Infertility: An Overview

The natural peak monthly fecundity rate is 35%, while the cumulative peak pregnancy rate after one year of trying to conceive is 85%, rising to 92% after 2 years, and 93% following 3 years.^1,2    Infertility affects 1 in 7 couples and is generally accepted to be defined by the absence of a live birth following 1 to 2 years of attempting pregnancy.³

Infertility is defined as a “failure to achieve a successful pregnancy after 12 months or more of regular unprotected intercourse”.⁴   Infertility may also be referred to as the inability to carry a pregnancy to the delivery of a live baby.⁵   Infertility varies across regions of the world and is estimated to affect 8 to 12 per cent of couples worldwide.^6,7   The WHO estimates of primary infertility in India are 3.9 per cent (age-standardized to 25-49 yr) and 16.8 per cent (age-standardized to 15-49 yr), using the “age but no birth” definition.⁸

ETIOLOGY

The causes of infertility are varied and complex. According to studies from around the world, both men and women are affected by infertility: about 40-60% of causes are linked to female factors, and 20-40% are related to male factors (Figure 1).

Initial Visit – Investigation and Counseling

It is very important to evaluate both the female and the male partner, as a diagnosis of infertility can be made only on the basis of the results of assessments of both partners.

Other than basic investigations like full blood count, urine analysis, papanicolaou smear, vaginal wet mount with appropriate culture, Rubella serology, Hepatitis B and C, HIV serology, and Chlamydia trachomatis serology, other investigations like semen analysis, detection of ovarian function by hormonal assay (early follicular FSH and LH levels, and mid-luteal progesterone), and evaluation of tubal patency by hysterosalpingography (HSG) should be done (Box 1).

Counseling plays an important role in the management of infertile couples. This supports psycho-social and emotional needs of infertile couples as well as their medical needs. The content of counseling may differ depending on the concerned couple and the existing treatment options. It usually involves treatment implication counseling, emotional support counseling, and therapeutic counseling. The couple needs to be given realistic information about their chances of having a live birth, as well as, the risks and costs of the management plan and its alternatives.

Evaluating male infertility

Fertility in men is dependent on normal functioning of the hypothalamus and pituitary gland (hormone producing glands in the brain), and the testes. Therefore, a variety of conditions can lead to infertility (Box 2).⁹   Infertility treatment in males includes various treatment regimens as outlined in algorithm 1.

Pharmacotherapy for the infertility treatment in men

Gonadotropin therapy

Infertility in men due to hypogonadotrophic hypogonadism is managed by hCG and hMG, which increases the sperm count within normal range in men with postpubertal onset hypogonadotrophic hypogonadism.

A recently conducted study demonstrated the influences of three different treatment strategies on biochemical parameters and testicular volume (TV) in patients with idiopathic hypogonadotrophic hypogonadism (IHH).¹⁰   This study compared the efficacy of hCG, testosterone enanthate and testosterone gel on 77 treated IHH patients. Results of this study demonstrated that hCG treatment resulted in favorable effects particularly on testicular volume and lipid parameters.

In one case series, it was suggested that gonadotropin (hCG and hMG) treatment may improve fertility (92%) in men with hypogonadotrophic hypogonadism.¹¹   A recently conducted study also demonstrated the efficacy of hCG and FSH in complete spermatogenesis following 12 months of treatment with gonadotropins.¹²

Anti-estrogens (clomiphene citrate)

Willets AE and colleagues conducted a review study to evaluate the efficacy and safety of clomiphene citrate in the treatment of male patients with infertility.¹³   In this review one study demonstrated the significant benefit on the pregnancy rate in the clomiphene group; however, the majority of other studies demonstrated a statistically significant increase in sperm concentrations. At doses used to treat male infertility, clomiphene was well tolerated with no identified serious adverse effects.

Evaluating female Infertility

In females, ovulatory disorders are the most important etiological factors of infertility. WHO has classified these ovulatory disorders as follows:¹⁴

Group 1: Hypogonadotropic hypogonadal anovulation/Hypothalamic-Pituitary failure –

This group accounts for approximately for 5-10% of anovulatory women and includes those with low or low-normal serum follicle-stimulating hormone (FSH) concentrations and low serum estradiol levels due to absent or abnormal hypothalamic secretion of gonadotropin-releasing hormone (GnRH). Examples include women with hypothalamic amenorrhea, and isolated gonadotropin deficiency. Treatment for this group of women has included GnRH, a hypothalamic hormone which, if given in pulses, induces the appropriate release of the pituitary gonadotropin hormones FSH and LH. Alternatively, women can be treated with gonadotropins.

Group 2: Eugonadotropic Euestrogenic Anovulation:

This group is the largest, including 75-85% of anovulatory women, and is characterized by normal serum FSH and estradiol levels and normal or elevated LH concentrations. The most common examples are women with polycycstic ovary syndrome (PCOS), some of which ovulate at least occasionally. Scarred ovaries as a result of extensive or invasive surgery for repeated ovarian cysts can prevent ovulation occurring.^15,16   These patients should also be screened for other causes of increased male hormones and also for metabolic disorders associated with the condition such as lipid profile abnormalities and diabetes. Treatment strategies in women with WHO Group II ovulation disorders, such as PCOS, include three established options. These options are the use of oral anti-oestrogens, the use of ovarian drilling and the use of injectable gonadotropins.

Group 3 : Hypergonadotrophic anovulation

This presents as diminished ovarian reserve initially. It is called as premature ovarian failure (POF) when menopausal state occurs before 40 years of age which requires certain test to assure general well-being of the patients. Most realistic chance to conceive for otherwise healthy patients with POF would be through oocyte donation.

Group 4: Hyperprolactinemic anovulation

This is considered as fourth and specific category which includes 5-10% of anovulatory women. Hyperprolactinemia has been proposed to block ovulation through inhibition of GnRH release. This is characterized by low or low-normal serum FSH and low serum estradiol concentrations.

Tubal factors

Prevalence of fallopian tube obstruction as a pathology is found in roughly 20% to 30% of infertile women.^17,18     The pathophysiology of tubal infertility includes adhesions, inflammation, cysts, polyps, hydrosalpinx, and/or scarring of the oviducts or fimbriae resulting from pelvic inflammatory disease (PID), a generalized constellation of upper reproductive tract disease; salpingitis; peritoneal infection, such as appendicitis with rupture or general peritonitis; and endometriosis. Rarely, congenital defects, such as maldescent or absence of fallopian tubes, are the cause of patency issues.

The most common cause of tubal infective damage is infection of genital chlamydia trachomatis, which is also the most common treatable sexually transmitted infection worldwide. Although, many infections with chlamydia cause few symptoms and may go undetected. Untreated chlamydial infection that moves up the female genital tract can cause pelvic inflammatory disease and scarring in the fallopian tubes, which can lead to tubal factor infertility.¹⁹

Endometriosis is a chronic condition characterized by the growth of endometrial tissue in areas other than the uterine cavity, most commonly in the pelvic cavity, including the ovaries. Endometrial deposits within the ovary are known as endometriomatas. Adhesions, inflammation, and distortion of the pelvic anatomy, in advanced cases of endometriosis, are responsible for mechanical infertility, but endocrine factors at work in early cases also are responsible factors (e.g., luteinized unruptured follicle syndrome, luteal phase defect). Approximately 20-30% of women with endometriosis have subfertility.

Pharmacotherapy for the infertility treatment in women

Clomiphene citrate

Clomiphene citrate induce gonadotropin release by occupying the estrogen receptors in the hypothalamus, thereby interfering with the normal feedback mechanisms, increasing gonadotropins and so stimulating the ovary to produce more follicles. Clomiphene is indicated as the initial treatment in the majority of women with amenorrhoea and oligomennorhoea. In women with irregular ovulation it seems to re-establish typical frequency of ovulation.

A review study was conducted to assess the effects of clomiphene citrate on ovulation and pregnancy in women with oligo-ovulatory subfertility demonstrated that efficacy of clomiphene citrate (at doses between 50 to 250 milligrams per day) as an effective method of inducing ovulation and improving fertility in oligo-ovulatory women.²⁰   To evaluate the efficacy of clomiphene citrate in women with unexplained infertility, a review was conducted on 5 studies.²¹   This review demonstrated that when compared to placebo, clomiphene citrate was associated with an increase in pregnancy rates. The odds ratio for pregnancy per patient was 2.38 (95% confidence interval 1.22 to 4.62). The odds ratio of pregnancy per cycle was 2.5 (95% confidence interval 1.35 to 4.62). This review analysis concluded that clomiphene citrate appears to modestly improve pregnancy rates in women with unexplained subfertility.

Women with World Health Organization Group II ovulation disorders (hypothalamic pituitary dysfunction) such as polycystic ovary syndrome should be offered treatment with clomiphene citrate (or tamoxifen) as the first line of treatment for up to 12 months because it is likely to induce ovulation.

Adjuvant and combination treatments

Although most properly selected women will ovulate in response to clomiphene treatment, many do not. Direct ovarian stimulation with exogenous gonadotropins is an obvious alternative treatment. But many CC resistant women respond supplemental or combination treatment regimens. Options include adjuvant treatment with glucocorticoids, exogenous human chorionic gonadotropin (hCG), metformin and preliminary suppressive therapy.

Aromatase inhibitors

These are basically used for the treatment of postmenopausal breast cancer, recently they have also been used in ovulation induction. However, their use in ovulation induction is controversial, primarily because they have not been approved for this purpose, and also the preliminary data suggested they might have significant fetal toxicity. Anastrazole and Letrozole are most commonly used aromatase inhibitors which act by blocking the estrogen production resulting in pituitary gonadotropin secretion that stimulates the ovarian follicular development. But as per the literature issued by the original discoverer, letrozole is embryotoxic and fetotoxic.

Exogenous Gonadotropins

These have been used to induce ovulation in gonadotropin deficient women and those who fail to respond to other, less complicated forms of treatment for nearly 50 years. They are highly effective. These are indicated in hypogonadotropic hypogonadism, CC resistant anovulation and also in unexplained infertility. These exogenous gonadotropins may be of urinary or recombinant type.

Human menopausal Gonadotropins- These are the most commonly used gonadotropins for ovulation induction. These have been used since 30 years, which is an extract from the urine of postmenopausal women containing equivalent amount of FSH and LH. Human menopausal gonadotropin is a purified extract which contains both LH and FSH.

Urinary FSH preparations (Urofollitriophin) – These are prepared by removing LH from urinary extracts.

For women with WHO Group I ovulation disorders, treatment with hMG, which includes FSH and LH, was reported to be more effective in improving ovulation than FSH alone.²²

Guidelines have recommended that Human menopausal gonadotropin, and FSH are equally effective in achieving a live birth when used following pituitary down-regulation as part of in vitro fertilization treatment.

Estrogen (Estradiol valerate)

Estradiol valerate is the most commonly used estrogens in endometrial preparation. Estrogen supplementation helps in preparing the endometrium for embryo implantation and its sustenance. Various studies have demonstrated the role of the estrogen in medical management of infertility as well as in assisted reproductions like IVF and IUI.

In assisted reproduction

GnRH antagonist is an integral part of assisted reproduction like IVF/ICSI cycles. This results in pituitary suppression and luteal phase deficiency with decline in serum E2 and progesterone 8 days after hCG administration for oocyte maturation. At the end of luteal phase serum estrogen levels drops. Hence estradiol supplementation may prove helpful during luteal phase of IVF cycles.

A retrospective observational study evaluated the relationship between endometrial thickness (ET) and outcome of medicated frozen-thawed embryo replacement (FER) cycles.²³    Patients included in this study were administered a daily dose of 6mg of oral E2 valerate on menstrual day 1, and P pessaries of 800mg daily for endometrial preparation. Results of this study showed that an endometrial thickness of 9-14 mm measured on the day of P supplementation is associated with higher implantation and pregnancy rates compared with an endometrial thickness of 7-8 mm and estradiol valerate was used to prepare endometrium for successful implantation (Figure.2).

In medical management of infertility

Estrogen supplementation has also shown benefits in endometrial preparation in women with ovarian dysfunction. According to a study conducted, addition of the exogenous estrogen to clomiphene citrate demonstrated favorable endometrial response in infertile women (PCOS). In this study patients who were administered estrogen along with CC showed increased endometrial thickness.²⁴   Adding exogenous estrogen to clomiphene citrate in ovulation induction regimens is a good strategy for maximizing pregnancy rates while reducing costs associated with serum hormone measurements, ultrasound examinations and repeated hCG injections.

Exogenous estrogen administration helps in increasing endometrial receptivity by increasing endometrial thickness in assisted reproduction as well as in medical management of infertility.

Protocols of gonadotropin use

Step-up protocol

The most common adverse effect associated with gonadotropin use is development of multiple follicles resulting in multiple pregnancies. This is thought to be result of failure to reproduce the precise dosage requirements which are normally maintained by feedback regulation.

In non-stimulated cycle, when estradiol levels increase, FSH is inhibited by the negative feedback mechanism, which allows the dominant follicle to grow while the subordinant follicles become atretic. Hence, this mechanism was tried in stimulated cycle. Initially, dosage of gonadotropins was increased every five days until an ovarian response was detected by urinary estrogen levels. This protocol uses chronic low dose gonadotropins administration to slowly stimulate the ovaries to produce one or a few follicles in each cycle. Gonadotropins are administered in increasing amounts until that threshold amount gonadotropins required for monofollicular development is reached. Once this threshold is reached it is maintained throughout the remaining cycle until the emerging follicle is ready for triggering for ovulation.

FSH therapy should begin at a dose of 75 IU daily. This dose should be increased after 7 days if no follicles ≥10 mm are seen and serum estradiol levels are <200pg/mL. Increments of 75 IU are then given weekly and once adequate follicle growth is documented, the dose should be maintained. hCG can be given once, one or two follicles have reached a diameter of 16-18mm, endometrial thickness is ≥7mm, and progesterone levels are 1 ng/mL.

This protocol introduces the right amount of FSH to correct the hormonal imbalance within PCOS ovary and allows ovulation of fewer follicles per cycle when compared to step-down protocol. This method allows for a safer, successful ovulation induction in these challenging PCOS patients. Thus, multifollicular development resulting in multiple pregnancies can be avoided in anovulatory women.

Step-down Protocol

The principal of Step-down protocol is based on activating pre-ovulatory follicles and limiting the number of growing follicles by decremental hormonal therapy. After surpassing the “FSH threshold” the serum-FSH is kept at a steady state above this level until follicle recruitment and dominance occur. This protocol is used for ovulation induction in oligoamennorheic PCOS patients and also in IVF patients especially in high responding patients.

FSH therapy at a daily dose of 150 IU is started 2-3 days after a spontaneous or progestin-induced bleed. This dose should be continued till a dominant follicle of ≥10mm in diameter is observed. The dose is then decreased to 112.5 IU daily for 3 days, followed by further decrease to 75 IU 3days later. This dose is continued until the day of hCG administration.

Combined clomiphene and gonadotropin protocols

Patients with previous history of cancelled IVF due to poor response, have responded well to the combined treatment regimen of clomiphene and gonadotropins. Benadiva et al conducted a study which demonstrated good results in 93 patients with poor response using similar protocol. Patients developed more oocytes and of better quality , that produced better pregnancy rate.²⁶

In another study which compared the efficacy of letrozole in combination with follicle-stimulating hormone (FSH) vs clomiphene citrate (CC) with FSH for ovarian hyper stimulation prior to intrauterine insemination (IUI), demonstrated increased number of follicles as well as better pregnancy rate with clomiphene and FSH combination regimen (Figure 4).²⁷

Ob/Gyn and fertility specialists

In infertility treatment the association of patient, gynecologists and fertility specialist plays an important role. To meet the reasonable expectations of the patient gynecologist and fertility specialist should act together to get best outcome. Fertility specialists have their role in assisted reproduction like IVF, IUI etc. Hence to determine reasonable expectations and optimal treatment course for the patient they both should work together.

Conclusion

Infertility has had a tremendous stigma attached, and in many ways the attitudes toward and perceptions of the infertile still exist today. It is important for all healthcare professionals to have a clear understanding of the many causes, risk factors, treatments, and psychological impacts of infertility in order to provide the best possible care to their patients. Gonadotropins and clomiphene citrate have proved their efficacy in successful management infertility with positive outcome. Clear understanding of the causes and their management play a significant role in effective treatment in males as well as females.

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