Elevated serum Chlamydia trachomatis IgG antibodies. What do they mean for IVF pregnancy rates and loss?

OBJECTIVE: To evaluate the impact of elevated serum Chlamydia IgG antibodies (Ab) on in vitro fertilization (IVF) outcome in a large infertility population. STUDY DESIGN: One hundred ninety-four women under 40 years of age undergoing a total of 316 IVF cycles were evaluated. All couples with positive serum Chlamydia IgG Ab were pretreated with doxycycline, 100 mg twice daily, for 10 days prior to the first IVF cycle. RESULTS: One hundred seven women (55.2%) had elevated serum Chlamydia IgG Ab. One hundred seventy-two IVF cycles (54.4%) were in patients with elevated Ab as compared to 144 cycles (45.6%) in controls with negative Ab. There were no significant differences in mean age, number of mature oocytes obtained or number of embryos transferred between the two groups. Patients with elevated IgG Ab had on ongoing pregnancy rate of 30.2% (52/172) and implantation rate of 13.5% (101/746) as compared to 34.7% (50/144) and 13.6% (88/649) in the negative Ab group, respectively (P = NS for both). Two ectopic pregnancies occurred in the elevated Ab group (1.2%, 2/172) vs. none in the negative Ab group. The incidence of early pregnancy loss was 8.7% (15/172) and 9.7% (14/144) in the positive and negative Ab groups, respectively (P = NS). CONCLUSION: The prevalence of elevated serum Chlamydia IgG Ab in patients presenting for IVF was higher than in the general population. In the absence of an active genital tract infection, the presence of elevated serum Chlamydia IgG Ab was not associated with a poor IVF outcome when couples were treated with antibiotics prior to stimulation. In addition, there was no correlation between IVF outcome and quantitative IgG Ab titers in women with elevated serum Chlamydia Ab. We recommend that all couples with elevated titers be treated with doxycycline prior to the first IVF attempt to optimize pregnancy rates and minimize infectious complications.

In-vitro fertilization outcome in women with hydrosalpinx.

Recent studies have suggested that the presence of hydrosalpinx has a negative effect on in-vitro fertilization (IVF) outcome, with markedly diminished implantation and pregnancy rates, and increased early pregnancy loss. We evaluated the impact of hydrosalpinx on IVF outcome in a large population with tubal factor infertility: 63 patients with hydrosalpinx and 60 without hydrosalpinx (no hydrosalpinx) underwent 103 and 89 IVF cycles respectively. Hydrosalpinx was diagnosed by hysterosalpingography and/or laparoscopy prior to IVF. Patients were further subdivided into those with or without elevated quantitative serum Chlamydia trachomatis IgG antibody (Ab) titres. All couples with elevated serum Ab titres (l: 16 or more) were treated with doxycycline (100 mg bid.) 10 days prior to the first IVF cycle. In all, 88 women (71.5%) had elevated C. trachomatis Ab: 47 women (74.6%) with hydrosalpinx had elevated titres, compared to 41 (68.3%) in the no hydrosalpinx group. There were no significant differences in mean age, number of mature oocytes obtained, and number of embryos transferred between the two groups. There was a trend for a higher implantation rate and ongoing pregnancy rate in the no hydrosalpinx group compared to the hydrosalpinx group (12.6 versus 9.8%, and 33.7 versus 24.8% respectively); however, this did not reach statistical significance. The incidence of early pregnancy loss was similar in the two groups. Two ectopic pregnancies were noted in the hydrosalpinx group compared to none in the no hydrosalpinx group. As expected, the prevalence of elevated titres of C. trachomatis IgG Ab in patients with tubal factor infertility presenting for assisted reproductive treatment was high. In contrast to recently published reports, our study did not confirm a negative effect of hydrosalpinx on IVF outcome when antibiotic treatment was given prior to assisted reproductive treatment. Prospective multicentre studies evaluating the effect of hydrosalpinx and its treatment on IVF outcome are needed.

The polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a multifaceted clinical entity the hallmark of which is ovulatory dysfunction associated with a relative luteinizing hormone excess and follicle-stimulating hormone (FSH) deficiency. Clomiphene citrate has been the first-line drug for ovulation induction in women with PCOS: because it is an attenuated estrogen, its action blocks the acyclic estrone effect in PCOS. However, many women fail to ovulate or conceive on clomiphene, and an appropriate agent for them was unavailable until relatively recently. The use of a "pure" FSH preparation, Metrodin, provides physiologic replacement of the deficient gonadotropin in PCOS; thus, Metrodin is the ideal second-line drug. Its use with a low-dose regimen should avoid the hyperstimulation seen with human menopausal gonadotropin in PCOS; spontaneous ovulation is an end point. Thus, PCOS patients who do not achieve pregnancy with clomiphene citrate have available a new, more physiologic approach to ovulation induction.

Pathological hyperprolactinemia suppresses hot flashes in menopausal women.

Hyperprolactinemia impairs pituitary-gonadal function in young women, but its effect in menopausal women is not known. The purpose of this report is to describe the effect of hyperprolactinemia on gonadotropin secretion and hot flashes in menopausal women before and after treatment with a dopamine agonist. We studied two such women with prolactinomas. Both had plasma LH and FSH levels in the range found in premenopausal women and no hot flashes. Treatment with bromocriptine was associated with normalization of plasma PRL levels, elevation of plasma gonadotropin levels, and the onset of menopausal hot flashes in both patients. We conclude that hyperprolactinemia can inhibit the augmented gonadotropin secretion that occurs in postmenopausal women and prevent hot flashes.

Life table analysis of intrauterine insemination pregnancy rates.

One hundred twenty-eight couples undergoing intrauterine inseminations were retrospectively reviewed. Life table methodology was used to analyze cumulative pregnancy rates and monthly fecundability. Respective 6- and 12-month cumulative pregnancy rates for each diagnostic group receiving intrauterine insemination were: cervical factor, 28.6% and 42.8%; male factor, 16.7% and 16.7%; female immune factor, 66.7% and 100.0%; male immune factor, 37.5% and 68.8%; and empiric treatment, 60.0% and 60.0%. There was no difference in pregnancy rates between sperm processed with a swim-up in Ham's F-10 or a two-gradient Percoll system. Abnormal sperm penetration assay results in patients with male factor did significantly (p = 0.05) lower the pregnancy rate. It is concluded that if no pregnancy has occurred after six cycles of inseminations, further workup or other treatment may be initiated, but additional pregnancies can be achieved from the seventh through the twelfth cycles of intrauterine insemination.

Oral contraceptives. Who, which, when, and why?

The risks of oral contraceptives are very small, and they cluster in a subset of users, although warning signs of cardiovascular complications must be heeded. The best choice of an oral contraceptive is one with an estrogen content of 30 to 35 micrograms. A greater (50 micrograms) content may be necessary if breakthrough bleeding or amenorrhea persists beyond a few treatment cycles. The starting date for the pill can be up to the sixth day of the cycle. Noncontraceptive benefits of the pill may include a protective effect against endometrial and ovarian malignancy, benign breast disease, and infection of the upper genital tract. Both the contraceptive and noncontraceptive benefits of low-dose combination oral contraceptives are desirable. They far outweigh the risks in women who require a high-efficacy, reversible contraceptive and who have no significant contraindication to use of the pill.

PIP: Prescription of oral contraceptives is reviewed by giving practical tips on the absolute contraindications, timing of the first dose, dose of estrogen, choice of type of progestin, reasons for changing the combination, and a list of benefits of oral contraceptives. The major risk in taking orals is cardiovascular disease, but actual risks are clustered in subsets of women. Those at high risk are women over 45, smokers over 35, and smokers of any age with cardiovascular risk factors. Generally women should start with a 30 or 35 mcg estrogen combined pill, and perhaps consider taking a higher estrogen dose if they experience breakthrough bleeding or amenorrhea. The 1st cycle can be started at any time up to 6 days after Cycle Day 1 or after spontaneous or induced abortion. Women taking bromocriptine should also begin contraception soon after delivery. Signs of potential major complications are abdominal pain, chest pain or dyspnea, headache or neurologic symptoms, visual or speech problems, or leg pain or weakness. Benefits of oral contraception include menstrual regulation, decreased menstrual flow, prevention of functional ovarian cysts, protection against ovarian and endometrial cancer by half, against benign breast disease, and possibly against pelvic inflammatory disease.

Comparison of urinary human follicle-stimulating hormone and human menopausal gonadotropins for ovarian stimulation in an in vitro fertilization program.

This report compares the effects of human menopausal gonadotropin (hMG) and purified urinary human follicle-stimulating hormone (hFSH) protocols in patients with irreparable tubal disease as the sole indication for in vitro fertilization-embryo transfer (IVF-ET). The hFSH protocol was associated with significantly more uniform folliculogenesis and more effective steroidogenesis than the one using hMG. In addition, the hFSH protocol showed a trend toward more oocytes per laparoscopy and more embryos per transfer than the hMG group, although the difference was not statistically significant. More oocytes in the hMG group were classified as immature when compared with the hFSH group (P less than 0.05). Pregnancy rates in both groups were not significantly different. An allergic drug reaction that occurred in one patient on the hFSH protocol is the first such reaction reported with hFSH in the literature. The hFSH protocol is associated with a trend toward parameters that correlate with improved success rates in the IVF-ET program.

Gonadotropins augment maturation and fertilization of human immature oocytes cultured in vitro.

The inclusion of hMG in the culture medium for immature human oocytes results in improved maturation and fertilization rates. The resulting increased number of conceptuses available for transfer may improve the incidence of IVF pregnancy.

Endometrial echo and its significance in female infertility.

The sonographic appearance of the endometrium was evaluated in 97 infertile women, 51 from a fertility unit (FU) and 46 from an in vitro fertilization (IVF) program. Three groups of patients were identified: those with normal findings, those with an incomplete endometrial echo, and those without any endometrial echo. Findings were correlated with the type of ovulation induction protocol, the peak estradiol level, and the number of successful pregnancies. In the IVF group, 72% of the patients did not exhibit normal endometrial echoes but had adequate estradiol levels, compared with 62% of the FU patients with normal endometrial echoes but significantly lower estradiol. The data suggest that IVF patients have a nonresponsive endometrium rather than inadequate estrogen stimulation and therefore that an endometrial abnormality may be an important cause of their infertility. Ultrasound may be used as a screening method to identify such patients.

Oxytocin in the corpus luteum of the cynomolgus monkey (Macaca fascicularis).

To determine if oxytocin (OT) is present in cynomolgus monkey corpus luteum, OT was measured by a specific and sensitive RIA in 13 corpora lutea, ovarian venous plasma on the ipsilateral side and peripheral venous plasma at different stages of the luteal phase. Serial dilution of acetic acid extract of the corpus luteum showed parallelism with standard OT in the RIA. Total content of OT in corpus luteum was 1.9 +/- 0.5 ng (mean +/- SEM) with a content of 0.4-0.8 ng in early luteal phase, 1.0-6.2 ng in midluteal phase, and 0.4-0.7 ng in late luteal phase. OT concentrations in corpus luteum were 21.0-75.2 ng/g wet wt in early luteal phase, increasing to 34.4-602.5 ng/g in midluteal phase; and declining to 3.4-117.4 ng/g in late luteal phase. OT concentrations per mg protein in the corpus luteum were 0.05-19.6 ng with peak concentrations of 14.7-19.6 ng/mg protein on day 22. Sephadex G-25 column chromatography of the corpus luteum extract revealed a single peak for binding activity similar to that of synthetic OT on the RIA. Ovarian vein blood from the same side as the corpus luteum had a significantly higher OT concentrations of 161.2 +/- 29.7 pg/ml on days 15-24 than 16.8 +/- 3.6 pg/ml on days 25-28 (P less than 0.01) and peripheral plasma OT levels of 23.2 +/- 3.4 pg/ml (P less than 0.025). Our findings indicate that OT is present and probably produced by monkey corpus luteum with peak OT concentrations found in midluteal phase. Thus OT may play a role in primate corpus luteum function.

Tubal pregnancy following late luteal vaginal hysterectomy.

A patient who had a vaginal hysterectomy performed on day 24-25 of her cycle by histological dating was found to have a ruptured left tubal pregnancy 55 days later. The patient used barrier contraception up to the time of hysterectomy, and an undetectable level of beta-HCG was noted the week prior to hysterectomy. The likelihood of delayed tubal implantation having occurred in the same luteal phase as the hysterectomy distinguishes this case from the 27 others previously reported, which are briefly reviewed.

Distinguishing the steroidogenic roles of granulosa and theca cells of the dominant ovarian follicle and corpus luteum.

In order to determine the relative contribution of granulosa cells and follicular fluid of the preovulatory follicle to ovarian and peripheral vein levels of principal steroids in the late follicular phase, as well as the importance of granulosa cells and theca cells in subsequent corpus luteum function, 32 rhesus and cynomolgus monkeys were studied. In group one (n = 10), they were bled from the femoral vein daily throughout the cycle and sera assayed for FSH, LH, estradiol, and progesterone. In addition, they were laparotomized in the late follicular phase when serum estradiol (by rapid assay) had exceeded 150 pg/ml for about 24 h. Ovarian vein blood was taken ipsilateral to the dominant follicle, followed by aspiration of follicular contents and rinsing of the antrum to remove as many granulosa cells as possible without disturbing the thecal layers. Also, blood from the contralateral ovarian vein was obtained, as well as a second collection from the ipsilateral ovarian vein 15 min after follicular aspiration; a second peripheral sample was obtained immediately thereafter. Ovarian vein asymmetry of estradiol, progesterone, and androstenedione, but not 17-OH progesterone, was noted in every case (i.e. higher steroid levels were associated with the putative dominant follicle). After follicular aspiration, high concentrations of estradiol, progesterone, and androstenedione in ovarian venous effluent fell (P less than 0.001) by nearly 70% from preaspiration levels; concurrently, peripheral levels of estradiol and progesterone were reduced by about 40%. Conversely, 17-OH progesterone was unaffected. Integrated progesterone levels throughout the subsequent luteal phase, but not serum estradiol, were significantly (P less than 0.001) less in the experimental monkeys (after aspirating/rinsing) compared to controls, although luteal phase length was unchanged (14.33 vs. 14.83 days). Groups two (n = 7) and three (n = 15) were employed to assess the influence of vascular trauma caused by either continuous cannulation or serial (up to six insults) venipuncture, on the concentrations of the principal ovarian steroids in ovarian vein blood.(ABSTRACT TRUNCATED AT 400 WORDS)

Antiestrogenic action of high-dose clomiphene in primates pituitary augmentation but with ovarian attenuation.

Since the dominant follicle is selected by days 5 to 7 of the menstrual cycle, we assessed the differential effects of high-dose clomiphene (25 mg daily) by giving 5-day courses either before (days 1 to 5), during (days 5 to 9), or after (days 9 to 13) emergence of the selected dominant follicle in monkeys. Peripheral sera were obtained daily and assayed for follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17 beta-estradiol (E2), and progesterone (P); serial laparoscopies were performed. Rather than enhancement of gonadotropin-dependent folliculogenesis during clomiphene treatment cycles, ovulation was delayed in 18 of 18 treatment cycles. Interestingly, the interval from treatment to next ovulation lengthened when clomiphene was given in the late follicular phase. Consistently, the clomiphene treatment cycles were characterized by a marked decline of the serum E2 during the 5 days of therapy, despite concurrent elevations of pituitary gonadotropins in circulation, especially FSH. These data suggest that a direct antiestrogenic effect of clomiphene imparted ovarian refractoriness to the prevailing, even enhanced, gonadotropin levels. The vulnerability of follicular maturation to these attenuating effects of clomiphene was greatest in the late follicular phase, well after the dominant follicle had been selected. Even after this clomiphene-induced ovarian hiatus and eventual resumption of new follicle growth, the initial apparent ovulation led to latent, severe corpus luteum insufficiency.

Asymmetric secretion of principal ovarian venous steroids in the primate luteal phase.

We have characterized the degree of asymmetry of ovarian steroid secretion in the luteal phase of the menstrual cycle in rhesus and cynomolus monkeys. Femoral blood levels of FSH, LH, progesterone, estradiol and 17-hydroxyprogesterone were determined. In addition, laparotomies were performed in the early, mid or late luteal phase to facilitate localization of the corpus luteum and collection of ovarian venus blood. We conclude that: 1) the ovary bearing the active corpus luteum contributes virtually all of the progesterone entering peripheral circulation in the luteal phase; 2) the ipsilateral ovary secretes more 17-hydroxyprogesterone one than the contralateral one, although both are active in the luteal phase; and 3) the asymmetrical secretion of estradiol was manifest only in the early and mid-luteal phase, with ovarian symmetry being reestablished in the late luteal phase.

Pulsatile pituitary gonadotropin secretion during maturation of the dominant follicle in monkeys: estrogen positive feedback enhances the biological activity of LH.

In the follicular phase of the menstrual cycle, pulsatile patterns of LH and FSH secretion in monkeys change during maturation of the dominant follicle. At the preovulatory surge, the most striking event is the prodigious elevations of bioassayable LH, rising up to 50-fold within 24 h. Principally, establishment of the surge is due to marked enhancement of the amplitude of LH secretory pulses. In contrast, LH and FSH measured by RIA enter, in parallel, the surge modes of secretion approximately 5 h later than bioassayable LH and rise more slowly; the B:I ratio may reach 10:1. This same disparity between bioassayable versus immunoassayable LH was induced in castrate monkeys under estrogen positive feedback stimulation. We conclude that the preovulatory estrogen surge promotes the secretion of an LH molecule(s) having enhanced biological activity.