John K. Findlay

Release of Luteinizing Hormone by Oestradiol-17β and a Gonadotrophin-Releasing Hormone in Ewes Affected with Clover Disease

Sheep grazing the oestrogenic varieties of subterranean clover ( Trifolium subterraneum L.) exhibit an irreversible loss in fertility that has been associated with changes in the mec

Effect of Progesterone on the Release of Luteinizing Hormone Induced by a Synthetic Gonadotrophin-Releasing Factor in the Ewe

A synthetic decapeptide (Gn-RH) structurally identical to ‘ovine LH-releasing hormone’ was given by intra-carotid infusions (0, 0.5 and 1.5 µ g/h for 3 h) to two groups of ewes late

A randomized study of the effect of mifepristone alone or in conjunction with ethinyl estradiol on ovarian function in women using the etonogestrel-releasing subdermal implant, Implanon®

BACKGROUNDnMifepristone alone or in combination with ethinyl estradiol (EE) can effectively stop an episode of uterine bleeding in women using the etonogestrel-releasing contraceptive implant, Implanon® but could impair contraceptive efficacy.nnnAIMnTo examine the effects of administration of mifepristone alone or with EE on ovarian function and cervical mucus consistency in women using Implanon.nnnSTUDY DESIGNnWomen using Implanon were randomized to mifepristone 25 mg twice daily on day 1 plus placebo 1 daily for 4 days or plus EE 20 mcg daily for days 2-5. Measurements of serum estradiol (E(2)), progesterone (P(4)), luteinizing hormone (LH), follicle-stimulating hormone (FSH), cervical mucus examination and maximal follicle size (by vaginal ultrasound) were carried out at various times.nnnRESULTSnFollowing mifepristone intake, there was a dramatic increase in E(2) levels ranging from 543 to 1183 pmol/L (p=.000), which was not correlated with maximal follicle size or preceded by LH or FSH increase. The increase in E(2) triggered an LH increase resulting in development of a luteinized follicle in four women with no evidence of ovulation. One of these women had estradiol and progesterone levels suggestive of ovulation, but no corpus luteum was seen. Almost all women had very low mucus scores, which did not correlate with E(2) levels.nnnDISCUSSIONnDespite a transient increase in E(2) levels after mifepristone, there was no evidence of subsequent ovulation irrespective of whether they also received EE. The mechanism by which mifepristone in the presence of etonogestrel results in a rapid increase in E(2) levels remains unclear and could not be related to any significant changes in FSH, LH, ovarian follicle dynamics or subsequent possible ovulation.nnnCONCLUSIONnPregnancy is very unlikely to occur if mifepristone and EE are given during use of Implanon to stop an episode of bleeding.

A critical role of Oct4A in mediating metastasis and disease-free survival in a mouse model of ovarian cancer

BackgroundHigh grade epithelial ovarian cancer (EOC) is commonly characterised by widespread peritoneal dissemination and ascites. Metastatic EOC tumour cells can attach directly to neighbouring organs or alternatively, maintain long term tumourigenicity and chemoresistance by forming cellular aggregates (spheroids). Cancer stem-like cells are proposed to facilitate this mechanism. This study aimed to investigate the role of Oct4A, an embryonic stem cell factor and known master regulator of pluripotency in EOC progression, metastasis and chemoresistance.MethodsTo investigate the expression of Oct4A in primary EOC tumours, IHC and qRT-PCR analyses were used. The expression of Oct4A in chemonaive and recurrent EOC patient ascites-derived tumour cells samples was investigated by qRT-PCR. The functional role of Oct4A in EOC was evaluated by generating stable knockdown Oct4A clones in the established EOC cell line HEY using shRNA-mediated silencing technology. Cellular proliferation, spheroid forming ability, migration and chemosensitivty following loss of Oct4A in HEY cells was measured by in vitro functional assays. These observations were further validated in an in vivo mouse model using intraperitoneal (IP) injection of established Oct4A KD clones into Balb/c nu/nu mice.ResultsWe demonstrate that, compared to normal ovaries Oct4A expression significantly increases with tumour dedifferentiation. Oct4A expression was also significantly high in the ascites-derived tumour cells of recurrent EOC patients compared to chemonaive patients. Silencing of Oct4A in HEY cells resulted in decreased cellular proliferation, migration, spheroid formation and increased chemosensitivity to cisplatin in vitro. IP injection of Oct4A knockdown cells in vivo produced significantly reduced tumour burden, tumour size and invasiveness in mice, which overall resulted in significantly increased mouse survival rates compared to mice injected with control cells.ConclusionsThis data highlights a crucial role for Oct4A in the progression and metastasis of EOC. Targeting Oct4A may prove to be an effective strategy in the treatment and management of epithelial ovarian tumours.

Production and Actions of Inhibin, Activin, and Follistatin in the Pituitary and Ovary

The overall aim of our research is to elucidate control of the production and mechanisms of action of inhibin (INH), activin (ACT), and follistatin (FS) in the pituitary and ovary. The broad hypothesis being tested is that, apart from the endocrine actions of INH on the pituitary, these substances exert autocrine or paracrine actions on the gonadotrophs in the pituitary and the follicular cells of the ovary to regulate follicle-stimulating homone (FSH) secretion and folliculogenesis, respectively. To test this hypothesis, it is necessary to demonstrate (a) that the cells of the pituitary and ovary are capable of secreting INH, ACT, and FS in a timely manner, and (b) that these substances can modify the functions of the target cells in a manner consistent with their roles in regulating pituitary and ovarian function. We also need to know the forms in which INH, ACT, and FS are secreted and measure the relative biological activities of these forms. To this end, we have concentrated on the following specific questions: n na. n nWhat are the relative biological activities of the high molecular weight (MW) forms of INH and ACT identified in biological fluids? n n n n nb. n nCan expression of the FS and INH-α and -β mRNA or protein be detected in pituitary and ovarian cells at times consistent with their proposed roles? n n n n nc. n nIs there a role for ACT in the acquisition of responsiveness of follicular granulosa cells to FSH during the early stages of folliculogenesis?

The effect of various steroids on corpus luteum function

n The effect of various steroids on corpus luteum function was investigated. The effect of d-norgestrel, R-5020, norethindrone, equilenin, megestrol acetate, estriol, and R-2323 was assessed by the effect on the progesterone secretion rate of the autotransplanted ovary of the ewe. Sheep with cervical ovarian autotransplants were used to facilitate infusion of the test compound directly into the arterial supply of the ovary and to allow progesterone secretion rates to be determined. Only 100mcg d-norgestrel/hour for 8 hours and 100 mcg R-5020/hour for 8 hours markedly suppressed progesterone ouput from the ovary.n