Ovulation disorders due to stress, exercise, and eating or weight disorders are caused by abnormalities in the pulsatile secretion of hypothalamic gonadotropin releasing hormone (GnRH). Obesity (BMI ≥ 25) is a common cause of anovulation. It has been estimated that 50 % of women who are more than 20 % over their ideal weight will be anovulatory or have luteal insufficiency . Often a 9 kg (20 lb) or 5 % reduction in body weight is all that is required to restore ovulation and potentially fertility. Underweight (BMI < 18.5) due to voluntary caloric restriction and hypoglycemia are dietary disorders associated with suboptimal ovulation. Both disorders may be diagnosed by a 4 h glucose tolerance test. A return to fasting serum glucose level 1 h after ingestion of a glucose load indicates inadequate carbohydrate in the diet. It can be corrected by consuming a diet containing 200 plus grams of carbohydrates, the “carb up” diet employed by Marathon runners. A serum glucose level of 60 mg/dL or less 3–4 h after a 75 g glucose load indicates hypoglycemia, correctable by replacing sugar and fructose in the diet with complex carbohydrates contained in wheat, rice, and other grains.

Obesity is associated with insulin resistance, but many patients with incipient insulin resistance may have normal weight. Insulin resistance was the primary cause in 12 % of patients who failed to conceive after three or more cycles of CC-IUI Table 20.2. Evidence of excessive androgen (excessive body and facial hair, oily scalp, and in young women acne) are commonly present in insulin resistant women due to elevated IGF1 levels and acanthosis nigricans, a thickening and darkening of the skin on the back of the neck and inner thighs is pathognomonic for insulin resistance. Hyperinsulinemia, if left untreated can lead to hypertension and an increased risk of cardiovascular disease as well as gestational diabetes. Insulin resistance is considered to be one component of a condition formerly called syndrome X and now labeled metabolic syndrome. In addition to insulin resistance and obesity, the metabolic syndrome requires there to be three or more of the following: [3]

Laboratory findings in IR are: fasting insulin levels greater than 20 µU/mL, and a fasting glucose to fasting insulin ratio less than 4.5 [4]. The first line of treatment for women with borderline and mild IR should be weight loss. Metformin 500–1000 mg twice a day with meals is indicated for women with sub-optimal ovulation who continue to have elevated insulin levels after weight loss. Addition of CC is often necessary as these women often remain anovuatory [5] .

Congenital adrenal hyperplasia is an autosomal-recessive inherited enzyme defect that results in metabolic disorders and in the classical form (complete enzyme block) masculinization of newborn females, salt wasting, and potentially death if not diagnosed in a timely fashion. It is fortunately rare. A mild form of adrenal hyperplasia with onset at or following menarche, is variously labeled, late-onset, adult onset, acquired, partial, attenuated, or nonclassical adrenal hyperplasia. Clinical signs include: hirsutism, mild acne; increased scalp sebum, and possibly mild hypertension. The diagnosis is confirmed by 17-hydroxy P levels ≥ 200 ng/dL or DHEAS sulfate levels ≥ 180 ug/dL. ACTH stimulated levels of 17-OHP can also be used to differentiate mild forms with borderline baseline levels. Elevated DHEAS is more common in mild cases and can be measured first. Treatment for either defect is low dose corticosteroid (0.5 mg dexamethasone or 5 mg prednisone) daily at bedtime. The addition of CC is often necessary for ovulation.

Hypothyroidism was identified in 5 % of patients who failed to conceive after three or more cycles of CC-IUI (Table 20.2). Hypothyroidism and hyperthyroidism are associated with menstrual dysfunction, with hypothyroidism being more common. Thyroid stimulating hormone (TSH) levels less than 0.4 µU/mL are abnormal and indicate the need for additional studies to diagnose hyperthyroidism. Although TSH levels ≥ 4.5 µU/mL are generally accepted as diagnostic of subclinical hypothyroidism, many medical and reproductive endocrinologists consider TSH levels ≥ 2.5 µU/mL as abnormal and may contribute to ovulatory dysfunction. Hypothyroidism during pregnancy is linked to miscarriage and mental retardation in children. Patients with TSH levels ≥ 4.5 should be treated with levothyroxine (LTX) 50–75 mcg per day before attempting pregnancy. Treatment with LTX 25–50 mcg per day may be considered for anovulatory patients when TSH levels are between 2.5 and 4.5 µU/mL. While pregnant, patients with TSH levels ≥ 2.0 µU/mL should be retested monthly during the first trimester and again post partum. Newly pregnant patients already using LTX should have the dose increased by 20–50 % (at least 25 mcg) as soon as pregnancy is confirmed. TSH levels are approximately 30 % lower when measured while patients are fasting.

Mildly elevated prolactin levels < 35 ng/mL are not associated with unexplained infertility but may be secondary to hypothyroidism . Moderate elevation of prolactin above 35–100 ng/ml can be associated with abnormal folliculogenesis and luteal phase dysfunction. The incidence of hyperprolactinemia in an infertile population has been reported to be as high as 20 % [6]. Causes of mild to moderate increases in prolactin include antidepressant and antipsychotic medications, physical activity, stress, nipple stimulation, high carbohydrate meal, etc.; mildly elevated levels should be repeated early am and fasting.

A comprehensive semen analysis requires strict morphology by Kruger [7] criteria and is difficult to obtain from commercial and hospital or non specialty clinical laboratories. Until 1980, the standards for normal semen were those established by MacLeod and Gold in 1951, who analyzed the sperm counts of 1000 fertile and 1000 infertile men. They observed that 19 % of infertile men had counts of less than 20 million/ml compared to 8 % of fertile men [8]. On this basis they stated that men with sperm counts above 20 million/ml were fertile, and men with counts below that concentration were subfertile, even though they had not further stratified counts of less than 20 million. They proposed that a minimum of 50 million total sperm, 30 % “active” sperm and 55 % normal morphology were necessary for normal male fertility [9]. Although reports with lower thresholds were subsequently published by others and had been published previously, MacLeod and Gold’s values were used to define male infertility for the next 30 years.

In 1980, the WHO published new standards for normal semen parameters. These were 20 million per ml, 40 million total count, 50 % forward progression, and 30 % normal forms [10]. In the fourth edition of The WHO Laboratory manual for the “Examination of Human Semen and Sperm-Cervical Mucus Interaction” published in 1999, there were two important changes [11] (Table 20.3). The first was that the new reference value for normal motility could be either 50 % overall motility or 25 % rapid progressive motility (PM) within 60 min of ejaculation. The second was a new reference value for normal morphology of 15 % by strict Kruger criteria based on results of IVF studies [12]. When evaluated by strict criteria, sperm with 15 % or greater normal forms were observed to have normal fertilization capability in vitro. Sperm with 5–14 % normal forms had intermediate, and sperm with < 5 % normal forms had poor fertilization capability in vitro [12]. Significantly, Kruger arrived at his definition of normal from the shape and measurements of progressively motile sperm found in cervical mucus 9–12 h after coitus [7]. When evaluating semen analysis reports from commercial centers, hospitals, and non-specialty laboratories, it is necessary to know which WHO criteria is being used and to realize that these criteria are very likely to change again.

Initial fresh semen quality necessary for normal pregnancy rates in IUI cycles differs from the WHO standard for semen analysis with respect to concentration (count per ml), and total sperm count because the entire volume is used to prepare the insemination specimen, the sperm are placed directly into the uterine cavity and fallopian tubes bypassing the cervix. Based on semen analysis performed before preparation for timed IUI in 4056 spontaneous, clomiphene, or gonadotropin cycles, sperm criteria for pregnancy rates of ≥ 8 % per IUI cycle (threshold levels) were: 5 million sperm per ml, 10 million total count, 30 % progression motility, 5 million total motile sperm (TMS) and 5 % normal forms. (Table 20.4) [13]. Pregnancy rates per cycle were 2.5 % when values were lower than these threshold levels. Pregnancy rates were 50 % higher when the total count was more than 80 million, forward motility was greater than 50 %, or TMS were more than 40 million. Pregnancy rates did not increase when there were more than 5 % normal forms.