Effects of recombinant LH treatment on folliculogenesis and responsiveness to FSH stimulation.

BACKGROUND: The role of LH in sensitizing antral follicles to FSH is unclear. LH is required for normal hormone production and normal oocyte and embryo development, but follicular responses to LH may depend upon the stage of development. Potential roles at the early follicular phase were explored in a clinical setting by employing a sequential approach to stimulation by recombinant human (r-h) LH followed by r-hFSH in women who were profoundly down-regulated by depo GnRH agonist. METHODS: We employed a multi-centre, prospective, randomized approach. Women (n = 146) were treated in a long course high-dose GnRH agonist (Decapeptyl, 4.2 mg s.c.) protocol and were randomized to receive r-hLH (Luveris, 300 IU/day) for a fixed 7 days, or no r-hLH treatment. This was followed by a standard r-hFSH stimulation regime (Gonal-F, 150 IU/day). Ultrasound and hormone assessments of responses were measured at the start of r-hLH treatment, on FSH stimulation Days 0 and 8 and at the time of HCG administration. RESULTS: The LH treatment was associated with increased small antral follicles prior to FSH stimulation (P = 0.007), and an increased yield of normally fertilized (2 PN) embryos (P = 0.03). There was no influence of the r-hLH pretreatment upon hormone profiles or ultrasound assessments during the FSH phase. Anti-mullerian hormone increased in both groups during the week prior to FSH stimulation (P = 0.002). CONCLUSIONS: This sequential approach to the use of r-hLH in standard IVF showed a possible modest clinical benefit. The results support other recent work exploring up-regulated androgen drive upon follicular metabolism indicating that clinical benefit may be obtainable after further practical explorations of the concept.

Clinical efficacy and safety of low-dose flutamide alone and combined with an oral contraceptive for the treatment of idiopathic hirsutism.

BACKGROUND AND OBJECTIVE: High doses of flutamide, which is the only antiandrogen that specifically blocks the androgen receptor, have recently been used with good clinical results in women with hirsutism. Since regression of hair growth requires long-term therapy, clinical and economic considerations are important. The use of the lowest efficacious dosage could reduce costs. This study was undertaken to compare safety and efficacy of a low dose of flutamide (125 mg twice daily) alone and in combination with a triphasic oral contraceptive (OC) in women with idiopathic hirsutism. PATIENTS: Flutamide was administered orally in a low dose of 125 mg twice daily for 12 months alone in women with no risk of pregnancy or during the use of an oral contraceptive. MEASUREMENTS: Women were seen every 3 months and were evaluated for hirsutism score, hormone and lipid measurements. DESIGN: The study, which was conducted as a prospective open trial, was proposed to patients with idiopathic hirsutism, that is, with serum androgen levels in normal range and LH/FSH ratio less than 2. RESULTS: A statistically significant decrease in hirsutism score as compared to baseline was observed after only 3 months with either treatment, flutamide alone (16.9 +/- 1.6 vs 14.2 +/- 1.7, P < 0.0001) or the combination of flutamide with OC (15.6 +/- 0.8 vs 11.9 +/- 0.8, P < 0.001). Three months after cessation of treatment a statistically significant decrease from baseline was observed in the two groups. Nevertheless, at 6 months post-treatment this decrease was still significant only in the group who took flutamide in combination with an oral contraceptive. Flutamide alone does not appear to modify the levels of lipoproteins. The association of flutamide with a triphasic formulation significantly increased the HDL-C levels. CONCLUSIONS: This study shows beneficial effects of a low dose of flutamide in women with idiopathic hirsutism. The addition of an oral contraceptive is judicious to prevent pregnancy and reduce recurrence of hirsutism after cessation of flutamide. Peripheral androgenic blockage does not modify lipid profiles and it might reduce the negative effect of oral contraceptive on HDL-C levels. The addition of electrolysis delays the recurrence of hirsutism after cessation of flutamide.

Phasic serum lipid excursions occur during cyclical oral conjugated oestrogens but not during transdermal oestradiol sequentially combined with oral medroxyprogesterone acetate.

BACKGROUND AND OBJECTIVE: Recent data indicate that oral medroxyprogesterone acetate (MPA) has limited unfavourable, neutral or even favourable effects on serum lipid fractions when added to oestrogen replacement therapy. The purpose of this study was to evaluate the serum lipid fractions at the beginning and at the end of each phase of a sequentially combined replacement cycle comparing the oral and the transdermal routes of oestrogen administration. DESIGN: Randomized study with a matched control group. Oral conjugated oestrogens (OCE, 0.625 mg) or transdermal oestradiol (TE 50 micrograms) was taken from day 1 to day 25 and MPA (5 mg) added on days 14 to 25. Serum lipids were evaluated on days 1, 14 and 25 of monthly replacement cycles. PATIENTS: The early post-menopausal women in the control group (n = 11) and in the treatment groups (OCE/MPA, n = 15; TE/MPA, n = 17) were evaluated every 3 months for 12 months and every 6 months for another 12 months. MEASUREMENTS: Serum levels of triglycerides (TG), cholesterol (C) fractions and apolipoproteins (Apo) and their respective ratios were measured at months 1, 3, 6, 9, 12, 18, 24. Menopausal symptoms and uterine bleedings were evaluated in parallel and an endometrial biopsy was performed at the end of the 12th and 24th months of treatment. RESULTS: After 14 days of OCE, C, LDL-C, and Apo B were decreased and TG, HDL-C and Apo A1 were increased. The sequential addition of MPA accentuated the reduction of LDL-C and Apo B but attenuated the elevation of TG, HDL-C and Apo A1. These changes tended to revert toward baseline during the period free of medication. By contrast, at the end of 14 days of TE there was a non-significant reduction in TG and LDL components and a limited increase in HDL-C and Apo A1. During the subsequent addition of MPA there was no significant decrease in TG, LDL-C or Apo B but an elimination of the increase in HDL components. These combined changes resulted in a significant reduction in the LDL-C/HDL-C ratio and a significant elevation in the Apo A1/Apo B ratio only in the OCE/MPA group. CONCLUSION: Overall, oral conjugated oestrogens induced favourable intragroup changes in cholesterol fractions whereas transdermal oestradiol maintained serum lipids at levels not different from baseline. The sequential addition of oral medroxyprogesterone acetate attenuated the beneficial elevation of HDL, did not affect the beneficial effect of oestrogens on ratios of cholesterol fractions and attenuated the unfavourable effect of oral conjugated oestrogens on triglycerides. The partial loss of beneficial effects on lipoproteins during cyclical interruption of hormone therapy would be an argument in favour of the evaluation of continuous regimens of oestrogen/progestagen replacement.

Serum FSH bioactivity and response to acute gonadotrophin releasing hormone (GnRH) agonist stimulation in patients with polycystic ovary syndrome (PCOS) as compared to control groups.

OBJECTIVE: We evaluated the biological activity of FSH in the serum of women with polycystic ovary syndrome before and after acute administration of a GnRH agonist as compared to control groups. DESIGN: FSH, oestradiol and androstenedione response to buserelin (100 micrograms s.c.) comparing seven polycystic ovary patients, six idiopathic hirsute women, 11 normal women in the follicular phase and nine normal men. MEASUREMENTS: Rat granulosa cell aromatase bioassay in the presence or absence of polyethyleneglycol (PEG) pretreated 2% serum. Serum biological FSH (B-FSH), immunological FSH (I-FSH) and B/I ratio at times 0, 1, 2, 3, 4, 8, 12 and 24 hours. Serum androstenedione and oestradiol at times 0 and 24 hours. RESULTS: Human gonadotrophin-free (oral contraceptive user and after FSH immunoabsorption) and PEG-pretreated serum increases the aromatase activity in response to increasing doses of purified FSH. The maximum enzymatic activity is however higher with 2% serum than with 4% serum. The amplitude of the B-FSH response to the GnRH agonist is markedly decreased in the polycystic group as compared to the group of normal women. There is also a small decrease in the I-FSH response in the polycystic women. When compared to that of normal women, the area under the curve in the polycystic ovary patients is reduced by 71% for B-FSH (P < 0.01) and by 23% for I-FSH (P < 0.05). The B-FSH and I-FSH responses in men are very small. After an initial decrease the B/I ratio returns to baseline level in normal women but remains low in the other groups. At time 24 hours, there is no significant change in the serum concentration of androstenedione but serum oestradiol, the baseline of which is significantly higher in the polycystic patients than in normal women, is also significantly higher at 24 hours (P < 0.05) in response to the pharmacological release of FSH. CONCLUSION: The gonadotrophin-free and PEG-pretreated human serum has an inherent stimulatory effect on the rat granulosa aromatase bioassay with a higher activity at 2% serum. Acute GnRH agonist stimulation reveals a deficiency in the FSH response in polycystic ovary patients. The greater deficit in B-FSH than in I-FSH would indicate a possible modification in the FSH isoforms in this syndrome. The meaning of this observation for the understanding of the physiopathology of the polycystic ovary syndrome remains to be evaluated.

Correlation between selective inhibition of the cyclic nucleotide phosphodiesterases and the contractile activity in human pregnant myometrium near term.

The present study was carried out to determine the ability of various pharmacological agents to selectively inhibit each cytosolic form of phosphodiesterase isolated from the longitudinal layer of human myometria near term. Among the drugs tested, zaprinast specifically inhibits the first form of PDE which hydrolyses both substrates (cAMP and cGMP) and is stimulated by the Ca2+-calmodulin complex. A second form of PDE specific for cAMP hydrolysis and Ca2+-calmodulin insensitive is only present during pregnancy. Rolipram is the most potent and selective inhibitor of this second form. It is also the most efficient compound to inhibit in vitro the spontaneous contractions of near term myometria. The double effect of rolipram suggests an important role of the second form of PDE in the mechanisms of contractility during the pregnancy. In addition rolipram or other derivatives might be of a therapeutic interest in the prevention of prematurity in so far as they are devoid of undesirable maternal and fetal side effects.