Research Paper on Infertility

Infertility is defined as the inability to conceive by a couple after one year of unprotected intercourse in women, with age less than 35 years or within six months for women aged more than 35 years1. Additionally, it is the most common gynecological problem affecting nearly 15% of couples worldwide.1 Additionally, the incidence of Infertility in India is 3.9-16.8 %.2   Moreover, the fertility of a couple depends upon several factors of which male factor accounts for 20%-30%, while a female factor is accounting for 40-55%. Also, combined, both male and female factor accounts for 10-40% cases of infertility. Additionally, unexplained infertility accounts for 10-20% cases of Infertility.1 Also, for the treatment of infertility both the partners have to be evaluated and appropriate treatment planned.

Furthermore, unexplained infertility is diagnosed when a complete evaluation of couple reveals no obvious cause, which is attributed to infertility. Also, it means that there is a normal ovulatory function, normal and patent fallopian tubes and also normal semen analysis of the male person3. Additionally, the complete evaluation of a couple has to be done before categorizing the couple with unexplained infertility. Also, the treatment modalities for unexplained infertility include superovulation, controlled ovarian stimulation followed by intrauterine insemination and in-vitro fertilization methods. Additionally, superovulation is the method by which concentration of female gametes is increased by using ovulation induction protocols1.

Types of Infertility

Primary infertility is the type of infertility in which there was no occurrence of previous pregnancy at all.1 On the other hand, secondary infertility is the type of Infertility in which previous pregnancy has occurred but not necessarily for a live birth.

Aims and Objectives

The study aims to compare the pregnancy rate using low dose human menopausal gonadotrophins with that of clomiphene citrate for ovarian stimulation in intrauterine insemination. Additionally, the primary objective is to assess the efficacy of low dose gonadotrophins on pregnancy rate and compare with that of clomiphene citrate. On the other hand, the secondary objective of the study is to identify the factors associated with efficacy of low dose gonadotrophins.

Review of Literature

Infertile couples treated with Intrauterine insemination have a greater chance of conception than timed coitus following ovarian stimulation. Evidence supports that Intrauterine insemination has a clear-cut advantage over natural cycles following ovarian stimulation. Pregnancy rate is between 8% -22% following ovulation induction and IUI.4 Additionally, numerous studies have shown that clinical pregnancy rate is higher with human menopausal gonadotrophin than Clomiphene citrate for ovulation induction followed by intrauterine insemination5.

The most commonly used protocol for controlled ovarian stimulation is Clomiphene citrate. Clomiphene citrate is cheaper and has a lower incidence of multiple pregnancies. Gonadotrophins have a comparatively greater incidence of ovarian hyperstimulation syndrome than Clomiphene citrate and are expensive than Clomiphene citrate. Intrauterine insemination combined with controlled ovarian hyperstimulation with human menopausal gonadotrophins has a higher incidence of pregnancy rates in cases of unexplained infertility and mild male factor infertility6. Additionally, it has also shown good results when used in patients with endometriosis. Using Clomiphene citrate ovulation induction was achieved in 42 -80% of cases, but the conception rate averaged up to 9-13 % only per cycle. This gap is attributed to the anti-estrogenic effects of the drug thinning of the endometrium, increased cervical mucus and luteal phase defect7.

Furthermore, more studies should be carried out to measure the efficacy of gonadotrophins over Clomiphene citrate combined with intrauterine insemination for clinical pregnancy rates. As such, all the other factors that contribute to the success of IUI needs to be studied. (8,9)

Unexplained Infertility

In this research, unexplained infertility was defined based on five primary criteria. The criteria were ascertained based on the normal semen analysis by WHO (2010) standards. These includes:

Sperm count more than 20x106 sperm/ml

Motility> 50% (Grade A or B, within 60 minutes of ejaculation)

Morphology> 50% normal forms.

Bilateral patent tubes based on hysterosalpingography and laparoscopy.

Normal ovulation as evidenced by regular menstrual cycles and mid-luteal serum progesterone levels > 10 ng/ml13

Mild Male Factor Infertility

It is defined with at least two of the following three criteria. First, a sperm analysis with 10-20 x106 sperms/ml. Second, 15% - 25% progressive motility and/or <20 million progressively motile spermatozoa in the ejaculate. Third, normal sperm morphology 30-50%20

Clomiphene Citrate

It is the most commonly used drug for ovulation induction in controlled ovarian hyperstimulation cycles. Clomiphene is chemically a non-steroidal triphenylmethanol derivative. It is an orally active drug. It is a combination of two isomers euclomiphene (=cis62%) and zuclomiphene (=trans 38%).

It has both estrogen agonist and antagonistic properties and acts depending on the existing levels of estrogen in the body. Additionally, it acts mainly as an anti-estrogenic agent. It has agonistic action only when endogenous estrogen levels are low. Enclomiphene is more potent isomer and is mainly responsible for ovulation induction property10. Additionally, clomiphene is cleared via the liver and excreted in stool with approximately 85% of administered dose is cleared within six days, and the rest may remain in circulation for months.

Mechanism of Action

It acts mainly by binding to the estrogen receptors due to structural similarity to estrogen. It typically binds to nuclear estrogen receptors for a prolonged period. It delays the replenishment of estrogen receptors and finally depletes the ER (Oestrogen receptors) thereby interfering with its normal process of recycling. The main action of clomiphene for ovulation induction is at the level of the hypothalamus. Hypothalamic ER depletion causes false interpretation of low levels of circulating estrogen levels11. Negative feedback trigger compensates and causes the release of a pulsatile Gonadotrophin-releasing hormone (GnRH).

Consequently, this stimulates pituitary gonadotrophins which in turn cause follicular growth and stimulation. It is particularly helpful in patients with an-ovulatory cycles. Clomiphene citrate has become the first line of management in treatment for ovulation induction in infertility patients. Several studies are done to conclude that ovulation induction with Clomiphene citrate followed by IUI has better pregnancy rates than timed coitus following controlled ovarian stimulation12. Hughes et al. (1996) in this study stated that Clomiphene citrate for ovulation induction is superior to expectant management in the treatment of unexplained Infertility13.

Human Menopausal Gonadotrophins

Another drug that is used in this study for ovulation induction is low dose human menopausal gonadotrophins. Various studies have been proved that use of gonadotrophins over Clomiphene citrate for ovulation induction has higher pregnancy rate when combined with intrauterine insemination. Despite the fact that multiple pregnancies and ovarian hyperstimulation are high, low dose gonadotropins are one of the potent drugs used for ovarian stimulation (14,15).

Structure of Gonadotrophin

Gonadotrophins are glycoproteins. They are heterodimers comprising of two subunits-alpha and beta. Among them, the beta subunit is hormone specific. Both the subunits are not covalently linked, but they are bound by a seat-belt region that wraps around the alpha subunit typically. This seatbelt region is the site for receptor binding. They act by stimulation of ovarian follicles thereby increasing the chances of follicular development.

In a study conducted by Brzechffa et al. (1998), it has been stated that clinical pregnancy rates of 23.9% were achieved by sequential treatment of Clomiphene citrate with Human menopausal gonadotrophins compared to Clomiphene citrate failed IUI cycles, in which pregnancy rate was only 5.9%. The overall fecundity rate was increased by the use of gonadotrophins when compared with Clomiphene citrate alone.16

In a study conducted by Manganiello et al. (1997), it was found that the conception rate per cycle with Human menopausal gonadotrophin following IUI is 6.6% when compared to that of clomiphene citrate (4.1%). Further, the relative rate of conception for Human menopausal gonadotropin versus Clomiphene citrate is 2.08% after adjusting for known risks for factors of infertility17.

In a study conducted by Peeraer et al. (1993), it has been concluded that pregnancy rates are higher in HMG (14.4%) induced cycles than that of Clomiphene citrate (9.4%). Further, there was a lower incidence of multiple pregnancies, less number of pre-ovulatory follicles, increased endometrial thickness and lower cancellation rate per induced cycle in HMG group18.

Moreover, Dickey et al. (1993) concluded in their study that fecundity per cycle of HMG alone is 18% when compared with that of clomiphene citrate which is 11%.18

Intrauterine Insemination

Intrauterine insemination is the method indicated for couples with unexplained infertility, mild male factor infertility, cervical mucus factor causing infertility, the presence of anti-sperm antibodies, mild to moderate endometriosis and other ovulatory disorders that have not responded to several previous cycles of ovulation induction19. It is considered that Intrauterine insemination increases fertility and fecundity in unexplained infertility and mild male factor infertility by increasing the density of gametes.

Furthermore, the quality of the sperms is increased by reducing the number of free radicals, lymphokines, and cytokines in the prepared sperm that is used for installation into the uterine cavity20. This procedure also bypasses cervical hostility factors that play a role in achieving pregnancy in ovulation induction cycles21. The prepared semen is instilled by using a soft catheter attached to a tuberculin syringe. Also, the success rate depends upon various parameters like- age of the patient, semen parameters, ovulatory function, uterine and tubal factors and hormonal profile of the patient. (22,23,24)

In a study conducted by Mahani et al. (2004), it was concluded that Intra-uterine insemination with superovulation has higher fertility rate in case of unexplained infertility and ovulatory disorders. Poor results were obtained when intrauterine insemination was done for natural cycles as compared to ovulation induction combined with IUI. It was also concluded in the study that Human menopausal gonadotrophin plus IUI had higher pregnancy rate than compared to natural cycle plus IUI and other ovulation induction protocols like Clomiphene citrate plus IUI and CC plus HMG followed by intrauterine insemination23.

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