The success of CC for unexplained infertility is in direct relationship to the number of preovulatory follicles > 10–12 mm at the time of LH surge or hCG trigger [23, 24]. CC increases the number of preovulatory follicles . The number of preovulatory follicles ≥ 12 mm averaged 2.7 in CC–IUI cycles and 6.4 in COH–IUI cycles from three combined studies (Table 25.2). The average pregnancy rates per cycle, 10–12 % for CC–IUI and 16–24 % for COH–IUI were proportional to the number of preovulatory follicles. The rate of twin pregnancy was 10 % for CC–IUI and 20 % for COH–IUI, and triplet and higher order rates per pregnancy were also proportional to the number of follicles ≥ 12 mm.

There was no difference in implantation rates per larger follicle between CC–IUI and COH–IUI (Fig. 25.1b). In a retrospective study of 1333 CC–IUI cycles that also included 803 COH–IUI cycles and 594 CC + hMG − IUI cycles, the number of follicles ≥ 12 mm and implantation rate per follicle ≥ 12 mm remained constant in CC–IUI cycles (average 2.7) from age < 28 until age 41 [23]. In contrast, in COH–IUI cycles the number of follicles decreased from a mean of 7.3 before age 28 to 3.5 for ages 42–43 and was less than CC–IUI for women > 44 years. This study demonstrated that follicle number may be the most important predictor of outcome in age-matched patients. Those who develop two, four, six, or more preovulatory follicles in CC–IUI cycles have the same chance of becoming pregnant or having multiple pregnancies as patients who develop two, four, six, or more preovulatory follicles in COH–IUI cycles.

Serum estradiol levels in the late proliferative phase are significantly higher during CC cycles than during control cycles [26]. Serum estradiol levels on the day of hCG trigger parallel the number of follicles ≥ 12 mm and reflect granulosa cell quantity and possibly quality [23]. The average estradiol level on the day of hCG trigger was 613 pg/ml in 524 CC–IUI cycles and 1194 pg/ml in 60 COH–IUI cycles performed for unexplained or male factor infertility, but the estradiol level per follicle ≥ 12 mm was similar, 254 pg/ml per follicle in patients using CC and 278 pg/ml per follicle in patients using gonadotropins [27]. The implantation rate per follicle was doubled when estradiol levels were ≥ 400 pg/ml compared to ≤ 200 pg/ml in both groups.

One rationale for using CC in unexplained infertility and possibly an explanation of how it may work is that it increases mid-luteal phase progesterone levels. Several studies have shown that luteal phase deficiency, whether characterized by low peak progesterone levels, short luteal phase, or delayed endometrial development is corrected by CC [28–31]. In one randomized placebo controlled study, CC increased mid-luteal progesterone levels 66 % (from 43 to 71 nmol/l) and 3-month cumulative pregnancy rates 53 % (from 14.6 to 22.3 %) [7]. The definition of normal progesterone in the luteal phase is a subject of controversy since progesterone is secreted in a pulsatile fashion in relation to pituitary LH release. Wide fluctuations of serum progesterone levels are possible within the same patient depending on whether the blood is drawn during the peak or nadir of the pulse. Progesterone levels after hCG trigger and pregnancy should be more consistent since hCG has a longer half life than LH. Progesterone levels in the mid-luteal phase of spontaneous cycles that result in term pregnancies average 2200 ng/dL (22 pg/ml). According to this author’s experience, progesterone levels in the mid-luteal phase, less than 1800 ng/dL (18 pg/ml) are evidence of possible luteal insufficiency, levels less than 1500 ng/dL (15 pg/ml) are infrequently associated with ongoing pregnancy [32].

Progesterone levels in CC cycles that result in term pregnancies average 3700 ng/dL (37 pg/ml) [33, 34]. The increased progesterone levels in response to CC persist throughout the first trimester of pregnancy. During the first 6 gestational weeks (4 weeks postovulation) serum progesterone levels are 200–300 % higher in CC pregnancies than in natural cycle pregnancies [33]. After the sixth gestational week levels decrease gradually but remain 50–70 % higher than in natural cycle pregnancies through at least the 14th gestational week.

Serum estradiol levels average 66 % higher in CC than in natural cycle pregnancies during the first to second week postovulation and remain so until at least the 14th gestational week. The increases in estradiol and progesterone levels in CC pregnancies are accompanied by an average 25 % increase in uterine artery (UA) blood flow volume during the first 8 weeks of pregnancy [33, 34]. Crown rump length during the first 8 weeks in IVF pregnancies that resulted in a live birth is positively related to UA blood flow [35].

Endometrial thickness and pattern on the day of the spontaneous LH surge or hCG administration are associated with implantation success or failure [27, 36, 37]. Conception rarely occurs in CC and CC–IUI cycles when endometrial thickness is < 6 mm on the day of spontaneous LH surge or hCG to trigger ovulation (Table 25.3 [27, 37]). Estradiol receptor content in the endometrium is 45 % lower during the late proliferative cycle in patients using CC compared to controls [26]. Endometrial glands in biopsies from patients treated with CC are described as narrower, less tortuous than normal, and having a decreased gland-to-stroma ratio [37–39].

The effect of CC on the endometrium is paradoxical. Studies of the effect of CC on the mid-luteal phase endometrium are suggestive of both an antiestrogen effect and progesterone deficiency. In the early proliferative phase of CC cycles, average endometrial thickness is decreased compared to natural cycles whereas one day after the LH surge, endometrial thickness is increased compared to natural cycles [31, 40]. The thinner endometrium in the early and late proliferative phases and thicker endometrium in the luteal phase of CC cycles may be explained by the declining levels of CC at the level of the estrogen receptors in the endometrium and by the rising levels of estradiol displacing CC from those receptors .

The luteal phase endometrial pattern seen on ultrasound (US) during CC cycles is less likely to be totally hyperechoic and more likely to show a center stripe (triple line pattern) compared to controls [26]. Conception rates in CC cycles are highest in patients who retained a central lumen and less than 50 % hyperechoic pattern in the mid-secretory phase which suggests delayed transformation to a typical secretory phase pattern.

In patients who were switched from CC to TMX because of a thin endometrium, average endometrial thickness increased by 23 % despite the fact that estradiol levels were 32 % lower (Table 25.4).

Sperm penetration and passage through the mucus are necessary for conception to occur with intercourse . Alterations of cervical mucus during CC use have been identified in up to 60 % of cycles [41–48]. While the validity of a postcoital test (PCT) has been questioned, cervical factor infertility, diagnosed by the failure to find any motile sperm on a PCT performed 12–18 h after intercourse during the mid- to late follicular phase and repeated 1–2 days later if abnormal was identified as the primary cause for failure to conceive after three or more cycles of CC and timed intercourse in 39 % of patients referred for COH–IUI [49]. Less than 20 directionally motile sperm is associated with moderately decreased possibility of pregnancy in the same cycle. Less than 5 motile sperm or no motile sperm is associated with markedly decreased possibility of pregnancy in the same cycle [50]. In a randomized comparative study of the effect of CC and TMX on cervical mucus, quantity, viscosity, ferning, spinnbarkeit and cellularity were all significantly decreased in the CC group compared to controls, while quantity, viscosity, and spinnbarkeit were significantly increased compared to controls in the TMX group [48]. The number of directionally motile sperm decreased from 6.7 per high-powered field (hpf) in the control cycle to 3.2 in the CC cycle. An increase from 11.0 motile sperm/HPF in the control cycle to 12.2 in the TMX cycle was not significant. Other studies showed no difference between cervical mucous alterations with either CC or TMX [47, 51, 52] or a decrease in mucus score for TMX compared to placebo [53].

The hostile effect of CC on cervical mucus was unrelated to serum estradiol levels in cycles in which 150 mg CC was given cycle days 3 through 7 [54]. Another study found no difference in unfavorable cervical mucus scores in patients receiving CC doses of 50, 100, and 150–200 mg [55]. Based on these results, it would appear that the empirical use of supplemental estrogen and use of a lower dose of CC would have little effect on improving cervical mucus or poor sperm penetration. However, a dose of 25 mg CC, which would be approximately equal to 20 mg TMX, was not tested .

One approach to potentially improve cervical mucus in the face of unsatisfactory cervical mucus identified during a CC cycle is to start CC earlier. In women with regular ovulatory cycles, CC may be started on the third cycle day to obviate the antiestrogenic effects of CC which diminishes with each day after finishing the 5-day course of CC [16]. Other methods that have been evaluated in an effort to improve cervical mucus in natural as well as OI cycles are the use of guaifenesin and an alkaline douche [56, 57] .

Despite some differences of opinion, the consensus opinion is that sperm penetration of cervical mucus is significantly decreased in a large enough proportion of women who take CC that pregnancy rates may be less than expected. Although the value of a PCT has been questioned to identify cervical mucus–sperm interaction abnormalities, it could be argued that one should be performed during the first cycle of CC. Rather than perform a PCT to determine if IUI is needed, some practitioners choose to perform IUI in all CC cycles. Whether the slight additional cost and inconvenience to the infertile couple of performing a PCT to determine if performance or referral to a more costly and inconvenient IUI is indicated is a decision for the physician. Some clinicians reserve IUI for patients who fail to conceive after two or three CC cycles with timed intercourse .

Elevated BMI as well as ovulatory disorders in obese women have been implicated in infertility. Overweight women often need higher doses of CC to become pregnant. The dose of CC needed for conception was related to weight in a retrospective study in which CC was started at 50 mg for 5 days and increased by 50 mg each cycle until a satisfactory ovarian response was evident by both a biphasic basal temperature and a mid-luteal progesterone ≥ 2000 ng/dL, or conception occurred, to a maximum dose of 250 mg a day [34]. CC (100 mg) was used during the cycle of conception in 48 % of patients who weighed ≥ 90 kg (> 198 lb), 45 % who weighed 75–89 kg (165–197 lbs), 37 % who weighed 60–74 kg (132–164 lbs), and 31 % who weighed between 45–60 kg (100–132 lbs). Amounts of CC > 100 mg were used during the cycle of conception in 27 % of patients who weighed ≥ 90 kg (198 lb), 18 % who weighed 75–89 kg (165–197 lbs), 17 % who weighed 60–74 kg (132–164 lbs), and 11 % who weighed 45–60 kg (100–132 lbs).

Failure of CC to improve pregnancy rates may be due to the presence of other endocrine abnormalities, fertilization failure due to functional sperm or oocyte abnormalities, tubal dysfunction or cervical mucus abnormalities or other unidentified factors. Failure may also be due to improper timing of intercourse or IUI. Endocrine abnormalities that cause suboptimal ovulation may adversely affect mother or baby during pregnancy. TSH and fasting insulin and glucose in anovulatory patients and in selected ovulatory patients should be measured. Dehydroepiandrosterone sulfate (DHEAS), testosterone, and 17 OH progesterone should be measured for clinical evidence of excess androgen. If no or insufficient sperm are present in a well-timed PCT with a normal mucus specimen taken from within the cervical canal, IUI should be performed for up to three cycles. In order to achieve optimal results with CC and to avoid HOMP, US and hormone monitoring should be performed to find the lowest ovulatory dose of CC and to identify patients with ≥ 3 preovulatory follicles .