Randy S. Morris

Endocrinology: Inhibition of ovarian-derived prorenin to angiotensin cascade in the treatment of ovarian hyperstimulation syndrome

The purpose of this experiment was to determine whether use of the angiotensin-converting enzyme (ACE) inhibitor, enalapril, would prevent the occurrence of ovarian hyperstimulation syndrome (OHSS) in the rabbit model. A total of 20 adult female New Zealand white rabbits were studied. All rabbits received 75 IU of human menopausal gonadotrophin s.c. each day for 7 days. On day 8, all rabbits received 2500 IU of human chorionic gonadotrophin (HCG). Ten rabbits were randomly chosen to receive enalapril orally. Five received 1 mg/kg of enalapril and five received 2 mg/kg of enalapril twice daily. The remainder received placebo orally twice daily. On day 10, all rabbits underwent surgical exploration. Total body weight was found to increase significantly in the placebo group (by 293 g, P < 0.001) but not in either group receiving enalapril. Haematocrit also increased significantly in the placebo group (by 3%, P < 0.013) but not in the enalapril groups. Ovarian weights were highest for the 2 mg/kg enalapril group (5.80 +/- 0.52 g), followed by the 1 mg/kg enalapril group (3.64 +/- 0.45), and least for the placebo group (2.69 +/- 0.17). All 10 placebo rabbits met criteria for severe OHSS whereas only six in the enalapril groups did. We concluded that angiotensin II may play a significant role in the development of weight gain, third space fluid accumulation and intravascular fluid depletion in OHSS. ACE inhibition resulted in a 40% decrease in the incidence of OHSS in the rabbit model.

A randomized prospective comparison between intrauterine insemination and fallopian sperm perfusion for the treatment of infertility

OBJECTIVE To determine if the pregnancy rates (PRs) in infertile women could be improved with fallopian sperm perfusion in comparison with IUI. DESIGN Randomized prospective analysis. SETTING Academically affiliated infertility center. PATIENTS Consecutive patients undergoing controlled ovarian hyperstimulation (COH). INTERVENTIONS After hCG administration, patients were randomized to either IUI or fallopian sperm perfusion. MAIN OUTCOME MEASURES Pregnancy rates with the two treatment modalities. RESULTS Of 240 COH cycles, those randomized to IUI included 44 clomiphene citrate (CC) (group I) and 76 gonadotropin (group III) cycles. Patients receiving fallopian sperm perfusion included 44 cycles of CC (group II) and 76 cycles of gonadotropin (group IV) treatment. The overall PRs per cycle (10.8% versus 10.8%) were similar for IUI and fallopian sperm perfusion, respectively. The PRs were also similar when compared for ovulation induction with CC (6.8% versus 9.1%) and gonadotropins (13.2% versus 11.8%). CONCLUSION We conclude that fallopian sperm perfusion offers no advantage over IUI. Because the process of fallopian sperm perfusion is more time consuming and more costly (because of increased media usage), fallopian sperm perfusion does not seem indicated as a routine infertility therapy and should not replace IUI.

The Effect of Progestins on Behavioral Stress Responses in Postmenopausal Women

OBJECTIVE: We assessed the effects of progestin when added to estrogen on the adaptive patterns to provoked stress in postmenopausal women. METHODS: Fourteen postmenopausal women were randomized to receive either a transdermal estrogen patch (TE2) (n = 7) for 6 weeks or TE2 with added medroxyprogesterone acetate (10 mg) (TE2/MPA) (n = 7) for the last 10 days of the 6-week regimen. Behavioral stress tests were administered to each group, with measurements of biophysical and neuroendocrine responses. In a crossover fashion, after each group received the first treatment and testing, treatment was continued for another 6 weeks with the alternate regimen, at which time another stress test was administered. Responses to stress in the two treatment groups were compared to each other and to established placebo responses. RESULTS: Biophysical responses in the TE2 group were significantly blunted compared to both TE2/MPA and placebo responses (P < .05). Without MPA treatment, there were significantly blunted speech (P < .05) and cold pressor (P < .01) blood pressure responses. With added progestin, there was a greater systolic blood pressure response (P < .01) compared with estrogen alone. Both groups (TE2 and TE 2/MPA) had blunted and nonsignificant responses of ACTH and cortisol upon testing, whereas the placebo group showed a significant response (P < .01). Plasma norepinephrine responses, however, were significantly blunted after TE2, compared with the increased responses observed with both TE2/MPA and placebo (P < .01). CONCLUSION: Although estrogen significantly reduces behaviorally induced stress reactivity in postmenopausal women, certain doses of progestin administration may blunt this effect. (J Soc Gynecol Invest 1994;1:79-83)

Increased angiotensin-converting enzyme activity in a patient with severe ovarian hyperstimulation syndrome

OBJECTIVE To assess plasma angiotensin-converting enzyme (ACE) activity in a patient with severe ovarian hyperstimulation syndrome (OHSS). DESIGN Case report. SETTING Private, university-affiliated infertility practice. PATIENT(S) A 35-year-old woman with OHSS. INTERVENTION(S) Clomiphene citrate induction of ovulation. MAIN OUTCOME MEASURE(S) Plasma ACE activity. RESULT(S) The patient had a brain stem infarction as a result of thrombosis caused by severe OHSS. Plasma ACE activity was significantly elevated and persisted long after resolution of the OHSS. CONCLUSION(S) Elevated ACE activity appears to have been associated with the development of OHSS in this patient. Further study of the ovarian renin-angiotensin system in the development of OHSS is warranted.

Alterations in the sensitivity of serum insulin-like growth factor 1 and insulin-like growth factor binding protein-3 to octreotide in polycystic ovary syndrome

OBJECTIVE To determine if the somatostatin analog, octreotide, affects insulin and related peptides and, hence, androgen levels differently between polycystic ovary syndrome (PCOS) patients and controls. DESIGN Prospective controlled trial. SETTING Reproductive endocrinology clinic of our medical center. PATIENTS Eleven women with PCOS and six matched ovulatory controls. INTERVENTIONS Octreotide (100 micrograms) was administered subcutaneously in the midfollicular phase. Serum was obtained before and at 60, 120, 180, and 240 minutes after octreotide. MAIN OUTCOME MEASURES Fasting insulin, insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), T, androstenedione (A), and LH. RESULTS In PCOS, baseline levels of T, A, LH, and fasting insulin were significantly higher than in controls. Pretreatment IGF-1 and IGFBP-3 levels were similar in PCOS and controls. Octreotide reduced fasting insulin levels significantly but to a similar degree in control and PCOS patients (77% and 90%, respectively). Both groups also experienced a significant decrease in LH levels after octreotide administration, but no significant changes were demonstrated in serum T or A. However, serum IGF-1 suppression in PCOS was greater (63% versus 8% in controls). Serum IGFBP-3 levels increased after octreotide administration in both groups with a larger increase (40%) occurring in the PCOS patients. CONCLUSIONS These data suggest that women with PCOS may be more sensitive to the effects of octreotide in decreasing IGF-1 and increasing IGFBP-3. Although no significant changes could be demonstrated in ovarian androgens after a single dose, octreotide effectively reduced serum LH and insulin and, as such, may prove useful in treating some patients with PCOS.

Ovarian derived prorenin-angiotensin cascade in human reproduction

OBJECTIVE To review the available literature concerning the renin-angiotensin system of the human and animal ovary and to outline the clinical relevance of this system. DESIGN The location, function, and regulation of the components of the ovarian prorenin cascade are described. The possible functions of this system as well as its association with common gynecologic problems are also given. CONCLUSIONS The ovary contains a complete cascade whose end product is the formation of angiotensin II. Angiotensin II may have a role in steroid synthesis, oocyte maturation, ovulation, and corpus luteum formation. Further, aberrations in this system are associated with ovarian tumors, ectopic pregnancy, pre-eclampsia, and ovarian hyperstimulation syndrome.

Prorenin is elevated in polycystic ovary syndrome and may reflect hyperandrogenism

OBJECTIVE To examine the null hypothesis that women with polycystic ovary syndrome (PCOS) produce similar levels of prorenin and other components of the ovarian-derived prorenin to angiotensin cascade (ODPAC) at baseline and after stimulation with clomiphene citrate (CC) or hMG when compared with normal age- and weight-matched ovulatory controls. DESIGN Prospective controlled clinical trial. SETTING Infertility clinic in a university-based county hospital and a hospital-based private infertility practice. PATIENTS Twenty-eight infertile women aged 18 to 35 years. Thirteen patients were diagnosed with PCOS. Fifteen normal ovulatory patients who were matched for age and weight served as controls. INTERVENTIONS Twenty patients were stimulated with CC and eight were stimulated with hMG. MAIN OUTCOME MEASURES Serum E2, P, T, androstenedione (A), DHEAS, LH, FSH, and plasma prorenin, active renin, and angiotensin II (Ang II) were measured at baseline and during the preovulatory and midluteal phases of the stimulation cycles. RESULTS Baseline plasma prorenin in PCOS was higher than that of follicular phase controls. Plasma prorenin correlated significantly with peripheral androgen levels. Prorenin, active renin, and Ang II increased in response to gonadotropins with the largest increases occurring in control patients receiving CC. An association was seen between ovulation with CC and lower baseline levels of active renin. CONCLUSIONS The null hypothesis was rejected. Infertile women with PCOS have higher baseline prorenin levels when compared with age- and weight-matched ovulatory controls. There is a significant correlation between prorenin and the peripheral levels of androgens produced during ovarian stimulation. Baseline active renin levels may be predictive of ovulation with CC.

Angiotensin-converting enzyme inhibition reverses luteal phase steroid production in oocyte donors*

OBJECTIVE To determine whether angiotensin-converting enzyme (ACE) inhibition would affect ovarian steroid synthesis in the oocyte donors undergoing controlled ovarian hyperstimulation (COH). SETTING The IVF program of the University of Southern California. DESIGN Prospective matched clinical trial. PATIENTS Twelve oocyte donors were studied in 28 hyperstimulation cycles. INTERVENTIONS Donors underwent a standard COH protocol. Follicle aspiration was performed 34 hours after administration of hCG. After the procedure, seven donors were administered the ACE inhibitor, captopril, 6.25 mg orally twice daily for 4 days. The remaining patients served as controls. MAIN OUTCOME MEASURES Serum E2, P, plasma prorenin, active renin, and angiotensin II (Ang II). RESULTS Angiotensin II increased after aspiration in both groups but was significantly lower in those receiving captopril. Peak P in the captopril group was significantly lower than controls (81.8 +/- 27.8 versus 208.5 +/- 23.9 ng/mL [conversion factor to SI unit, 3.180]). Peak E2 was significantly higher (2,222.4 +/- 875.3 versus 425.6 +/- 490.4 pg/mL [conversion factor to SI unit, 3.671]). Active renin and Ang II correlated with P. CONCLUSIONS In stimulated cycles, inhibition of Ang II production appears to raise serum E2 and lower P levels. Angiotensin II, therefore, may have a role in the regulation of ovarian steroid synthesis.

Altered regulation of insulin-like growth factor binding protein-I in patients with polycystic ovary syndrome

Objective: Insulin-like growth factor (IGF-I) action is influenced by circulating as well as tissue levels of its binding proteins. Because serum IGF binding protein-1 (IGFBP-1) levels have been found to be decreased in patients with polycystic ovary syndrome (PCOS), we tested the hypothesis that regulation of IGFBP-1 secretion may be different in patients with PCOS compared with normal women. Methods: We studied 15 normal ovulatory women and 15 women with PCOS of similar age (21 ± 1 and 22 ± 1 years, respectively). All subjects were studied after an overnight fast between days 5-8 after spontaneous or progestin-induced menses. Perturbations included the administration of insulin intravenously, maintenance of a euglycemic clamp, and, in a subsequent cycle, the administration of a long-acting somatostatin analogue (octreotide, 100 μg) given subcutaneously. Blood samples were collected before treatment, every 15 minutes for 6 hours after insulin, and every 30 minutes for 3 hours after octreotide administration. Serum levels of IGF-I, IGFBP-1, IGFBP-3, and insulin were measured by specific immunoassays. Results: Compared with the controls, patients with PCOS had significantly higher insulin levels, similar IGF-I and IGFBP-3 levels, and significantly lower IGFBP-1. INsulin did not change serum IGF-I levels in either group, although a significant decrease in IGFBP-1 levels occurred in normal women but ot in patients with PCOS. Octreotide treatment also did not change serum IGF-I levels in either group, but serum insulin levels decreased significantly and IGFBP-1 levels increased significantly in both groups; this response was significantly greater in controls. Conclusion: Our data are compatible with the notion that regulation of IGFBP-1 is altered in women with PCOS and that several factors may be involved.

New advances in the treatment of infertility in women with ovarian failure.

Ovarian failure is heterogeneous in etiology and may occur at various points in a womans life. As such, it may interfere with fertility. Clinical presentation ranges from complete cessation of menses to oligomenorrhea to the continuation of menses with elevated gonadotropins. Various therapies have been used in an attempt to induce fertility, including sex steroids and gonadotropin-releasing hormone agonists to suppress circulating gonadotropin levels, or clomiphene citrate and human menopausal gonadotropins alone or in combination with estrogen or gonadotropin-releasing hormone agonists to induce ovulation. Corticosteroids are also used to overcome autoimmunity. Randomized therapeutic trials are rare and fail to demonstrate any significant improvement in ovulation and pregnancy rates. Donor oocytes have demonstrated high success rates and have proven to be useful in patients with both premature ovarian failure and natural menopause. Pregnancies have been initiated and maintained in women through 60 years of age. Thus, for those accepting of the technique, oocyte donation appears to be the treatment of choice for hypergonadotropic hypogonadism.