenuated, and the effect of oestrogen on cervical mucus and endometrium is antagonized (i.e watery cervical mucus and proliferation of the endometrium), potentially important actions affecting implantation, sperm transport, and early embryonic development. However, no significant effects on luteal phase endometrial morphology could be detected when clomiphene was administered to normal women. Clomiphene has no progestational, corticotropic, androgenic or antiandrogenic effects. Clomiphene does not interfere with adrenal or thyroid function. Selection of Patients for Clomiphene treatment:

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The main indication for clomiphene therapy is either absent or infrequent ovulation. Before commencing clomiphene therapy the clinician must first exclude disorders of pituitary, adrenal, and thyroid (these are treatable causes of anovulation – they have their specific treatment). Initial management includes a complete history and physical examination, laboratory investigation such as LFT, especially if history and physical examination suggest liver disease. Steps in management: • Precede therapy with semen analysis, to avoid an unnecessary waste of time and effort in the presence of azoospermia. • Efforts are directed towards detecting galactorrhea and serum prolactin measured, as galactorrhea and hyperprolactinemia requires a different therapeutic approach: dopamine agonist treatment. • For a patient with prolonged anovulatory periods, it is a wise precaution to perform endometrial biopsy, because of the tendency for these patients to develop hyperplasia and even carcinoma of the endometrium. • It is not absolutely necessary to document infrequent or absent ovulation by BBT charts. Note: for a patient with no previous medical or surgical problems, the remainder of the infertility workup is deferred until after a trial of Clomiphene therapy (because approximately 75% of pregnancies occur during the first 3 treatment cycles). The infertility workup is only pursued after the patient has responded with 3 months of ovulatory cycles and has not become pregnant. This is appropriate because clomiphene is simple, safe and costeffective. Note: Cases of ovarian failure do not respond to any form of ovulation induction. Therefore, those with amenorrhea need a progesterone challenge (medroxyprogesterone acetate 10mg daily for 5 3

days) to induce withdrawal bleeding. Those that fail to have withdrawal bleeding needs further evaluation such as hormone profile (serum gonadotropin) to exclude ovarian failure (hypergonadotropic hypogonadism). Patients most likely to respond to clomiphene therapy display some evidence of pituitary-ovarian activity as expressed in the biologic presence of oestrogen (spontaneous or withdrawal menstrual bleeding). These are anovulatory women who have gonadotropin and oestrogen production, but do not cycle, or women with inadequate luteal phase. The patient who is deficient in gonadotropin secretion (hypogonadotropic hypogonadism), and as a result is hypoestrogenic, do not respond to clomiphene therapy as they cannot be expected to respond to further lowering of the oestrogen signal. This is not completely true clinically, as some occasional patient respond to clomiphene. Therefore, other treatment options, rather than clomiphene is required. Clomiphene therapy may also be necessary to improve timing and frequency of ovulation, and to enhance the possibilities of conception in the patient who ovulates only occasionally. Clomiphene can also be used to regulate the timing of ovulation in women undergoing insemination. The use of clomiphene may aggravate the clinical problems of acne and hirsuitism during the treatment cycle by increasing LH stimulation of ovarian steroid production. Clomiphene does have value in the empirical treatment of unexplained infertility, particularly prior to undertaking the more expensive and more complicated assisted reproductive technologies. How To Use Clomiphene: A programme of clomiphene therapy is begun on the 5th day of a cycle following either spontaneous or induced bleeding. The initial dose is 50 mg daily for 5 days commencing clomiphene therapy on the 5th day of the

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menstrual cycle was arrived at empirically, however, used like that, the incidence of multiple gestation is less as the clomiphene-induced increase in gonadotropin during days 5-9 occurs at a time when the dominant follicle is being selected. Beginning clomiphene earlier can be expected to stimulate multiple follicular maturations resulting in a greater incidence of multiple gestations. In standard ovulation induction protocol, no differences have been observed in the rates of ovulation, pregnancy, or spontaneous miscarriage whether clomiphene was started on day 2, 3, 4 or 5 of the menstrual cycle. If ovulation is not achieved in the very first cycle of clomiphene treatment, dosage is increased to 100 mg and thereafter increased in a staircase fashion by 50 mg increments to a maximum of 200-250 mg daily for 5 days, if ovulation does not occur at lesser doses. The dose at which ovulation was achieved is used for 3-4 months before considering the patient to be a clomiphene failure. Following the 5-day course of clomiphene treatment, the ovulatory surge of gonadotropin would be expected to occur anywhere from 5-12 days after the last day of clomiphene administration (more commonly on cycle day 16 or 17 when clomiphene is administered on days 5-9). The patient is advised to have intercourse every other day for 1 week beginning 5 days after the last day of clomiphene medication. Note: Patient should avoid the use of prostaglandin synthetase inhibitors during treatment cycles – this may impair ovulation. Basal body temperature chart is used to monitor response to clomiphene – Biphasic changes indicates ovulation. If an inadequate luteal phase is evident (temperature elevation less than 11 days duration), the amount of clomiphene is increased to the next dose level. If the patient is already at the maximal level, then manage patient as those with clomiphene failure.

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Maintenancy of the temperature elevation beyond the expected time of menses is the earliest practical indication of pregnancy. Caution: After the first treatment cycle the patient is evaluated for side effects – residual ovarian enlargement, and basal body temperature changes. Pelvic examination every month is unnecessary as ovarian enlargement is an infrequent complication. Ovarian cyst within 3-5 cm in size do not require suspending therapy. Those With Clomiphene failure: The additional use of HCG is limited to those cases in which there failure to ovulate at the maximal dose level or when at that level, a short luteal phase is demonstrated. The reason for HCG is to improve the midcycle LH surge; therefore 10,000iu of HCG is given as a single intramuscular dose on the 7th day after the last day of clomiphene administration, when follicular maturation is at its peak. Following HCG administration, intercourse is advised for that night and for the next 2 days. The precise timing for the administration of HCG following clomiphene therapy can be determined by measuring blood oestradiol level or estimation of follicular cyst size (18-20 mm diameter) by sonography, because premature HCG administration may interfere with normal ovulation by down-regulating LH receptors. Note: In properly selected patients, 80% can be expected to ovulate, and approximately 40% become pregnant. The percentage of pregnancy per induced ovulatory cycle is about 20-25%. The multiple pregnancy rate is approximately 10%, almost entirely twins. Complications of Clomiphene therapy: Side effects do not appear to be dose-related, occurring more frequently at the 50mg dose. The most common side effects include: (i) vasomotor flushes (10%). (ii) Abdominal distension, bloating, pain or soreness (5.5%).

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(iii) Breast discomfort (2%). (iv) Nausea and vomiting (2.2%). (v) Visual symptoms (blurring vision, scotoma {visual spots or flashes}, or abnormal perception) (1.5%). (vi) Headache (1.3%). (vii) Dryness or loss of hair (0.3%). Notes: Patients who are extremely sensitive to the side effects of clomiphene can be successfully treated with half a tablet (25mg) daily for 5 days, and even with half a tablet daily for 3 days. A common antioestrogenic effect is an increase in the basal body temperature during the 5-day period of clomiphene administration. This is sometimes incorrectly interpreted as evidence of an early ovulation. Visual symptoms in almost all cases disappear upon discontinuation of medication, usually within a few days, but may take 1 or 2 weeks. Treatment should be discontinued following the persistence of this side effect. Significant ovarian enlargement is associated with longer periods of treatment and is infrequent (5%) with the usual 5-day course of clomiphene. The maximal enlargement of the ovary usually occurs several days after discontinuing the clomiphene (in response to the increase gonadotropins). If the patient is symptomatic, pelvic examination, intercourse, and undue physical exercise should be avoided because the enlarged ovaries are very fragile. Ovarian enlargement resolves rapidly and only rarely is a subsequent treatment cycle delayed. Note: There is increased risk of ectopic pregnancy in clomiphene treatment cycle, due to multiple ovulations (only slightly). What to do with Clomiphene Failures: Patients that are most likely not to respond to clomiphene are those with hyperandrogen and overweight (and probably insulin resistant).

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Other explanation for Clomiphene failure – (i) The effects of excessive LH in the follicular phase. (ii) The dysfunctional effects of an untimely LH surge. (iii) Excess local concentrations of androgens. (iv) Hyperinsulinaemia. The above enumerated reasons leads to impaired folliculogenesis, increased atresia, poor oocyte quality, precocious or impaired oocyte maturation, low fertilization rates, variable implantation rates, and deficient corpus luteum function. The management options for the above mentioned causes of clomiphene failure includes – (A)The treatment of hyperinsulinaemia. (B)The supplemental use of dexamethasone (to reduce androgen burden). (C)GnRH agonist (to eliminate endogenous LH intrusion). (D)Pulsatile GnRH therapy (to preserve physiologic interactive feedback mechanism), and finally. (E)The use of human gonadotropins. (F)Ovarian surgical procedures – wedge resection, laser drilling Before proceeding to the treatment options above, first exclude galactorrhea and measure serum prolactin (for patients with clomiphene failure). It is worth performing a postcoital test to assess the quality of the cervical mucus in patient on clomiphene therapy. Despite the antioestrogen action of clomiphene, the incidence of poor cervical mucus on the postcoital test is only 15%. In the past, oestrogen (0.625mg to 2.5mg conjugated oestrogen daily) was administered from day 10 to day 16 (for 1 week starting the day after the last day of clomiphene administration) in an effort to improve cervical mucus production (makes it watery and thin). Although high dose of oestrogen do not interfere with the gonadotropin response, ovulation or the pregnancy rate, there is reason to believe that oestrogen treatment is not effective.

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The alternative treatment option for patient with poor cervical mucus following clomiphene therapy is intrauterine insemination of prepared sperm. Note: After 6 months of clomiphene therapy, and in the absence of any other infertility factors – the above management options are followed. Treatment of Hyperinsulinemia: Anovulatory women with polycystic ovaries and hyperinsulinaemia are more resistant to clomiphene treatment (clomiphene failure). The best therapy for those who are obese is weight loss. Both the hyperinsulinaemia and the hyperandrogenism can be reduced with weight loss (at least, loss of more than 5% of the initial weight), resulting in resumption of ovulation and pregnancy. The goal in weight loss is to achieve a body mass index (BMI) of less than 27Kg/m2. Note: It is reasonable to assume that all overweight, anovulatory women with PCOS are hyperinsulinaemic. However, to determine hyperinsulinaemia (insulin resistance), measure the ratio of fasting blood sugar to fasting insulin level (a ratio of less than 4.5 is consistent with insulin resistance). All anovulatory women with hyperandrogenism should be assessed for insulin resistance and glucose tolerance with measurement of: 1. The fasting glucose : insulin ratio. 2. the 2-hour blood glucose level after a 75g glucose load: Results: • Normal -------------- less than 140mg/dl • Impaired ------------ 140-199mg/dl • Non-insulin dependent DM------- 200mg/dl and higher. Treatment of Hyperinsulinaemia is with drugs: (A)Metformin (500mg tid), it improves insulin sensitivity. The primary effect is a significant reduction in gluconeogenesis, thus decreasing hepatic glucose production. Metformin treatment reduces 9

hyperinsulinaemia, basal and stimulated LH levels, and free testosterone (hyperandrogenism) concentrations in overweight women with polycystic ovaries. A significant number of these anovulatory women treated with metformin ovulate and achieve pregnancy. Metformin causes weight reduction. The complication of metformin use, includes lactic acidosis (rare) especially in patient with medical problems such as sepsis, renal insufficiency, and congestive heart failure. Note: metformin should be discontinued, if the patient becomes ill during medication. Metformin should not be administered to patient with abnormal renal function test. (B) Thiazolidinediones (400mg daily) improve insulin sensitivity and insulin secretion (improved peripheral glucose utilization and β-cell function) without weight changes. It decreases hyperinsulinaemia, and improves metabolic abnormalities (decreased androgens, increased sex hormone binding globulin, decrease PAI-1 consistent with improved fibrinolytic capacity and decreased LH), and a return to ovulation in very obese women. Liver function must be monitored during troglitazone treatment (i.e. monitoring of serum alanine aminotransferase levels). Note: if an ovulatory response does not occur within 3 months of clomiphene treatment in those discovered to have hyperinsulinaemia, the clomiphene therapy should be recommenced at the lowest dose in addition to the drug therapy for hyperinsulinaemia. The Addition of Dexamethasone to Clomiphene: Patients with hirsuitism and high circulating androgen concentrations are more resistant to clomiphene. Dexamethasone, 0.5mg at bedtime to blunt the night time peak of ACTH, is added to decrease the adrenal contribution to circulating androgens and, thus, diminish the androgen level in the microenvironment of the ovarian follicles. Higher ovulation and conception rates are achieved with this treatment, when the circulating level of dehydroepiandrosterone sulphate (DHAS) is greater than

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the upper limit of normal. The dexamethasone is maintained daily until pregnancy is apparent. The dose of clomiphene restarted at 50mg per dose when adding dexamethasone to treatment and thereafter, increased in incremental fashion as needed. It is also reported, that non-responders to clomiphene with normal DHAS achieve ovulation and pregnancy with the addition of a 10-day course of dexamethasone started concurrently with clomiphene. Extended Clomiphene Treatment (types) • 250mg of clomiphene is given for 8 days, followed by 10,000iu of HCG 6 days later. • The clomiphene dose is increased every 5 days, with some patients receiving up to 25 days of consecutive treatment, the last 5 days at 250mg daily. This method of clomiphene therapy requires oestrogen monitoring, with discontinuation of the clomiphen when an increase in oestrogen is detected. No patient ovulated after more than 21 days of treatment.

The addition of Bromocriptine to Clomiphene The use of bromocriptine to induce ovulation is indicated in the presence of galactorrhea or hyperprolactinaemia. Elevated prolactin levels interfere with the normal function of the menstrual cycle by suppressing the pulsatile secretion of GnRH. This is manifested clinically by a spectrum ranging from a subtle inadequate luteal phase to total suppression and hypoestrogenic amenorrhea. In women with persistent anovulation and polycystic ovaries, LH secretion is decreased by bromocriptine treatment. Side effect of bromocriptine Nausea, diarrhoea, dizziness, headache and fatique. Side effects can be minimized by slowly building tolerance toward the usual dose of 2.5mg bid. Treatment is started at an initial dose of 2.5mg at bedtime. If intolerance 11

occurs, the tablet can be cut in half. Usually the second dose is added, after 1 week, at breakfast or at lunch. Some patients respond to as little as 0.625 or 1.25mg daily. Patients extremely sensitive to the side effects of bromocriptine can be treated by administering the drug intravaginally. Usually one 2.5mg tablet daily will be effective: if the prolactin level is elevated, the dose can be titrated to bring the prolactin level into the normal range. The usual regimen of bromocriptine dose is administered daily until it is apparent the patient is pregnant, as usually determined by the basal body temperature chart. Ovulatory menses and pregnancy are achieved in 80% of patients with galactorrhea and hyperprolactinaemia. Response is rapid, and, therefore, if there is no indication of ovulation (a rise in the basal body temperature) within 2 months, clomiphene is added to the regimen. The starting dose of clomiphene is 50mg daily for 5 days, given and increased in the usual fashion. Induction of Ovulation With Human Gonadotropins: Human menopausal gonadotropins is a preparation of gonadotropins extracted from the urine of postmenopausal women containing FSH and LH in ratio 1:1 (commercial preparation is with either 75units of FSH and 75units of LH per ampule or 150units of each gonadotropins). Gonadotropins are given perenterally because they are inactive orally. The heavy protein content of the urinary preparations requires intramuscular injections. A more purified urinary preparation of FSH is available by removing most of the LH in the urinary product, it is given intramuscularly. Recombinant FSH is produced from Chinese hamster ovary cells transfected with the human FSH subunit genes. It is more homogenous and free of contamination by proteins, which allows a simpler subcutaneous administration. Types of Gonadotropins preparation Trade Names

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• • • • • • •

Human menopausal gonadotropins Menogon, Repronex Purified urinary FSH Orgafol. Highly purified urinary FSH HP Recombinant FSH Follistim Human chorionic gonadotropin Recombinant HCG Recombinant LH

Pergonal, Humergon, metrodin, Normegon, Fertinex or Metrodin Puregon, Gonal-F, Pregnyl, Profasi, A.P.L. Ovidrel L.Hadi

Selection of Patients for Gonadotropin treatment: Patients that should be on gonadotropin therapy should be carefully evaluated because of its high cost and greater complications rate. An absolute requirement for gonadotropin therapy is the demonstration of ovarian competence. Abnormally high serum gonadotropins with failure to demonstrate withdrawal bleeding indicate ovarian failure and preclude induction of ovulation. Requirement for Gonadotropin therapy: • Demonstration of Ovarian competence • A thorough infertility investigation • Tubal and uterine pathology must be ruled out. • Semen analysis obtained • Anovulation documented. • Nongynaecologic endocrine problems must be treated. • Hypogonadotropic function (low serum gonadotropins), including galactorrhea syndromes, requires evaluation for an intracranial lesion, with appropriate imaging and measurement of prolactin levels. It is imperative to take all steps necessary to exclude treatable pathology to which anovulation is secondary. Note: hyperprolactinaemia has no adverse effect on response to gonadotropins.

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How to Use Gonadotropin therapy: First step: a thorough instruction and counselling of the couple with an understanding of the need for daily treatment and frequent observation, the partner can be taught to administer injections. Daily recording of the basal body temperature chart and body weight is important for proper management. The couple should be informed about the need for scheduled intercourse, the possibility that more than one course of treatment may be necessary, and the expensive cost of treatment. Above all, the patient must be prepared for the anguish that accompanies failure. Because this is a pressure-packed situation, unexpected impotence is occasionally encountered on the days of scheduled intercourse. Evidence shows that Recombinant FSH yield better results with in vitro fertilization, however, in ovulation indication none of the gonadotropins are better than the other. Optimal success is dependent on the experience and judgement of the clinician. Some LH is necessary for normal ovarian steroidogenesis and very low day 3 LH levels (less than 3iu/L) is known to predict poor response to gonadotropin stimulation. Therefore in such circumstances perhaps a preparation containing some LH would be a better choice for treatment; for example, in patients with amenorrhea due to weight loss and anorexia. A variable dosage method is used to achieve follicular growth and maturation. Follicle stimulation is achieved by 7-14 days continous gonadotropin, beginning with one ampoule daily. The response is judged by the degree of oestrogen produced by the growing follicles. The patient is monitored periodically with the measurement of the circulating oestradiol level and vaginal ultrasound assessment of the number and size of follicles. The patient is seen on the 7th day of treatment and a decision is made to continue or increase the dose (step up method). After the 7th day, the patient is seen anywhere from daily to every one or two days. Another approach, the step down method, starts with a higher dose (2-3 ampoules) and reduces the dose to one ampoule after the initial

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response, theoretically approximating the changes in FSH in a normal ovulatory cycle. Care should be taken with PCOS patient since they are more sensitive to gonadotropin stimulation, and therefore, at greater risk for multiple pregnancy and the ovarian hyperstimulation syndrome. The reason for the increased sensitivity is apparently due to the availability of a larger cohort of small follicle ready to respond to FSH (recruitable follicles). Therefore, in PCOS, monitoring begins on the 4th or 5th day of treatment. Excessive stimulation can be avoided in women with PCOS by using lower doses of gonadotropin extended over a longer duration of treatment. In addition, good results are inversely correlated with the degree of insulin resistance and therefore consideration must be given to treatment that improves insulin sensitivity. When serum oestradiol levels and ultrasound monitoring indicates that the patient is ready to receive the ovulatory stimulus, 10,000units of HCG is given as a single dose intramuscularly. The patient is advised to have intercourse the day of the HCG injection and for the next 2 days. Ovulation occurs approximately 36 hours after administering HCG. In view of the fragility of hyperstimulated ovaries, further intercourse as well as strenuous physical exercise should be avoided. Pregnancy is usually achieved with the administration of gonadotropins for 7-12 days. The best results are obtained when the treatment duration is for 10-15 days; when less than 10 days, the spontaneous miscarriage rate is increased. In general there is a direct relationship between dose and body weight; however, the same empiric approach is needed even in obese patients. In some individuals, presumably with extremely hyposensitive ovaries, adequate follicular stimulation requires doses up to 4, 6, and more ampoules/day. In this group of amenorrheic women massive doses of gonadotropins are necessary, and with proper monitoring, pregnancy can be achieved safely.

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The range between the dose that does not induce ovulation and the dose that results in hyperstimulation is narrow. The situation is made even more difficult because the ovaries may react differently to essentially similar doses from month to month. Close supervision and experience in the use of gonadotropin therapy are necessary to avoid difficulties. There is no reason to avoid consecutive cycles of ovarian stimulation; indeed, an increased cycle fecundity has been observed in consecutive treatment cycle when compared to alternating stimulation and nontreatment. Oestradiol monitoring: It is a necessary monitoring measure to help determine the correct time for administering the ovulatory dose of HCG in order to prevent hyperstimulation. On day 7 of the therapeutic cycle, blood is assayed for oestradiol, depending on the finding the gonadotropin dose may be altered accordingly for the remaining duration of the cycle. The timing for collection of blood sample used in assaying for serum oestradiol level is necessary for accuracy of result. This is in relationship to the last injection of gonadotropin (when gonadotropin injections are given between 5 and 8 PM and blood samples are obtained first thing in the morning, an oestradiol window of 10001500pg/ml is optimal. The risk of hyperstimulation is significant from 1500-2000pg/ml and as a general rule, over 2000pg/ml, HCG should not be given, and the ovarian follicles should be allowed to regress. Ultrasound monitoring: USS assessment of the growth and development of the ovarian follicle indicates the degree of follicular maturity and capability. During normal cycles, the growing cohort of follicles can first be identified by ultrasonography on days 5 to 7 as small sonolucent cyst. The dominant follicle will become apparent by days 8-10. the maximal mean diameter, indicating ovum maturity, of the preovulatory dominant follicle varies from 20 to 24mm (range 1428mm) in normal, spontaneous cycles.

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During the 5 days preceding ovum expulsion, the dominant follicle exhibits a linear growth pattern of approximately 2 to 3 mm per day, followed by rapid exponential growth during the last 24 hours prior to ovulation. USS surveillance of ovaries reveals that mittelschmerz is associated with the rapid expansion of the dominant follicle rather than with follicular rupture, which is usually preceded by the pain. With gonadotropin therapy, the maximal follicular diameter (15-18mm) is smaller than that seen during spontaneous and clomiphene induced cycles (both within 20-24mm). Hyperstimulation is associated with the presence of more follicles, therefore when there are more than 3-5 follicles 13mm or greater in diameter, HCG should not be administered. Measurement of endometrial thickness: successful implantation correlates with endometrial thickness on the day of HCG administration. The chances of pregnancy is greatest, no matter what programme of ovarian stimulation is being used, if endometrial thickness is 910mm or more. The effect of persistent ovarian cyst: the presence of a baseline ovarian cyst greater than 10 mm in diameter is associated with decrease fecundity in ovulation induction with gonadotropins. With large cyst, treatment should either be delayed or cyst suppression with a GnRH agonist or oral contraceptives should be considered. With the exception of the above, there is no advantage in avoiding multiple successive treatment cycles (such as alternating treatment and non-treatment cycles). Clomiphene-Gonadotropin combination therapy: This combination was explored in order to minimize the amount and the cost of gonadotropin alone. The usual method of treatment is to administer clomiphene 100 mg for 5-7 days, then to immediately proceed with gonadotropin beginning with 2 ampoules per day.

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Oestrogen levels are monitored as usual. This method may decrease the amount of gonadotropin required by approximately 50%, however, the same risk of multiple pregnancy and hyperstimulation can be expected. Pulsatile administration of gonadotropin: it is given either subcutaneously or intraveneously in doses of 6-9 units per pulse every 90 minutes, with adjustment upwards depending on the response. The aim is to reproduce the pulsatile pattern of gonadotropin secretion during the normal menstrual cycle. Monitoring is with serum oestradiol level and USS Results with Gonadotropin treatment: The most significant result is that it does achieve pregnancy in otherwise untreatable situations. A cumulative conception rate of 90% after 6 treatment cycles can be achieved in women with hypothalamic amenorrhea (this rate exceeds that observed in spontaneously ovulating women), with a 23% rate of spontaneous miscarriage. Women with normogonadotropic anovulation achieve only a slightly lower cumulative conception rate with relatively, but slightly, higher rates of miscarriage. The slightly higher miscarriage rates reflects the combination of better detection of early pregnancy loss, advanced maternal age, and the increased incidence of multiple pregnancies. The risk of ectopic pregnancy is increased with ovulation induction, a consequence of multiple oocytes and high hormone levels. Women with PCOS and moderate obesity require larger doses of gonadotropin and ovulate at a lesser rate compared to leaner women with PCOS. Note: After at least one gonadotropin-induced pregnancy, the subsequent spontaneous pregnancy rate reaches 30% after 5 years. With most of the subsequent spontaneous pregnancy occurring within the first 3 years.

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Multifetal Pregnancy Reduction: so as to improve the chances of carrying the pregnancy successfully, under ultrasound guidance selective reduction of embryos in multiple pregnancies can be accomplished. A gestation sac can be aspirated or a cardiotoxic drug (potassium chloride) can be injected into, or adjacent to, the fetal heart under ultrasound guidance. The transvaginal procedure is best performed between 8th and 9th weeks of gestation and the transabdominal procedure between the 11th and 12th weeks. A later procedure is worthwhile because the spontaneous disappearance of one or more gestational sacs in multiple gestation can occur, an incidence of approximately 5% after fetal heart beat have been identified. The reduction of a monochorionic pregnancy is not advisable because of shared vasculature and the high risk of losing all fetuses. The selection of which gestational sac to terminate is based solely on technical considerations, such as accessibility. The subsequent risk of losing one or more of the remaining fetuses is 4-9%, and of losing the pregnancy, 10% by experienced clinician and higher with less experience. The Hyperstimulation Syndrome: Ovarian hyperstimulation can be life-threatening. In mild cases the syndrome includes ovarian enlargement, abdominal distension, and weight gain. In severe cases, a critical condition develops with ascites, pleural effusion, electrolyte imbalance, and hypovolemia with hypotension and oliguria. The ovaries are tremendously enlarged with multiple follicular cysts, stromal oedema, and many corpora lutea. Because of this enlargement, torsion of the adnexa is a relatively common complication of this syndrome. What to Do with Gonadotropin failure: they either repeat the expensive treatment cycle or proceed to assisted reproduction technologies. After a properly managed 6 cycles of gonadotropin therapy, move on to ART. GnRH Agonist and Gonadotropin combined Treatment: Recognising that women with significant oestrogen, androgen and gonadotropin levels do not respond well to

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induction of ovulation, attention was turned to a method that could turn off a woman’s endogenous reproductive hormone production. The availability of GnRH agonist provided such a method. It works by converting normogonadotropic anovulators to a hypogonadotropic hypogonad state by the process of pituitary GnRH receptor desensitization and down-regulation. Premature LH effects on the follicles and the burden of excess local androgen can be diminished and an improved therapeutic response achieved. There is reason to believe that women with anovulatory polycystic ovaries have a higher incidence of spontaneous miscarriage following induction of ovulation with gonadotropin, combining the GnRH agonist with gonadotropin yield a greater pregnancy rate as well as a reduced miscarriage rate. The combination also reduces the risk of ovarian hyperstimulation syndrome. Leuprolide acetate (Lupron) is administered twice daily (0.5mg subcutaneously) for 2 weeks. Suppression of gonadotropin secretion is confirmed by measuring the oestradiol level, a concentration less than 25pg/ml should be achieved before treatment is initiated with gonadotropins. Lupron treatment is maintained throughout the gonadotropin regimen until HCG is administered. It is not unusual to require higher doses of gonadotropins. With this combination, no difference has been observed in the number of follicles recruited, the rate of rise and final oestradiol level achieved, or the number of cycles cancelled compared with gonadotropin alone. Hyperstimulation is not avoided, but per cycle fecundity appears to be modestly increased. The administration of a GnRH agonist to a woman who has menstrual function will initially produce a stimulatory response, known as the “flare”. The magnitude of the flare response depends upon when in the cycle the agonist is administered. During the follicular phase or in anovulatory women, the flare is greater, and enlarged follicular cysts can occur. This response can be minimized by beginning therapy during the midluteal phase or by administering a progestational agent (e.g. 10 mg medroxyprogesterone acetate daily for 10 days) and beginning GnRH agonist treatment after 3 days of progestin.

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During the hypoestrogenic period of time, menopausal-like symptoms are common, especially hot flushes. Utilization of a GnRH agonist suppresses endogenous LH levels to such a low level that, after ovulation, the corpus luteum requires additional exogenous support. One can administer HCG (2000iu) twice, 3 days, and 6 days after ovulation, or progesterone suppositories, 25 mg twice per day, intramuscular progesterone, 50 mg per day, or oral micronized progesterone, 300 mg per day. The dose of micronized progesterone is relatively high and should be administered at bedtime to avoid side effects. Progesterone in a gel that adheres to the vaginal mucosa (Crinone) is available in a prefilled vaginal applicator, applied with one 8% (90 mg progesterone) application daily. Vaginal administration accomplishes targeted delivery to the uterus without producing high circulating levels. The pregnancy rates with either HCG or progesterone treatment are the same, but the use of HCG adds to the risk of hyperstimulation. GnRH Antagonist: GnRH antagonist binds to the GnRH receptors and totally block any stimulation of the pituitary gonadotropinsecreting cells. GnRH antagonist can be used concomitantly with gonadotropin induction of ovulation to prevent premature LH surges. Because GnRH antagonist are competitive inhibitors, a GnRH agonist could be used for the ovulatory signal, possibly avoiding the use of HCG and reducing the risk of ovarian hyperstimulation. The optimal use of GnRH antagonist is currently being explored. Adding Growth Hormone: The insulin-like growth factor-1 plays a critical role in ovulation, since growth hormone stimulates the production of insulin-like growth factor-1. its addition to gonadotropin for induction of ovulation facilitates ovulation in poor responders. The dose is 24iu given intramuscularly every other day. Initial results in poor responders were favourable, although this may be limited to patients with PCOS. In women with normal responses, however, the

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addition of GH did not improve results or reduce the total dose of gonadotropin. Thus in normally responding women, the growth hormone and IGF-1 system may be operating at maximal levels. In poorly responding women, concomitant treatment with growth hormone can reduce the amount of gonadotropin necessary, shorten the duration of treatment, and increase the chance of a pregnancy. However, not all poorly responding women respond favourably to growth hormone treatment. The effective selection of patients, dosage, and treatment regimens remains to be standardized, and the extreme cost of GH is a significant disadvantage. Induction of Ovulation with Gonadotropin-Releasing Hormone (GnRH): Pulsatile GnRH therapy is quite safe, and simple to use, requires no extensive or expensive follicular monitoring. Ovarian hyperstimulation and multiple pregnancy are rare because only “physiologic” levels of FSH should be generated. Because GnRH serves largely a permissive role, the internal feedback mechanism between the ovary and pituitary are operative, yielding follicular growth and development similar to a normal menstrual cycle in response to the “turning on” of the system by GnRH. The GnRH is administered constantly in a pulsatile fashion by a programmed minipump. Induction of ovulation with the GnRH pump is most effective in women with hypothalamic amenorrhea (absence of menstrual bleeding following a progestin challenge) where endogenous GnRH is dysfunctional or absent. The GnRH pump is also effective in women with hyperprolactinaemia, providing good alternative if dopamine agonist treatment cannot be tolerated. Patient with PCOS are less responsive and at greater risk of ovarian hyperstimulation and multiple gestations and as such require lower dose (2.5mcg per bolus). GnRH is available in crystalline form that when reconstituted in the aqueous diluent is stable for at least 3 weeks at room temperature. GnRH can be administered by either intravenous or subcutaneous route. The pulse frequency of treatment is 90 minutes cycle. The

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subcutaneous dose is 20mcg per bolus, for intravenous route its 5mcg per bolus. After ovulation, the luteal phase is maintained by either continuing the pump or administering HCG (2000iu intramuscularly at the time of the temperature rise and then every 3 days for 3 doses). Usually ovulation occurs by 14 days of treatment, but the range extends from 10 days to 22 days. Ultrasonic monitoring of follicular development may be required, or more conveniently, the couple can use one of the urinary LH test kits to detect the LH surge and have intercourse for 2-3 days beginning the day of the colour change. The pregnancy rate in anovulatory women is 20-30% per treatment cycle, which approximates the pregnancy rate of normal couples. If this method is to be used for women with PCOS, it is recommended that desensitization and down-regulation of the pituitary with a GnRH agonist precede treatment (and retreatment will be necessary with each cycle).

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