Peter Kovacs, MD, PhD


September 07, 2005


I have a patient with subfertility of 5 years. Her menstrual cycle is regular at 29 to 30 days. On follicular tracking, however, we noticed that her follicle grows to more than 40 mm. This phenomenon occurred in 3 consecutive unstimulated cycles and resolves spontaneously at or around the 28th day. What is this condition, and how does one treat it?

Response from Peter Kovacs, MD, PhD

A menstrual cycle is divided into 4 phases: follicular phase, ovulation, luteal phase, and menstruation. An average cycle lasts 28 days, but cycles that last 21 to 35 days are considered normal. In general, variability in the cycle length is determined by the length of the follicular phase. The luteal phase typically lasts 14 days.

During the follicular phase, a cohort of follicles enters the last 2 weeks of their maturation process. This phase is controlled by predominantly follicle-stimulating hormone and luteinizing hormone (LH) as well as by local autocrine and paracrine factors. By Day 6 or 7 of the follicular phase, the dominant follicle is selected. The rest of the follicles in the cohort undergo atresia. The dominant follicle continues to grow, and when it reaches 22 to 24 mm in diameter it ruptures.

Ovulation is associated with significant hormonal changes, and the ovulatory process is primarily under the control of LH. The midcycle LH surge that leads to ovulation is induced when at least 150 pg/mL estradiol is produced for at least 48 hours. Prostaglandins and proteolytic enzymes weaken the wall of the follicle, resulting in its rupture. The cumulus-oocyte complex is released and enters the fallopian tube where the oocyte is ready to be fertilized. The granulosa cells of the dominant follicle luteinize, and the ruptured follicle forms the corpus luteum. The enzymatic activity of the granulosa cells changes as well and will favor progesterone production. The secretion of progesterone prepares the endometrium for implantation (secretory phase). If pregnancy does not occur, the activity of the corpus luteum declines, and when steroid hormone levels fall menstruation will follow.

Part of an infertility evaluation is the documentation of ovulation. When a woman has regular cycles, in 95% of cases it is the sign of regular ovulation. Most tests that are used to document ovulation do not actually confirm the oocyte release but document only the hormonal changes. The measurement of basal body temperature, changes in the cervical mucus, measurement of luteal phase progesterone level, and secretory changes as indicated by endometrial biopsy all reflect an increased progesterone production.

The actual rupture of the follicle and the release of the oocyte can be demonstrated during laparoscopy. Serial ultrasound studies can also be used to follow the growth of the follicle and its collapse following ovulation.

In a small percentage of women, the dominant follicle will undergo the luteinization process without rupture following the midcycle surge. As a result of the increased progesterone secretion, the endometrium undergoes the secretory changes, but, obviously, without the release of the oocyte pregnancy cannot occur. Hormonal studies, the basal body temperature curve, and the findings in an endometrial biopsy will all be consistent with ovulation. The cycles will follow each other regularly. This phenomenon is called the luteinized unruptured follicle (LUF). According to some studies, LUF is more common among women with endometriosis. Others question the existence of LUF. Laparoscopy has been used to check for ovulatory changes in the ovaries and therefore to establish the diagnosis of LUF. More recently, ultrasound monitoring with serial scans has replaced laparoscopy in the diagnostic process. The lack of follicle rupture and the lack of free peritoneal fluid around the time of ovulation are used to establish the diagnosis of LUF.

If ovulation does not occur on its own, hormonal induction may be attempted. Human chorionic gonadotropin (hCG) in doses of 5000-10,000 IU intramuscularly, or, more recently, 250 micrograms subcutaneously, can be administered to induce ovulation. When the lead follicle reaches 18-20 mm in diameter, the injection can be given. It takes about 36 to 40 hours for the oocyte to be released after the injection. Intercourse or insemination should be timed accordingly. Ultrasound can be used to document ovulation. If it still does not take place, the dose of the hCG injection can be increased. If ovulation still cannot be achieved even with the hCG injection, in vitro fertilization with the retrieval of oocytes could become the ultimate solution, but it seems to be a rather drastic step in the management of LUF.