Infertility- And
all related treatments

INTRODUCTION

Infertility is a complex disorder with significant medical, psychosocial, and economic aspects. Great strides have been achieved in infertility therapy, particularly the development of assisted reproductive technology (ART).
Once the cause of infertility is identified, therapy aimed at correcting reversible etiologies and overcoming irreversible factors can be implemented. The couple is also counseled on lifestyle modifications to improve fertility, such as smoking cessation, reducing excessive caffeine and alcohol consumption, and appropriate frequency of coitus (every one to two days around the expected time of ovulation).
The patient should be involved in fertility treatment choices. These choices involve four major factors: effectiveness (eg, live birth rate), burden of treatment (eg, frequency of injections and office visits), safety (eg, risk of ovarian hyperstimulation and multiple gestation), and financial costs.

CONTRAINDICATIONS

The only absolute contraindications to infertility therapy are contraindication to pregnancy and contraindication to use of the drugs or surgeries used to enhance fertility. The ethics of restricting infertility therapy for other reasons, such as parental child-rearing ability, severe obesity, lifestyle issues (tobacco smoking, alcohol consumption), are controversial and beyond the scope of this review [2-4]. The parent's marital status, sexual orientation, and HIV status should not be used to deny fertility treatment.

OVULATORY DISORDERS

The World Health Organization (WHO) classifies ovulatory disorders into three groups.

• WHO class 1 – Hypogonadotropic hypogonadal anovulation is the least common, occurring in 5 to 10 percent of cases. Examples of women in this category are women with hypothalamic amenorrhea from functional etiologies such as excessive exercise or low body weight.
• WHO class 2 – Normogonadotropic normoestrogenic anovulation is the most common, accounting for 70 to 85 percent of cases. Women with polycystic ovary syndrome usually fall into this category.
• WHO class 3 – Hypergonadotropic hypoestrogenic anovulation occurs in 10 to 30 percent. Women with primary gonadal failure (previously called premature ovarian failure) or gonadal dysgenesis, comprise the majority of these cases.

Oligoovulation unrelated to ovarian failure can usually be treated successfully with ovulation induction; these women achieve fecundability nearly equivalent to that of normal couples (ie, 15 to 25 percent probability of achieving a pregnancy in one menstrual cycle) [7]. However, normal fecundability is achieved at the expense of an increased risk of multiple pregnancy.

The method of ovulation induction selected should be based upon the underlying cause of anovulation and the efficacy, costs, risks, and potential complications associated with each method as they apply to the individual woman. Options include:

• Weight modulation
• Clomiphene citrate
• Aromatase inhibitors
• Gonadotropin therapy
• Metformin or other insulin-sensitizing agents
• Laparoscopic ovarian diathermy
• Bromocriptine or other dopamine agonist (only in cases of hyperprolactinemia and anovulation)
• Assisted reproductive technology

Most of these approaches are effective for WHO class 2 patients. WHO class 1 patients respond best to therapy involving lifestyle modification or gonadotropins. Some WHO class 3 patients respond to gonadotropin therapy and in vitro fertilization (IVF), but those who fail require oocyte donation. A synopsis of these therapies is reviewed below; recommendations regarding the choice and dosing of first-line, second-line, and further therapy for ovulation induction according to WHO class are provided separately.

Weight modulation — Women who are far above or below ideal body weight are prone to ovulatory dysfunction and subfertility [8]. Weight modulation in these women can enhance fertility.

High body weight — Women with elevated baseline weight or body mass index (BMI) greater than 27 kg/m2 and anovulatory infertility are advised to lose weight. For obese women with polycystic ovarian syndrome (PCOS), the loss of just 5 to 10 percent of body weight is sufficient to restore ovulation in 55 to 100 percent of these women within six months. Weight loss is an inexpensive, low-intervention modality with no side effects and with other health benefits and thus should be a first-line treatment for obese anovulatory women.

A large, multicenter trial of obese (BMI ≥29 kg/m2) and infertile women reported no difference in rates of vaginally delivered term singletons at 24 months among women who received a six-month structured weight-loss intervention prior to infertility treatment and control women who went directly to infertility treatment [14]. In the trial, women who underwent a six-month lifestyle intervention to lose weight prior to fertility treatment were more likely to conceive spontaneously compared with control women (26 versus 16 percent). The women in the intervention groups also underwent fewer fertility treatment cycles compared with the control women (679 versus 1067 treatment cycles). However, weight reduction was not associated with increased fecundability, as the overall term singleton vaginal birth rates and live birth rates were the same between groups. In addition, there were no differences in the obstetric outcomes of gestational diabetes or hypertensive disorders of pregnancy between intervention and control groups. Study limitations include that target weight loss was reached by only 38 percent of women in the intervention group and the intervention discontinuation rate was 22 percent. It is not known if greater weight reduction per person, increased proportion of women reaching target weight loss, or increased patient continuation rates would increase fecundability. However, we continue to advise weight loss for infertile women with an elevated BMI because weight reduction appears to aid spontaneous conception and reduce the need for fertility treatment, in addition to providing long-term benefits for overall health.

Low body weight — Anovulatory women with low BMI (less than 17 kg/m2), with eating disorders, or strenuous exercise regimens, may develop hypogonadotropic hypogonadism and/or hypothalamic amenorrhea. Psychogenic stress may also disrupt the gonadotropin releasing hormone (GnRH) pulse generator and impair ovarian function as a result of reduced pituitary gonadotropin secretion. Such women should be advised to gain weight, modify diet, and reduce exercise; however, these women are often reluctant to alter their behaviors.
The importance of modifying suboptimal behavior was underscored in a randomized trial of women with functional hypothalamic amenorrhea [22]. These women were randomly assigned to either observation or 16 sessions of intrapersonal therapy that assessed eating behavior, nutritional intake, energy expenditure, exercise, and attitudes. The goal of therapy was to correct nutritional deficiencies, energy deficit, and problematic attitudes. Treatment was effective: ovarian function recovered in 87 percent of women who received therapy, but in only 25 percent of women who did not receive the intervention. However, as discussed above, women with eating disorders, other psychiatric conditions, or compulsion to excessive exercise are often unable to change these behaviors after just a brief exposure to counseling.
Patients with hypogonadotropic hypogonadism due to eating disorders or intensive exercise who do not respond to behavioral modification may conceive with pulsatile GnRH therapy [23]. Pulsatile GnRH therapy for ovulation induction has been approved by the FDA, but no pharmaceutical company makes it available in the United States at this time. This treatment is available in Europe.

Ovulation induction agents

Clomiphene — Clomiphene citrate is a selective estrogen receptor modulator (SERM) with both estrogen antagonist and agonist effects that increase gonadotropin release. It is an effective method of inducing ovulation and improving fertility of oligoovulatory women in WHO class 2 (normogonadotropic normoestrogenic ovulatory dysfunction). By comparison, clomiphene is often ineffective in WHO class 1 (hypogonadotropic hypogonadism) and class 3 (hypergonadotropic hypogonadism) patients.

Ovulation induction with clomiphene is reviewed in detail elsewhere.

Aromatase inhibitors — Anovulatory WHO 2 patients who have a poor outcome with clomiphene (no ovulation or thin endometrium) may have a better response with aromatase inhibitors. Advantages of these agents over clomiphene include (1) production of fewer follicles and lower estradiol levels, thereby decreasing the risk of multiple gestation, and (2) shorter half-life (50 hours versus 5 days), resulting in reduced antiestrogen effects on the endometrium and cervical mucus. In patients with polycystic ovarian syndrome, a multicenter randomized double-blind trial showed that letrozole was superior to clomiphene in inducing ovulation and live birth [24]. This topic is reviewed in detail elsewhere.
Aromatase inhibitors in combination with gonadotropins have also emerged as novel ovarian stimulants for performing IVF in women with breast cancer. A presumed advantage of ovarian stimulation with aromatase inhibitors is that the resultant peak estradiol levels are close to those observed in natural cycles.
The FDA has not approved aromatase inhibitors for treatment of infertility.

Gonadotropin therapy — Gonadotropin therapy is used in normogonadotropic (WHO class 2) anovulatory women who have not ovulated or conceived with clomiphene treatment and/or insulin sensitizing agents, and in hypogonadotropic (WHO class 1) anovulatory women with hypopituitarism or as second-line therapy in women with hypothalamic amenorrhea. In one trial of normogonadotropic anovulatory women who did not conceive with six cycles of clomiphene citrate therapy, subsequent treatment with gonadotropins was associated with an increased livebirth rate compared with continued treatment with clomiphene (52 versus 41 percent) [25]. However, compared with clomiphene, treatment with gonadotropins requires close hormonal and sonographic monitoring, is expensive, and typically carries a higher risk of multiple gestation. Dosing protocols, monitoring, side effects, and outcomes of gonadotropin therapy are discussed in detail elsewhere.