Elisabetta Ricciarelli

Human intraovarian interleukin-1 (IL-1) system: highly compartmentalized and hormonally dependent regulation of the genes encoding IL-1, its receptor, and its receptor antagonist.

To delineate the scope of the human intraovarian IL-1 system we used a solution hybridization/RNase protection assay to test for expression of the genes encoding IL-1, its type I receptor (IL-1R), and its receptor antagonist (IL-1RA). IL-1 transcripts were not detected in whole ovarian material from days 4 or 12 of an unstimulated menstrual cycle but transcripts (IL-1 beta much greater than IL-11 alpha) were detected in preovulatory follicular aspirates from gonadotropin-stimulated cycles. Concurrently obtained peripheral monocytes did not contain IL-1 beta transcripts but macrophage-depleted follicular aspirates did, thus implicating the granulosa cells as the site of IL-1 expression. IL-1R transcripts were detected in RNA from whole ovaries and follicular aspirates but not in RNA from peripheral monocytes. IL-1RA transcripts were detected in whole ovarian material as well as in macrophage-free follicular aspirates. Cultured human granulosa and theca cells did not contain mRNA for IL-1 beta or IL-1RA but did contain mRNA for IL-1R. Treatment of cell cultures with forskolin (25 microM) induced IL-1 beta transcripts in granulosa but not theca cells. Forskolin also increased the basal levels of IL-1R transcripts in both granulosa and theca cells but did not induce IL-RA transcripts in either cell type. Taken together, these findings reveal the existence of a complete, highly compartmentalized, hormonally dependent intraovarian IL-1 system replete with ligands, receptor, and receptor antagonist.

The potential relevance of growth hormone to female reproductive physiology and pathophysiology

OBJECTIVE To assess possible interfacing between the somatotrophic and reproductive axes. DESIGN Literature review. MAIN OUTCOME MEASURES Ovarian growth hormone reception and action. RESULTS The available literature strongly supports a permissive role for the somatotrophic axis in the reproductive process. CONCLUSIONS Although a role for growth hormone in reproductive biology appears highly likely, its relevance to the process of puberty and to the normal workings of the menstrual cycle, as well as its possible application in reproductive pathology must await further investigation.

Blastocyst transfer and monozygotic twinning.

OBJECTIVE To report two cases of monozygotic twinning after IVF-blastocyst transfer. DESIGN Case report. SETTING Private practice in an assisted reproductive technology clinic. PATIENT(S) Two women treated with IVF-ET at the blastocyst stage. INTERVENTION(S) Pituitary down-regulation with luteal leuprolide acetate, ovulation induction with gonadotropins, IVF, sequential culture, blastocyst transfer, and P for luteal support. MAIN OUTCOME MEASURE(S) Levels of hCG, pelvic ultrasound examination, amniocentesis, obstetric follow-up, and cesarean section. RESULT(S) Two intrauterine monozygotic twin pregnancies occurred after IVF and blastocyst transfer. One of them was complicated by fetus-to-fetus transfusion syndrome and was delivered preterm by cesarean section; the other woman had a normal pregnancy and vaginal delivery. CONCLUSION(S) Monozygotic multiple gestations may be increased in IVF blastocyst transfers. The potential obstetric complications of this type of pregnancy should be discussed with patients.

Granulosa cell-derived insulin-like growth factor (IGF) binding proteins are inhibitory to IGF-I hormonal action. Evidence derived from the use of a truncated IGF-I analogue.

An increasing body of information now suggests that insulin-like growth factor (IGF) binding proteins (BPs) may serve as antigonadotropins at the level of the ovary. It is the objective of the present communication to evaluate the functional role of endogenous (granulosa cell-derived) IGFBPs by exploiting the unique properties of des(1-3)IGF-I, a naturally occurring IGF-I analogue characterized as a weak ligand of IGFBPs but not of type I IGF receptors. Given IGFBP-replete circumstances, des(1-3)IGF-I proved more potent (10-fold) than its intact counterpart in promoting the follicle stimulating hormone (FSH)-stimulated accumulation of progesterone by cultured rat granulosa cells. In contrast, des(1-3)IGF-I proved virtually equipotent to the unmodified principle under IGFBP-deplete circumstances. Taken together, these findings are in keeping with the notion and that the apparently enhanced potency of des(1-3)IGF-I (under IGFBP-replete conditions) is due to its diminished affinity for endogenously generated IGFBPs and that rat granulosa cell-derived IGFBPs are inhibitory to IGF (and thus inevitably to gonadotropin) hormonal action. Accordingly, the reported ability of gonadotropins to attenuate IGFBP release by granulosa cells may be designed to enhance the bioavailability of endogenously generated IGFs in the best interest of ovarian steroidogenesis.

Triggering ovulation with gonadotropin-releasing hormone agonist in in vitro fertilization patients with polycystic ovaries does not cause ovarian hyperstimulation syndrome despite very high estradiol levels

OBJECTIVE To determine whether inducing ovulation with a GnRH agonist in patients with polycystic ovaries (PCO) would permit oocyte retrieval without the burden or risk of cancellation, coasting, or ovarian hyperstimulation syndrome (OHSS), thus maintaining pregnancy rates by allowing embryo cryopreservation for transfer in a subsequent cycle. DESIGN Retrospective observational study. SETTING Private institution. PATIENT(S) Forty-two women who had previously experienced a controlled ovarian hyperstimulation (COH)/IVF cycle that had to be cancelled because of an elevated risk of OHSS. INTERVENTION(S) Forty-two PCO patients with a previous cancelled IVF cycle were assigned to a second controlled ovarian stimulation with recombinant FSH (75-150 IU/day) + GnRH antagonist (0.25 mg/day). Embryos were cryopreserved and transferred in a later cycle. MAIN OUTCOME MEASURE(S) OHSS, oocyte retrieval, and pregnancy rates. RESULT(S) In the first COH, the cycle had to be cancelled to avoid OHSS because E(2) serum levels were above safety levels (4809.6 +/- 2947.7). However, in the second cycle (ovulation triggered with a GnRH agonist) and independent of E(2) serum levels (4518.5 +/- 2118.85), all PCO patients eventually completed oocyte retrieval and frozen ET. With regard to pregnancy rates, 33% of patients receiving a transfer of a previously frozen embryo were successful. No patient developed OHSS. CONCLUSION(S) Triggering ovulation with a GnRH agonist followed by embryo cryopreservation allows PCO patients to complete a COH/IVF cycle with no cycle cancellation, coasting, or OHSS and, finally, to attain good pregnancy rates.

No room for cancellation, coasting, or ovarian hyperstimulation syndrome in oocyte donation cycles

We retrospectively studied 429 IVF donor cycles in which ovulation was triggered with either hCG (175 cycles) or GnRH agonist (254 cycles). Of the donors in whom ovulation was triggered with hCG, 3.2% developed symptoms of moderate (2.2%) or severe (1%) ovarian hyperstimulation syndrome, while none of the IVF donor cycles that were triggered with the GnRH agonist presented ovarian hyperstimulation syndrome, needed coasting, or were cancelled.

Rat ovarian insulin-like growth factor binding protein-4 : A hormone-dependent granulosa cell-derived antigonadotropin

Objective: To assess the in vivo regulation of ovarian insulin-like growth factor binding protein-4 (GFBP-4) mRNA expression by gonadotropins and estrogen. Methods: Whole varian RNA, obtained from two models of follicular development, was extracted and analyzed by Northern blotting. Immature rats were treated with pregnant mare senum gonadotropin (PMSG) followed 48 hours later with hCG, or alternatively were hypophysectomized and treated with FSH and/or diethylstilbestrol (DES). Localization of IGFBP-4 expression was assessed in the former study by in situ hybridization. Finally, the ability of human IGFBP-4 to antagonize FSH-stimulated progesterone accumulation was assessed in vitro. Results: The ovarian content of IGFBP-4 transcripts increased threefold (P < .05) at 12 hours after PMSG but was near baseline at 24 and 48 hours. The abundance of IGFBP-4 mRNA increased (P < .05) again at 6 and 24 hours after hCG. The expression of IGFBP-4 was localized to granulosa cells of prenatral (untreated) and small antral (12 hours after PMSG) follicles. No IGFBP-4 expression was noted in large (gonadotropin-primed) antral follicles. Hypophysectomy increased (P < .05) the ovarian content of IGBP-4 mRNA by 1.5-fold, an effect further enhanced (1.8-fold; P < .05) by the provision of FSH and DES. In vitro studies revealed the ability of increasing concentrations (0.01-1 μg/mL) of recombinant human IGFBP-4 to inhibit the FSH-supported accumulation of progesterone. Conclusion: Increased expression after administration of PMSG, hCG, and FSH/DES suggests that IGFBP-4 is a dynamic and hormonally responsive component of the ovarian cycle. The lack of expression in preovulatory follicles and its antigonadotropic actions in vitro imply that the attenuated expression of IGFBP-4 may constitute a requirement for successful follicular maturation.

The Ovarian and Testicular IGF-I System: A Comparative Analysis

As the significance of putative intraovarian regulators becomes increasingly recognized, much of the attention centers on insulin-like growth factors (IGFs). Indeed, a large body of evidence now suggests the existence of an intraovarian IGF system complete with ligands, re-ceptors, and binding proteins (Adashi et al. 1985c). More importantly, IGFs have been shown to exert a variety of significant effects in murine (Adashi et al. 1985a,b,d; 1986b; Bicsak et al. 1986; Cara and Rosenfeld 1988; Davoren et al. 1985; Magoffin et al. 1990; Zhiwen et al. 1987), porcine (Baranao et al. 1984; Maruo et al. 1988; May et al. 1988; Veldhuis and Demers 1985; Veldhuis and Furlanetto 1985, Veldhuis et al. 1986a, b; Veldhuis et al. 1987; Veldhuis and Rodgers, 1987; Veldhuis and Gwynne 1989), and human (Erickson et al. 1989, 1990; Steinkampf et al. 1988) somatic ovarian cells, thereby raising the possibility of a meaningful in vivo role.