A naturally occurring genetic variant in the human chorionic gonadotropin-beta gene 5 is assembly inefficient.

The hCGbeta gene family is composed of six homologous genes linked in tandem repeat on chromosome 19; the order of the genes is 7, 8, 5, 1, 2, and 3. Previous studies have shown that hCGbeta gene 5 is highly expressed during the first trimester of pregnancy. The purpose of our study was to identify naturally occurring polymorphisms in hCGbeta gene 5 and determine whether these alterations affected hCG function. The data presented here show that hCGbeta gene 5 was highly conserved in the 334 asymptomatic individuals and 41 infertile patients examined for polymorphisms using PCR followed by single stranded conformational polymorphism analysis. Most of the polymorphisms detected were either silent or located in intron regions. However, one genetic variant identified in beta gene 5 exon 3 was a G to A transition that changed the naturally occurring valine residue to methionine in codon 79 (V79M) in 4.2% of the random population studied. The V79M polymorphism was always linked to a silent C to T transition in codon 82 (tyrosine). To determine whether betaV79M hCG had biological properties that differed from those of wild-type hCG, a beta-subunit containing the V79M substitution was created by site-directed mutagenesis and was coexpressed with the glycoprotein hormone alpha-subunit in Chinese hamster ovary cells and 293T cells. When we examined betaV79M hCG biosynthesis, we detected atypical betaV79M hCG folding intermediates, including a betaV79M conformational variant that resulted in a beta-subunit with impaired ability to assemble with the alpha-subunit. The inefficient assembly of betaV79M hCG appeared to be independent of beta-subunit glycosylation or of the cell type studied, but, rather, was due to the inability of the betaV79M subunit to fold correctly. The majority of the V79M beta-subunit synthesized was secreted as unassembled free beta. Although the amount of alphabeta hCG heterodimer formed and secreted by betaV79M-producing cells was less than that by wild-type beta-producing cells, the hCG that was secreted as alphabeta V79M heterodimer exhibited biological activity indistinguishable from that of wild-type hCG.

Progesterone:estradiol ratios at implantation in ongoing pregnancies, abortions, and nonconception cycles resulting from ovulation induction.

UNLABELLED: The purpose of this study was to compare progesterone (P):estradiol (E2) ratios after ovulation induction at the time of implantation in cycles resulting in ongoing pregnancies or abortions and in nonconception cycles. Material included 43 stimulated conception cycles, 29 with human menopausal gonadotropins (hMG) and human chorionic gonadotropins (hCG), 14 with clomiphene citrate (CC) with or without hCG, and 28 nonconception cycles (13 hMG and hCG, 15 CC with or without hCG). Midluteal P and E2 were measured and expressed in ng/mL. There were no differences in P:E2 ratios (mean +/- SE) for ongoing pregnancies after hMG and hCG (n = 20, 112.6 +/- 14.9), CC and hCG (n = 6, 97.0 +/- 15.9), or CC alone (n = 5, 96.2 +/- 25.5), and the data were pooled. Progesterone:estradiol ratios in 31 ongoing pregnancies and 28 nonconception cycles were 107.0 +/- 10.7 and 115.2 +/- 12.5, respectively, both significantly higher than in 12 abortions (64.5 +/- 13.2). IN CONCLUSION: (1) P:E2 ratios at the time of implantation were similar after CC with or without hCG and hMG and hCG treatment; (2) high luteal P:E2 ratio was associated with ongoing pregnancies; and (3) lower P:E2 ratio was seen in cycles leading to spontaneous abortion.

Human chorionic gonadotropin rise in normal and vanishing twin pregnancies.

OBJECTIVE: The purpose of the study was to describe and to compare the rate of rise of human chorionic gonadotropin (hCG) in vanishing twin and normally progressing twin pregnancies during the first trimester. DESIGN: All patients with twin pregnancies between 1985 and 1989 were prospectively studied. Human chorionic gonadotropin was measured one to three times per week between days 12 and 52 after luteinizing hormone (LH) surge or day of hCG administration (day 0). Pelvic ultrasound (US) was performed weekly beginning on day 24. SETTING: The study was performed at Rush-Presbyterian-St. Luke's Medical Center in an academic private practice setting of the Section of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology. PATIENTS: Forty patients who conceived after treatment of infertility and who had two gestational sacs on US examination were included in the study after the following criteria were met: (1) both sacs progressed to exhibit a fetal pole and (2) day of LH surge and/or day of hCG administration was known. MAIN OUTCOME MEASURE: The rate of rise of hCG was slower in vanishing twin pregnancies than in normally progressing twin gestations for the entire time period studied (P less than 0.05). RESULTS: A vanishing twin occurred in one third of the twin pregnancies. Forty-six percent of these losses occurred after fetal heart activity had been established. CONCLUSIONS: Vanishing twin phenomenon occurred in a large proportion of twin pregnancies in this infertility population. Fetal heart activity was not a reliable predictor of continuing fetal viability in early twin gestations. Vanishing twin conceptions were characterized by a slower rate of rise of hCG than normally progressing twin pregnancies.

Successful use of gonadotropin-releasing hormone agonist leuprolide for in vitro fertilization in a patient with polycystic ovarian disease and infertility unresponsive to standard treatment.

A patient with PCO and primary infertility had undergone numerous failed attempts of ovulation induction. She then was treated with GnRHa leuprolide 500 micrograms subcutaneously daily for 4 weeks, later combined with hMG 225 IU IM daily for 8 days and hCG 5000 IU IM. Six oocytes were retrieved for IVF, four fertilized and two were replaced. Twin pregnancy was established and delivered at term. Hyperstimulation syndrome was managed conservatively.

Occult ovulatory dysfunction in women with minimal endometriosis or unexplained infertility.

Characteristics of follicular development and hormonal patterns were evaluated in 17 women with minimal endometriosis and 11 with unexplained infertility. The controls were 7 women with male factor infertility and 8 who conceived during an investigational cycle. Women with minimal endometriosis had more and smaller follicles at luteinizing hormone (LH) surge, lower preovulatory estradiol (E2), and lower E2 at LH surge. Women with unexplained infertility had lower LH surges and a trend to a shorter follicular phase. Occult ovulatory dysfunction and may contribute to infertility in women with minimal endometriosis or unexplained infertility.

Endosalpingosis as a cause of chronic pelvic pain.

Endosalpingosis, a condition characterized by ectopic oviduct epithelium, is diagnosed histologically by the appearance of benign ciliated and nonciliated columnar cells in an abnormal location. Endosalpingosis is typically without symptoms. Our unusual case report shows symptomatic endosalpingosis first seen with chronic pelvic pain. Various aspects of this disease will also be discussed.

Early endocrine events in induced pregnancies.

Progesterone (P) and human chorionic gonadotropin (beta-hCG) levels were measured randomly or serially in 141 single clinical intrauterine pregnancies resulting from treatment of infertility. Seventy (group I) were conceived during spontaneous cycles, 36 (group II) with clomiphene citrate, and 35 (group III) with menotropins (hMG). Each group was subdivided into subgroup A (normal pregnancies) and B (pregnancies ending in abortion). Thirteen percent of patients in group I aborted, 19% in group II, and 31% in group III (P less than .05). The overall mean (+/- SD) P level in group IA was 25.8 +/- 10.3 ng/mL and in group IB, 16.6 +/- 9.9 ng/mL (significantly lower, P less than .001); in group IIA the mean P level was 37.8 +/- 21.9 ng/mL and in group IIB, 22.9 +/- 17.9 ng/mL, again significantly lower (P less than .01). In subgroups IB and IIB, 11 of 16 patients showed early abnormal beta-hCG patterns; these findings suggest defective embryonic development and/or deficient corpus luteum function as the cause of abortion. There was no significant difference between mean P in group IIIA (71.1 +/- 43.7 ng/mL) and IIIB (75.7 +/- 55.9 ng/mL). In group IIIB, the mean "peak" P level of 101.1 +/- 73.6 ng/mL was followed by a mean "nadir" of 35.4 +/- 24.8 ng/mL at 6-9 weeks. In group IIIB, 7 of 11 patients showed normal beta-hCG patterns. Three patients with precipitous P decline aborted karyotypically normal fetuses in spite of normally rising beta-hCG levels and the presence of fetal cardiac activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Transforming growth factor beta receptor expression in hyperstimulated human granulosa cells and cleavage potential of the zygotes.

A possible relationship between transforming growth factor beta receptor type I (TbetaRI) and type II (TbetaRII) protein expression in human granulosa cells and the quality of preimplantation embryo development in vitro was studied using immunoblot analysis of TbetaRI and TbetaRII in hyperstimulated granulosa cells and morphological assessment of the cleavage potential of the zygotes in vitro. Washed granulosa cells were collected from

Failure of elimination of paternal mitochondrial DNA in abnormal embryos.

Paternal mitochondrial DNA is normally eliminated from mammalian embryos. We have shown the presence of paternal mtDNA at the blastocyst stage in some abnormal human embryos.