Ovulation defects despite regular menses: Part III

OBJECTIVE: To describe subtle ovulatory defects that can contribute to infertility and/or miscarriage despite regular menses with apparent ovulation. METHODS: By using follicular maturation studies and measurement of serum estradiol, progesterone, and LH certain imperfections in the ovulatory process can be ascertained. RESULTS: Careful evaluation of follicular maturation was able to determine infertility factors, e.g., premature luteinization, luteinized unruptured follicle syndrome, and luteal phase defects. Effective treatment agents include follicular maturing drugs and gonadotropin releasing hormone antagonists in the follicular phase, human chorionic gonadotropins and leuprolide acetate at time of peak follicular maturation and progesterone in the luteal phase. CONCLUSIONS: Progesterone supplementation alone is more effective than follicle maturing drugs in women with luteal phase defects with mature follicles. Small doses of follicle stimulating hormone in the late follicular phase is most effective for luteal phase deficiency associated with immature follicles. Sometimes leuprolide acetate can allow egg release when hCG has failed.     

Ovulation disorders: Part II. Anovulation associated with normal estrogen

PURPOSE: To present various types of anovulatory states associated with normal estrogen and various treatment options. METHODS: Evaluation and treatment of various conditions including polycystic ovarian syndrome, hyperprolactinemia, congenital adrenal hyperplasia are discussed as are methods to prevent certain complications of these therapies. RESULTS: Clomiphene citrate seems equally effective to gonadotropins at least for the first three cycles but has a frequent complication of adversely affecting the cervical mucus so intrauterine insemination is frequently needed. Glucocorticoid therapy and insulin receptor drugs can exert a primary or more commonly an ancillary benefit when used in combination with other follicle maturing drugs. Complications, e.g., adverse cervical mucus, luteinized unruptured follicle (LUF) syndrome, premature luteinization, luteal phase deficiency and treatment options are presented. CONCLUSIONS: Vaginal progesterone can correct luteal phase problems, human chorionic gonadotropin (hCG) and follicle stimulation hormone (FSH) and gonadotropin releasing hormone (GnRH) agonists can help LUF syndrome and GnRH agonists and antagonists can help the complication of premature luteinization.     

The Luteinized Unruptured Follicle Syndrome: Anovulation in Disguise

The luteinized unruptured follicle syndrome is a form of anovulation and a subtle cause of female infertility. The syndrome cannot be diagnosed by traditional progesterone-dependent ovulation detection methods. Without the use of invasive procedures or sophisticated equipment, the luteinized unruptured follicle syndrome may go unnoticed. The patient diagnosed as ovulatory, on the basis of traditional ovulation detection methods, who does not conceive may be experiencing the luteinized unruptured follicle syndrome, and thus infertility. The syndrome's incidence, detection, etiology, and treatment are described.     

Comparison of various therapies for the luteinized unruptured follicle syndrome.

A study was initiated to evaluate the prevalence of the luteinized unruptured follicle (LUF) syndrome in a group of 355 women with infertility. The diagnosis was established by carefully observing daily sonograms along with measuring estradiol, progesterone, and luteinizing hormone (LH) levels. Two distinct types of LUF syndrome were identified: mature follicle LUF, in which release of an ovum was not demonstrated after a follicle attained maturity (serum estradiol reached 200 pg/mL while serum progesterone remained less than 2.5 ng/mL), versus premature luteinization LUF, where the serum progesterone increased above 2.5 ng/mL before follicular maturation was attained. The use of either hCG alone or hCG in combination with hMG in a single injection at the time of follicular maturation successfully corrected mature follicle LUF in 21 of 46 patients (46%), whereas ovulation-inducing drugs plus hCG or hCG and hMG corrected LUF in 24 of 25 patients (96%). Clomiphene citrate proved inferior to hMG in that it corrected LUF in 3 of 25 patients (12%) versus 12 of 22 patients (95%) who had undergone hMG therapy. Thus, hMG-hCG therapy is the most efficacious for mature follicle LUF, but because release can occur spontaneously on occasion by an appropriately timed single gonadotropin injection, one could offer the less costly options first. For premature luteinization, speeding up follicular maturation with gonadotropin therapy is effective. Upon failure of this technique, the more costly endogenous gonadotropin suppression followed by hMG can be employed.     

Luteinized unruptured follicle in the early stages of endometriosis as a cause of unexplained infertility.

OBJECTIVE: We attempted to clarify the relationship between luteinized unruptured follicle, which occurs in the early stages of endometriosis, and unexplained infertility. STUDY DESIGN: Seventy patients who had unexplained infertility were reviewed. RESULTS: Laparoscopic examination showed that 47 patients (67%) had endometriosis; of these, 40 (85%) had minimal or mild disease. The incidence of luteinized unruptured follicle was higher (p < 0.05) in patients who had endometriosis (35%/patient and 25%/cycle) compared with patients who did not have endometriosis (11%/patient and 7%/cycle). Degenerated oocyte cumuli were collected in 6 (43%) of 14 luteinized unruptured follicles diagnosed by transvaginal ultrasound. CONCLUSIONS: These results show that luteinized unruptured follicle is common in patients who have mild or minimal endometriosis and that it may be one of the causes of endometriosis-associated infertility. Transvaginal ultrasound-guided follicular puncture of luteinized unruptured follicle during the mid luteal phase may be useful in establishing a definitive diagnosis of luteinized unruptured follicle.     

Peritoneal fluid in female fertility and sterility (author's transl)

The authors have analyzed samples of peritoneal liquid to determine how and in which measure the level of steroid hormones allows to distinguish between follicular rupture and ovulation, and follicular luteinization without rupture and lack of ovulation. Volume of peritoneal fluid is not influenced by endometriosis or by pelvic varicosities, but it increases during the luteal phase; peritoneal protein concentration is also at its highest during the luteal phase. Progestin and estradiol-17 beta are higher in peritoneal fluid than in serum; such high concentration is maintained for at least a week after ovulation. The concentration of such hormones is higher in women with ovulatory scars than in those with luteinized unruptured follicle syndrome. Such findings show that peritoneal liquid is a transudate of the hyperemic active ovary, and that the level of concentration of progestin and estradiol-17 beta can be used in the diagnosis of luteinized unruptured follicle syndrome.     

Effect of indomethacin on the vascular architecture of preovulatory ovine follicles: possible implication in the luteinized unruptured follicle syndrome

Ovarian follicles sometimes fail to rupture and accumulate large quantities of fluid, yet undergo luteinization and form a steroidogenically competent luteal structure, the luteinized unruptured follicle syndrome. This condition can be mimicked in mammals by administration of indomethacin, an inhibitor of biosynthesis of prostaglandins. Blockade of ovulation by this drug is exerted at the follicular level. Ovulatory failure in sheep given a single intramuscular injection of indomethacin after induction of a surge of of luteinizing hormone was associated with follicular hyperemia as assessed by scanning electron microscopic examination of microcorrosion vascular casts and light microscopic quantification of follicular vascular space. The apical stigma of control (ovulatory) follicles was ischemic. The luteinized unruptured follicle syndrome appears to be the consequence of a chronic follicular inflammatory-like reaction involving inhibition of synthesis of prostaglandins.     

The efficacy of progesterone in achieving successful pregnancy: II. In women with pure luteal phase defects

Controversy still exists as to the proper therapy of luteal phase defects. Some advocate using drugs to improve follicular dynamics, e.g., clomiphene citrate, while others treat luteal phase defects with progesterone. The possibility exists that in some cases the luteal phase defect is secondary to failure to produce a mature follicle, the better drug then being an ovulation-inducing drug, e.g., clomiphene. However, if the follicle is mature, then progesterone may be the best treatment. We defined mature follicle as one between 18 and 24 mm while the serum estradiol (E2) level is over 200 pg/mL. The efficacy of exclusive P therapy was evaluated in 50 women, all with a minimum of 1 1/2 years infertility and with no obvious fertility problems other than luteal phase defect. Seventy percent of the women conceived within 6 months. The abortion rate was 14.7%. The average period of infertility was 2.8 years in the 35 patients who conceived within 6 months. These data suggest that determining the degree of follicular maturation by serum E2 and pelvic sonography plus excluding the luteinized unruptured follicle syndrome by pelvic sonography helps determine the proper therapy for luteal phase defect.     

Follicle growth curves and hormonal patterns in patients with the luteinized unruptured follicle syndrome

A prospective longitudinal and standardized study is presented, dealing with ultrasonographic and hormonal characteristics of the luteinized unruptured follicle (LUF) syndrome. Among 600 cycles monitored in 270 infertility patients, 40 cycles in 27 patients showed no evidence of follicle rupture, in spite of signs of luteinization, as reflected by basal body temperature recordings and progesterone determinations. In this study, 20 LUF cycles in 20 infertile patients were compared with 45 ovulatory cycles in 45 control women. During the follicular phase, no substantial difference in follicle growth was found, but after the luteinizing hormone peak, LUF follicles, instead of rupturing, showed a typical accelerated growth pattern. Both mean luteinizing hormone peak levels and midluteal progesterone levels were significantly lower in LUF cycles than in the control cycles. However, the duration of the luteal phase was not affected. Both central and local factors can be held responsible for the lack of follicle rupture. Ultrasound offers new possibilities as a noninvasive method in diagnosing the LUF syndrome.     

Subtle abnormalities in follicular development and hormonal profile in women with unexplained infertility

A prospective study of six unselected couples diagnosed as having unexplained infertility was done. In three of six patients, subtle abnormalities in follicular development were detected. In the first case poor follicular growth was observed. There was a premature small rise of luteinizing hormone (LH) with subsequent low levels of estradiol (E2) in the late follicular phase and unusual wide LH peak. This was followed by low progesterone levels in the luteal phase. In the second case follicular growth was abrupted by premature LH surge. This surge was triggered by early rise of E2 level while the follicle was still small in size. In the third case luteinized unruptured follicle syndrome was diagnosed, on ultrasound examination. All of the abnormalities were repetitive.     

Pregnancy results in in vitro fertilization in one case of luteinized-unruptured-follicle syndrome

Luteinized unruptured follicle syndrome can explain female infertility. The precise mechanism by which the ovulatory follicle fails to rupture is unclear. The following case reports a pregnancy result in in vitro fertilization (IVF). The first stimulation, a long IVF protocol with low FSH dose, was successful. Different methods used for detection and treatment are discussed.     

Oocyte retention after follicle luteinization

Indirect evidence supports the existence of the luteinized unruptured follicle syndrome in infertile women. To seek direct evidence of oocyte retention, infertile and normal women were studied in the early and midluteal phase by visual documentation of ovulation stigma, needle aspiration of ovarian follicles, and peritoneal fluid collection for estradiol and progesterone assay. Luteal phase was confirmed by endometrial biopsy (postovulation day 2 to 8). In normal control subjects (n = 16), 25% of test cycles were stigma-negative and no oocytes were recovered. In infertile group (n = 23), 43% of test cycles were stigma-negative. Five oocytes were recovered including one from a stigma-bearing follicle. Peritoneal fluid steroid levels failed to discriminate stigma-positive from stigma-negative cycles in either group. Oocyte retention after luteinization occurs in infertile women.     

Histologic and hormonal documentation of the luteinized unruptured follicle syndrome

Histologic and hormonal documentation of a luteinized unruptured follicle that occurred during a spontaneous menstrual cycle in a rhesus monkey is presented. Frequent (every 2 hours) blood sampling to assess midcycle hormonal dynamics in the monkey with the luteinized unruptured follicle and in five monkeys with an ovulatory stigma revealed significant aberrations in the gonadotropin and steroid hormone profiles associated with a luteinized unruptured follicle. Although the midcycle 17 beta-estradiol surge was normal, the monkey with the luteinized unruptured follicle demonstrated (1) blunted midcycle bioassayable luteinizing hormone, immunoassayable luteinizing hormone, and follicle-stimulating hormone surges; (2) absence of disparity in the bioassayable luteinizing hormone: immunoassayable luteinizing hormone ratio during the gonadotropin surge; (3) absence of progesterone and 17 alpha-hydroxyprogesterone secretion during the gonadotropin surge; and (4) delayed and blunted rise in progesterone and 17 alpha-hydroxyprogesterone after the gonadotropin surge. These findings suggest that an impaired luteinizing hormone surge, perhaps mediated by insufficient midcycle progestin secretion, is one possible cause of the luteinized unruptured follicle syndrome.     

Exaggerated prolactin response to thyrotropin-releasing hormone in infertile women with the luteinized unruptured follicle syndrome

Summary Ten cases of luteinized unruptured follicle (LUF) syndrome out of 250 women with unexplained infertility were detected on ultrasonography, giving a frequency of 4%. Hormonal analysis revealed lower serum progesterone levels at mid-luteal phase in LUF cases, suggesting a link between LUF syndrome and inadequate luteal phase. Prolactin response to thyrotropin-releasing hormone was exaggerated in LUF cases as compared with ovulatory cases. Aberrant prolactin release may be a contributory factor in the pathophysiology of the LUF syndrome.     

Opposite responses to the addition of leuprolide acetate to human menopausal gonadotropin therapy in two perimenopausal women

Leuprolide acetate was used to suppress the endogenous gonadotropins in order to prevent premature luteinization in two women under ovulation induction therapy. One patient had previously developed premature luteinization with clomiphene citrate, but consistently produced only one mature follicle with hMG therapy. However, when leuprolide acetate was started prior to hMG during an attempt for in vitro fertilization, it failed to stimulate even a mild rise in her serum estradiol. The other patient, who was not able to make a mature follicle with hMG alone because of premature luteinization, was enabled to make mature follicles with leuprolide therapy alone (without hMG). The exact mechanism for these totally different responses to leuprolide acetate in two perimenopausal women is not known.     

Partial follicular aspiration for salvaging an IVF cycle after improper hCG administration. A case report

BACKGROUND: Failure of oocyte retrieval during in vitro fertilization (IVF) is considered "empty follicle syndrome." Many theories have been postulated, some related to an underlying ovulatory disorder or premature oocyte atresia. As illustrated in this case and in a review of empty follicle syndrome at our institution, often it is related to improper administration of human chorionic gonadotropin (hCG). CASE: A 40-year-old woman underwent IVF for a 10-year history of unexplained secondary infertility. Two ultrasound-guided oocyte retrievals were performed 34 hours apart due to improper hCG administration prior to the first procedure. The number of oocytes successfully aspirated at the second retrieval, fertilization rate and pregnancy outcome were analyzed. Successful retrieval of 16 oocytes, all mature and fertilized, occurred subsequent to the second oocyte retrieval. No pregnancy was established with the fresh cycle. CONCLUSION: This case report supports the premise that an IVF cycle in which improper hCG administration occurs can be salvaged. After partial follicular aspiration, no ovulation or luteinization of the remaining follicles occurred because of continued suppression by the gonadotropin releasing hormone analog. It is critical to consider the possibility of improper hCG administration when facing failure of oocyte retrieval. The procedure should be terminated and hCG readministered, and a second retrieval should be performed 34 hours later.     

LUF-Syndrom

The luteinized unruptured follicle (LUF) syndrome is estimated to be present in 6–12% of cases of female subfertility. When ovarian stimulation is used the incidence rises to 20–25%. A LUF syndrome tends to return in subsequent cycles. Diagnosis is made by several ultrasound scans starting the day before the expected ovulation. Typical for a LUF syndrome is the missing follicle collapse. There may be different causes leading to a LUF syndrome. The data in this review lead us to the conclusion that a LUF syndrome really exists. In fertile women the prevalence is about 10%, which will not reduce the fertility potential. One should keep in mind the possibility of LUF syndrome in idiopathic infertility. The only possible therapy is IVF as long as no other treatment options are available, which also are addressed in this review.     

Follicle size by ultrasound versus cervical mucus quality: normal and abnormal patterns in spontaneous cycles

Ultrasound (US) has been demonstrated to be the method of choice for diagnosing luteinized unruptured follicle syndrome and to be a valuable adjuvant in the assessment of luteal phase defect. In this prospective study, the use of US with postcoital testing (PCT) is evaluated. Fifty control infertility patients were examined with serial US for follicle dynamics in conjunction with PCT. Standard curves for follicle dynamics versus cervical mucus quality (Insler score) were calculated. Eighteen patients referred for abnormal mucus underwent similar evaluation. Their follicle dynamics versus mucus quality were compared with those of the controls. The findings were: (1) there is a predictable relationship between follicle size and mucus quality, (2) the majority of patients with abnormal mucus have normal follicular dynamics, and (3) a minority of patients with abnormal mucus have either a narrow mucus window or abnormal follicular dynamics. In addition, US was found to be cost-effective in the overall fertility evaluation.     

Luteal cysts and unexplained infertility: biochemical and ultrasonic evaluation

A prospective, controlled study of ovarian function using ovarian ultrasound and daily plasma hormone estimations (estradiol, progesterone [P], follicle-stimulating hormone [FSH], luteinizing hormone [LH]) was carried out on 175 spontaneously cycling patients with unexplained infertility. Forty-one (23.4%) demonstrated luteal phase cyst formation. In 21 cycles the dominant follicle reduced in size after the LH peak (cystic corpus luteum cycles), and in 20 no shrinkage was seen (luteinized unruptured follicles). Progesterone concentrations in the early luteal phase were significantly reduced in the luteinized unruptured follicle cycles. Elevation in plasma FSH was seen in the early follicular and luteal phases of both cyst forming groups and may be due to disturbances in ovarian metabolism. Follicular rupture is important for efficient P release by the corpus luteum.     

Ultrasonographic assessment of luteinized unruptured follicle syndrome in unexplained infertility

Ultrasound can be used to monitor the growth and rupture of the dominant follicle. Thirty-three patients with unexplained infertility underwent serial sonography (mean, 3.2 scans/cycle) for luteinized unruptured follicle syndrome (LUFS). The incidence of LUFS was 9% (three patients) in the initial scan cycle. Three patients (9%) demonstrated rupture of a follicle significantly smaller than the mean (22.1 mm) (z less than 0.01) in the initial scan cycle. At standard radiology fees ($7000 +/ diagnosed LUFS) the cost/benefit ratio of this method of diagnosis will be controversial. It is suggested that scanning at reduced fees in the gynecologist's office, particularly in conjunction with postcoital tests, would decrease cost and increase the potential benefit.