Fertility Treatments

Medications Used Commonly in Fertility Treatments for female.

For ovulation induction

Clomiphene Citrate

Clomiphene Citrate (Clomid) is a compound that is very similar in structure to estrogen. Because of this likeness, Clomid is able to bind to estrogen receptors in the hypothalamus (a part of the brain that regulates ovulation). This prevents the brain from seeing the negative signal from estrogen that is being released by the ovaries. As a result, the hypothalamus continues to stimulate the pituitary gland to make FSH and LH. These hormones stimulate follicular growth in the ovary.

Dose and administration:

Clomiphene citrate is administered orally in 50 mg increments (50, 100, 150) over 5 days.The recommended starting dose is 50 mg/day as almost half of the pregnancies are achieved with this dose. In very few women with extremely sensitive ovaries, the starting dose may be as low as 25 mg/day. The tablets are usually given for 5 days following the onset of a spontaneous or a progesterone induced period. Administration of clomiphene citrate can start at any time from day 2,3,4 or 5 of the cycle as there is no difference in the outcome between these time-points. Unless normal ovulation occurs the dose should be increased in each of the next cycles by 50 mg/day up to a maximum dose of 150 mg/day. Maximum recommended dose is 150 mg/day as there is no clear evidence of efficacy at higher doses. Not much in use but probably underestimates is the titrated dose of clomiphene citrate or extended CC therapy in which prolonged administration (7- 10 days) of high doses of clomiphene citrate is used.

Monitoring:

Monitoring by ultrasound is not mandatory but it is better to monitor the first cycle to allow adjustment of the dose in subsequent cycles based on the observed response. An ultrasound is usually done on day 10 (if taken on days 3-7) or day 12 (if 5-9).  In the absence of complete cycle monitoring, a pretreatment ultrasound is often performed to evaluate ovarian and endometrial morphology, which may be followed by serum progesterone measurement .

Efficacy:

Pregnancy rates with Clomid range from 6-10% in most cases. Of the pregnancies that occur using Clomid, 85% will occur in 3 months, 99% will occur within 5 months. Treatment beyond 6 months is generally not seen as useful. There are various other medications that can be used with Clomiphene citrate. Among these are glucocorticoids like dexamethasone, and metformin. Approximately 75% to 80% of patients with PCOS ovulate after CC administration. Although there appears to be discrepancy between ovulation and pregnancy rates life table analysis of the largest and most reliable studies indicates a conception rate of up to 22% per cycle in those ovulating on CC .

Duration of treatment:

Treatment generally should be limited to six ovulatory cycles. Further cycles (Maximum 12 in total) may be considered on an individual basis after discussion with the patient. Cumulative live birth rates vary between 50% and 60% for up to six cycles .

Adverse effect:

Hot flushes, headaches and visual complaints are well recognized side-effects during CC treatment, but the drug is generally well tolerated. The multiple pregnancy rate is less than 10% and ovarian hyperstimulation syndrome (OHSS) is rare. Anti-oestrogenic effects on endometrium and cervical mucus may occur but appear to represent an idiosyncratic response.

Clomiphene failure:

As the goal of treatment is the induction of ovulation and pregnancy, CC failures must be sub-classified into those who fail to ovulate (ovulation failure) and those who ovulate but fail to conceive (conception failure). While considerable overlap exists between these two sub-groups, the distinction is important as the clinical management of the two problems may be quite different.

a) Ovulation failure:

The term CC non-responsiveness usually refers to ovulation failure despite maximal conventional doses. Women who fail to ovulate after maximum dose of CC are considered as clomiphene resistant. In women with PCOS, the rates of CC resistance are around 10-30%. Several investigators have identified a relationship between CC dose and body weight, body mass index (BMI) or ponderal index. It has been speculated that the higher esterone concentrations found in obese women necessitate higher CC doses in order to compete with the endogenous oestrogens for hypothalamic receptor sites. Clomiphene nonresponders tend to have significantly larger ovarian volumes with significantly more intermediate sized follicles than CC responders and normal controls, although considerable overlap exists. Increasing level of LH elevated total or free testosterone fasting hyperinsulineamia or insulin resistance and decreasing concentrations of sex hormone binding globulin (SHBG) tend to predict or poor response to CC. Although CC has been shown to have a beneficial effect on the secretion of FSH and SHBG, the ovary may not be able to respond to an apparently adequate rise in serum FSH. Alternatively the beneficial effects may be outweigh by a concomitant increase in the already elevated concentrations of LH and ovarian androgens, thus perpetuating the hyperandrogenic anovulation . In general the more severe the hormonal and ultrasonographic abnormalities the less likely it is that ovulation will be induced with CC.

b) Conception failure:

In spite of ovulation with CC when patients fail to conceive it is called clomiphene failure or conception failure. Considerable discrepancy exists between ovulation rates 70%-90% and conception rates 22% . Among women with PCOS the factors that predict ovulation ( obesity, hyperandrogenism and insulin resistance)  differ from those that predict conception (age, severity of the menstrual cycle abnormality and other infertility factors). Approximately 75% of the pregnancies achieved during CC treatment occur within the first three cycles of treatment. Among those who do not conceive within six ovulatory cycles are couples with other infertility factors or PCOS related factors which may account for these continuing infertility. The antioestrogenic actions of CC may adversely affect vaginal cornification, cervical mucus, and endometrial thickness, thus potentially affecting sperm transport, sperm survival and early implantation. In addition to the potential antioestrogenic effects of CC, ovulation induction in women with PCOS occurs in an environment characterized by high basal LH and androgen concentration both of which may be exacerbated during CC treatment and may have a negative impact on outcome. This suboptimal environment may affect oocyte quality and fertilization rates as seen during in vitro fertilization cycles in women with PCOS or it may increase the likelihood of an early pregnancy loss.

Aromatase inhibitor:

Aromatase inhibitors are antioestrogenic agents which exerts their action by inhibiting aromatase enzyme. Administering an aromatase inhibitor early in the follicular phase can induce ovulation by releasing the hypothalamus or pituitary from oestrogen negative feedback on GnRH and gonadotropin secretion leading to an increase in gonadotropin production which would stimulate ovarian follicular development. It also appears that CC accumulates in the body because of long half life leading to negative effect on endometrial development and quality and quantity of cervical mucus. Half life of aromatize inhibitor is only 45 hours so there is no profound antioestrogenic effect on endometrial or cervical mucus. Different studies proved the efficacy of aromatase inhibitor in ovulation induction. Initial preliminary study suggests that letrozole appears to be as effective as CC for induction of ovulation. But the drug is currently not approved for treatment of infertility. It may however, be considered as an off-label option for some patients after appropriate discussion of risks and benefits.

Gonadotropins:

Gonadotropins are hormone medications to make the ovary produce extra follicles. Gonadotropins include follicle stimulating hormone (FSH) and lutenizing hormone (LH). There are several different brand names of medications available. Some drugs which available in our country are Gonal-F, Puregon and Menogon. All are imported and not available in general stores. Drugs are supplied directly to the fertility centers to restore cold chains. As these drugs are heat sensitive so it needs to maintain the temperature. These drugs must be used under the supervision of a doctor to prevent harmful side effects such as ovarian hyperstimulation (OHSS). Detailed mixing and administration instructions are provided in the clinic. Starting dose is usually smaller and adjusted according to the response of the drug. Extensive ultrasonographic monitoring is needed to see the response of the drug and to avoid the OHSS.

Low dose gonadotropins:

For anovulatory patients who do not respond to other ovulation inducing agents,  gonadotropin is the supreme drug for induction of ovulation. For PCOS gonadotropin should be given with caution to avoid clinical hyperstimulation. In the first treatment cycle, a very low dose of HMG, pure FSH or a mixture of these (FSH and LH ) should be given for the first 5 days, gradually increasing the daily doses by 37.5-75 IU every day until the threshold dose is found. Advantage of using gonadotropin is chance of ovulation is more precise. Disadvantages are it requires meticulous judgement for application, dose is very much individualized, expensive, chances of OHSS (sometimes fatal) is more so needs meticulous monitoring. Chances of multiple pregnancies is also more.

Currently, two low-dose regimens are used:

1. Step-up regimens: Step-up regimens are based upon the principle of a stepwise increase in FSH supply to determine the FSH threshold for follicular development. After commencement of gonadotropin administration, if follicle development is not observed on ultrasound after 1 week, an increase in the dose is recommended. Once follicle growth is observed, the same FSH dose is maintained until follicular selection is achieved. To further reduce the risk of ovarian hyperresponsiveness, the duration of the initial dose of FSH is extended (from 7 to 14 days), and the weekly dose increment is reduced (from 100% to 50% of the dose), leading to the so-called chronic low-dose regime.

2. Step-down regimens: This regimen is designed to achieve the FSH threshold through a loading dose of FSH with a subsequent stepwise reduction as soon as follicular development is observed on ultrasound. Preliminary studies report that both step-up and step-down regimens achieve similar high rates of monofollicular development. However, the largest study published so far has shown that the step-up regimen is safer in terms of monofollicular development. Moreover, it is widely accepted that monitoring of a step-down cycle may require more experience and skill compared with a low-dose step-up regimen . Alternatively, a combined approach of sequential step-up and step-down regimens has been shown to help reduce the risk of over response

Pulsatile GnRHa:

Gonadotropin releasing hormone (GnRH) agonists are synthetic peptide analogues of hypothalamic GnRH. The repeated administration causes pituitary desensitization and induces a reversible state of medical hypophysectomy. The idea of using GnRH agonists in ovulation induction in PCOS stems from the assumption that the endogenous secretion of relatively large amounts of LH may well be the cause of the higher incidence of development of the ovarian hyperstimulation syndrome. Moreover, the high tonic secretion of LH may be deleterious to the quality of the ovum is reduced by GnRHa. Therefore, the use of GnRHa in order to suppress endogenous gonadotropin secretion in PCOS patients and to mimic hypogonadotrophic hypogonadism seemed to be a logical approach for ovulation induction.

Combined treatment with GnRHa and gonadotropins:

The use of combined treatment for women with PCOS is indicated in cases who have been found to have persistently raised follicular phase LH levels, proven premature LH surges on hMG treatment alone, an inadequate luteal phase , or those who have had two or more early pregnancy losses on clomiphene or hMG. It has been suggested that increased luteinizing hormone (LH) secretion in PCOS may interfere with fertility. The mechanisms include premature oocyte maturation through inhibition of oocyte maturation inhibitor and deleterious LH effect on granulosa cell steroidogenesis, although more recent data are not consistent with this assumption

The concomitant use of a GnRH agonist with gonadotropin administration to improve pregnancy rates in patients undergoing ovulation induction has not been firmly established. Moreover, combined therapy was associated with an increased risk of OHSS  but there are insufficient data to draw solid conclusions on miscarriage and multiple pregnancy rates. Therefore, the significantly higher hyperstimulation rate, the associated risk of multiple pregnancies, and the additional inconvenience and cost of concomitant GnRH agonist administration, in the absence of documented increases in pregnancy success, do not justify the routine use of GnRH agonists during ovulation induction with gonadotropins in PCOS patients.

GnRH antagonist
Though GnRHa suppress LH concentration, higher number of follicles during stimulation is an adverse effect. GnRH antagonists have some advantages over agonists. Since the antagonist suppress LH immediately, it can be administered in the late follicular phase when the LH peak is expected thereby reduce premature LH surge in PCOS patients.

Monitoring
Ultrasound assessment of the ovary can be performed at baseline before the initiation of each cycle. Serial ovarian ultrasound is an excellent method of determining follicle growth and development in response to gonadotropin stimulation. In particular, documentation of all follicles greater than 10 mm may be helpful to predict the risk of multiple pregnancies. Adherence to the chronic low-dose regimen of FSH administration in women with PCOS should markedly reduce the likelihood of excessive ovarian stimulation and OHSS. However, before ovulation induction with gonadotropins, it is mandatory to counsel the patient about the risks associated with higher-order multiple pregnancies after polyovulation.
Efficacy
Overall, low-dose regimens result in a monofollicular ovulation rate of approximately 70%, a pregnancy rate of 20%, and a multiple live birth rate of 5.7%. Correspondingly, there is a low incidence of multiple pregnancies (<6%) and OHSS (<1%) . These results compare favorably to the unacceptable high risk of multiple follicular development, multiple pregnancies (36%), and severe OHSS (4.6%) reported for conventional dose protocols

Adjuvant

i). Insulin sensitizers

At least five different modalities have been used to lower insulin levels in PCOS. These include weight loss, diazoxide, metformin, thiazolidinedeones (pioglitazone, rosiglitazone, troglitazone is no longer available for use) and D-chiro inositol. Among all drugs metformin is the most comprehensively evaluated drug. Both metformin and the thiazolidinediones effect reductions in insulin levels but they do so by fundamentally different mechanism. None of the insulin sensitizing drugs have Food and Drug administration (FDA) approval for use in PCOS. Nonetheless the scientific evidence supporting their salutary effects in PCOS is substantial and progressively mounting and their use for this purpose by clinicians is already established. Although troglitazone is effective in resulting ovulation in PCOS due to need of liver transplantation and death from hepatic failure it is withdrawn from the market. Much published data assessing rosiglitazone and pioglitazone and D-chiro inositol in PCOS are not available. Moreover, D-chiro inositol is not yet commercially available.

Metformin
Metformin is a biguanide antihyperglycemic that is approved for the management of type 2 diabetes mellitus. The mechanism by which metformin enhance insulin sensitivity are not fully characterized. At a molecular level, metformin may increase the activity of the enzyme adenosine monophosphate-activated protein kinase. Metformin appears to suppress hepatic glucose output, decreased intestinal absorption of glucose, increased insulin mediated glucose utilization in peripheral tissues and has an antilypolytic affect on fatty acid concentration reducing gluconeogenesis . It does not produce hypoglycemia in either normal subjects or patients with type 2 diabetes. It is rapidly absorbed from the small intestine and without metabolism largely excreted in the urine. It is available in a generic form as 500 mg, 850mg and 1000 mg tablets. The target dose of metformin is in the range of 1500 mg to 2550mg . Metformin is given with meals to reduce the gastrointestinal side-effects. The most common side-effects of metformin are diarrhea, nausea, vomiting, flatulence, indigestion and abdominal discomfort. The gastrointestinal side-effects may be caused by high intestinal metfromin concentration that cause builds up of lactic acid in the bowel. A rare problem caused by metformin is lactic acidosis, which is fatal in as many as 30%-50% of cases . Chances of lactic acidosis is increased when patients have renal insufficiency. So it should not be prescribed if serum creatinine level is greater than 1mg/dL. Liver disease, congestive heart failure and previous history of lactic acidosis are other contraindications of metformin therapy. Metfromin should be temporarily suspended for all major surgical procedures that involve restriction of fluid intake. Among metformin users in 10% of cases lactic acidosis occurred after the intravenous administration of iodinated contrast agents. So most authorities recommend that metformin should be discontinued 48 hours before any radiologic procedure that involves intravenous administration of iodinated contrast material. Though some authorities believe that it is safe to give contrast media to person taking metformin as long as renal function is known to be normal.

For triggering of ovulation:

Human Chorionic Gonadotropin (hCG)
hCG is given when follicle is get matured that is it attains a size of ≥17mm. 5000 – 10000 iu is given for final maturation of follicle. It is not essential always. It is essential for  IUI and IVF. GnRHa .1-.2 mg can be used for triggering of ovulation. But it is not applicable in GnRHa downregulated cycle.

Complications of induction:

OHSS:
Ovarian hyperstimulation syndrome (OHSS) can be life threatening. It is not unusual to experience mild symptoms of OHSS. Moderate to severe OHSS may result in cycle cancellation. Things to look for include:

  • Rapid weight gain
  • Nausea
  • Bloating
  • Abdominal and pelvic discomfort
  • Shortness of breath

The monitoring ultrasounds will help avoid OHSS as well as determining when the growing follicles are most likely to be mature.

For down regulation:

GnRHa:
GnRHa is used to block the pituitary function during ART. It is used to stop the function of the pituitary gland so it can not interfere the artificial treatment cycle. It starts on D2 or D21 of regular or progesterone withdrawal cycle. Inj suprefact (GnRHa) .5ml sc daily is given in long protocol for 14 days. It takes 2-3 weeks for complete down regulation. It is tested by doing USG and observing the endometrial and ovarian status. Emdometrium becomes thin and ovaries become acystic. Sometimes blood testing for E2 and LH is needed.

GnRH Antagonists
These medications directly block the effect of brain’s stimulation of the pituitary gland. They can usually be taken for a shorter duration than Lupron. Great care must be taken to avoid accidental ovulation and timing of the medication is crucial. When used properly, these medications can provide equal prevention of ovulation as Lupron. Pregnancy rates are fairly equivalent for between the agonists and antagonists.

For Luteal Support:

Human Chorionic Gonadotropin (hCG)
hCG has a chemical structure that is very similar to LH (luteinizing hormone) which triggers ovulation. hCG is also the hormone produced by pregnancies from the chorionic villi and placenta. It is used to minimize the deficient production by the chorionic villi.

Progesterone
Progesterone is produced by the corpus luteum in the ovary after ovulation. During the retrieval process in ART cycles some of the hormone producing cells are removed from the inside of the follicles. As an attempt to support the lining of the uterus and prepare for implantation, supplemental hCG or progesterone is usually used. This supplemental hCG can further stimulate hormone production in the ovary and worsen the symptoms of ovarian hyperstimulation. To avoid this undesired effect progesterone can be administered. There are several forms of progesterone available including vaginal suppositories, and injectable progesterone. Progesterone injections are usually continued until 10-12 weeks of pregnancy.