Principles and Practice of Controlled Ovarian Stimulation in ART 1st ed.

27. Luteinizing Unruptured Follicle

Pikee Saxena 

(1)

Department of Obstetrics and Gynecology, Lady Hardinge Medical College and SSK Hospital, J-36 Saket, New Delhi, Delhi, 110017, India

Pikee Saxena

Email: pikeesaxena@hotmail.com

Abstract

Ovulation, the most crucial event of the menstrual cycle, is dependent on an intricate balance between central and ovarian hormones, local growth regulators, enzymes, prostaglandins, steroids, and local connective tissue. Diagnosis of luteinized unruptured follicle (LUF) can be made by direct visualization of ovaries during laparoscopy, serial ultrasounds for follicular monitoring, and measuring peritoneal fluid/serum ratio of estradiol and progesterone during the second half of the cycle. The incidence of LUF seems to be significantly higher in women with unexplained infertility, endometriosis, and pelvic inflammatory disease and in women who have undergone prior ovarian surgery. The pathophysiology, diagnostic modalities, and therapeutic options have been discussed.

Keywords

Luteinized unruptured follicleUnexplained infertilityEndometriosis

27.1 Definition

Luteinized unruptured follicle (LUF) syndrome is defined as a failure of ovulation in which, despite the absence of follicular rupture and release of the oocyte, the unruptured follicle undergoes luteinization under the action of LH [1].

27.2 Introduction

The term luteinized unruptured follicle syndrome was coined by Jewelewicz in 1975 to describe the condition of infertile women with regular menstruation and presumptive evidence of ovulation without release of ovum. In this condition the egg may have matured properly, but the follicle either fails to burst or the follicle may burst without releasing the egg. In earlier attempts, the LUF was first created by using intrafollicular injection of indomethacin and PGF2alpha antiserum in experimental animals [1]. As compared to fertile women, LUF is more commonly observed in women with unexplained infertility, during ovulation induction by clomiphene citrate/hMG [23], endometriosis [45], pelvic inflammatory disease, and after previous ovarian surgery [2].

27.3 Pathophysiology

The mechanism or etiology of LUF is unclear. Many observations regarding etiopathogenesis have been postulated.

It has been observed that lower mean LH peak level occurs in LUF cycles as compared to normal ovulatory cycle [2]. The actual mechanism of attenuated LH response resulting in LUF may be explained as the final follicular maturation, and ovulation is a result of three distinct processes [6] that are dependent on LH:

1.

2.

3.

The threshold of LH for the first two steps is lower as compared to the third step of release of the follicle. Therefore, at blunted LH levels, luteinization of the granulosa cells and elevation of progesterone levels may occur without initiation of processes for the breakdown of the follicular wall resulting in trapped follicle.

During the menstrual cycle, cellular growth, differentiation, function, and degeneration of the follicles are under the influence of changing levels of pituitary gonadotropins and local regulators like estrogens, progesterone, prostaglandins, catecholamine, inhibin, and growth factors. One week prior to ovulation, the follicle enters its rapid growing phase when its diameter increases from below 12 mm to 21.8 + 3.2 mm on the day before ovulation when the steroid hormones and proteoglycans produced by the granulosa cells lead to increase in volume by increasing the intrafollicular colloid osmotic pressure.

Follicle-stimulating hormone (FSH) also stimulates the plasminogen activator to convert plasminogen to its active proteolytic form, plasmin. Plasmin then changes zymogen pro-collagenase to collagenase, which causes degradation of collagen for follicle extrusion. A large number of collagens are known, but the ones of interest in the ovary are the interstitial collagens (type I and III), present in the theca cell layers, and the basement membrane collagen (type IV), present in the basal lamina separating the granulosa from the theca layers. Breakdown of both classes of collagens results in a gradual digestion of the follicle wall, leading to the local protrusion of a conical bleb on the surface of the preovulatory follicle [6]. Enzymatic disorder inhibiting collagen degradation may prevent extrusion of the oocyte. It has been observed that protease inhibitors, which block plasminogen activity, may inhibit ovulation.

The ultimate ovulatory stimulus of LH is mediated by prostaglandins. Both prostaglandin E2 (PGE2) and PGF2alpha have been implicated in ovulation [6]. The preovulatory increase in follicular pro-collagenase is independent of prostaglandin production. As prostaglandin inhibitory drugs like indomethacin block ovulation, it has been observed that the activation of pro-collagenase may be prostaglandin dependent [611].

During ovulation induction with clomiphene citrate, hMG or pure FSH incidence of LUF is increased and it may recur in subsequent cycles [3]. During ovulation induction, multiple follicles may be induced which may result in relative deficiency of LH. It has been observed that hCG injection may increase the rate of follicular rupture in some cases although LUF may occur in spite of hCG stimulus.

Mild cases of endometriosis are commonly associated with LUF although the exact mechanism is not clear. Minimal or early endometriosis interferes with the process of ovulation and fertilization. It is postulated that prostaglandins, proteolytic enzymes, and cellular components such as macrophages and lymphocytes in the peritoneal fluid of patients who have minimal or mild endometriosis may individually or jointly affect the ovulation [4]. LUF may be a cause of infertility in endometriosis [5]. In mild endometriosis, women with pelvic inflammatory disease, and women with history of previous ovarian surgeries, the prevalence of LUF is higher and it may be recurrent as compared to other women. The cause of LUF in these women appears to be mechanical adhesion formation due to subclinical oophoritis, which prevents release of the oocyte.

Hyperprolactinemia associated with psychogenic or stress-related infertility might also be the cause of LUF syndrome [2] as it has been observed that about 30 % of patients conceive spontaneously during the time they are being investigated and few also conceive after they have stopped all treatments.

27.4 Diagnosis

The incidence of LUF varies and depends on the population chosen and on the method for diagnosing ovulation. The incidence of LUF as assessed by laparoscopy varies from 6 to 79 % and by ultrasound is approximately 57 % in unexplained infertility [2]. Incidence of LUF in the infertile patients as compared to fertile patients is 3–8 times greater [2]. Detection of ovulation is made on the basis of visualization of stigma during laparoscopy, serum progesterone levels, LH surge, rise in basal body temperature, and follicular monitoring through ultrasonography and through endometrial dating [2].

27.4.1 Laparoscopy

Direct laparoscopic identification of the ovulation point, the stigma, is used for the diagnosis of LUF. The stigma is clearly identified if laparoscopy is performed within 3–5 days of presumed ovulation. All sides of the ovary should be thoroughly inspected by double-puncture technique and after resting the ovary over the uterine surface. After this period the stigma is healed due to re-epithelization and may not be recognized in the corpus luteum even if the normal ovulation has taken place. However laparoscopic visualization of the stigma is subjective. For confirmation of ovulation, extended laparoscopy may be required to be done consecutively for several days, which make it inconvenient and impractical. It is observed that up to 50 % of patients with no stigma at laparoscopy may actually have ruptured the follicle based on the peritoneal fluid hormonal concentration [2].

27.4.2 Peritoneal Fluid Sampling

The limitations of laparoscopy in diagnosing LUF prompted the development of alternative ways to detect the failure of the follicle to rupture. It has been observed that at the time of ovulation, the peritoneal fluid/serum ratio for progesterone increases from 0.9 on day −2 to 56.4 on day +2 (P < 0.001) [24]. In the same period of the cycle, the estradiol peritoneal fluid/serum ratio increases from 0.7 to 6.3 (P < 0.001) [24]. These extreme shifts in the peritoneal fluid/serum ratios result from the discharge of the follicular content, with its high steroid concentrations, into the peritoneal fluid through the rupture in the follicle wall. Therefore, if rupture of the graafian follicle fails to occur, this should be reflected in the peritoneal fluid steroid levels and in the peritoneal fluid/serum ratios [12]. On comparing LUF with non-LUF patients, estradiol and progesterone levels in serum are similar. However, peritoneal fluid concentration of these steroids increases significantly in non-LUF patients [24].

27.4.3 Ultrasound

A reduction in follicle size, combined with the appearance of fluid in the cul-de-sac and changes in the pattern of the endometrium, is considered presumptive evidence of ovulation on ultrasound examination. Ovulation either results in complete disappearance of the follicle, a reduction in its volume with thickening of the follicle wall, or replacement of the follicle by an area of spongy appearance and a crenation pattern [1315]. Failure of the follicle to rupture is defined as continued growth up to 3 days after the dominant follicle has reached a mean diameter of 30 mm or until no further growth occurs for 3 consecutive days [1315]. Although serial ultrasonographic scans are fairly accurate in diagnosing LUF, some authors have made a confirmed diagnosis of LUF by aspirating the follicular fluid under transvaginal ultrasonography in which the degenerated oocyte mass was found [16].

27.5 Treatment

Since the cause of the LUF phenomenon is still not definite, no strict guidelines for treatment can be formulated. In most women with unexplained infertility, LUF represents a biological variable rather than a syndrome, and treatment should only be considered in women with frequent recurrence of LUF.

Marik and Hulka [17] reported that 28 patients with unruptured luteinized follicles at the time of laparoscopy and with no other obvious infertility factor were treated with ovulation induction agents clomiphene and hMG. Fifteen of these patients conceived subsequently. Injection of 5000 IU of hCG intramuscularly to support the natural LH surge may result in normal ovulation in patients with a central cause of LUF. For LUF occurring during ovulation induction cycles, increasing the dosage of hCG to 10,000 IU or addition of human menopausal gonadotropin (hMG) may be the treatment of choice.

Qublan et al. [1] conducted a study to determine the recurrence rates of LUF in three consecutive cycles during clomiphene citrate induction. The results of their study illustrate that the incidence and recurrence rates of LUF syndrome were increased significantly in consecutive cycles. Possible implication of clomiphene citrate in the etiology of the syndrome exists. In such cases, other options like hMG might be justified. However, LUF has been observed during ovulation induction with both clomiphene citrate and hMG. Martinez and coworkers [18] studied 303 cycles in 115 patients with regular ovulatory cycles. They induced ovulation to increase the chances of conception with clomiphene citrate (122 cycles) or hMG (82 cycles). Ninety-nine spontaneous cycles were monitored. LUF occurred in 1 % of spontaneous cycles, 4 % of clomiphene citrate cycles, and 5 % of hMG cycles. These patients respond well to in vitro fertilization as LUF may recur in subsequent cycles.

Bromocriptine is given at mid cycle, in case of transient hyperprolactinemia. Counseling of the patients may alleviate stress and reduce prolactin levels. For patients on nonsteroidal anti-inflammatory drugs, these drugs need to be avoided in the peri-ovulatory period, and for patients with endometriosis, pelvic inflammatory disease, and post-ovarian surgery with recurrent LUF, an early laparoscopic inspection followed by in vitro fertilization should be planned.

27.6 Conclusion

The luteinized unruptured follicle syndrome is a form of subtle, anovulatory infertility that cannot be diagnosed by traditional progesterone-dependent ovulation detection methods. Without the use of laparoscopy, steroid hormone concentration in the peritoneal fluid, or ultrasonography, the luteinized unruptured follicle syndrome may go unnoticed and the patient may be falsely diagnosed as ovulatory. The exact mechanism of infertility in LUF is not clear. LUF syndrome occurs statistically more frequently in women with unexplained infertility than in a control group of women. In the absence of standard protocols, different treatment regimens may be used depending on the characteristics of the patient with variable success rates.

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