Thatchers Thoughts: Drug Therapy

Aspirin and infertility

Title: Low-dose aspirin for infertile women with thick endometrium receiving intrauterine insemination: A prospective, randomized study
Author: Y. Hsieh
Address: Taichung, Taiwan
Source: Journal of Assisted reproduction and Genetics 17:174-178 (March) 2000
Summary: To evaluate the effect of aspirin on infertile women with thin endometrium, 114 women were placed into an aspirin group and 122 women into a nonaspirin group. These subjects had an endometrium £ 8mm and intrauterine insemination. Endometrial pattern and thickness, the pulsatility index and resistance index of the uterine artery, spiral artery, and ovarian dominant follicles, and pregnancy rates of both groups were measured. Significantly higher percentages of trilaminar endometrium (46.5% vs. 26.2%) and pregnancy rate (18.4% vs. 9.0%) after aspirin therapy were noted. Researchers concluded that higher pregnancy rates and better endometrial pattern were achieved in patients with thin endometrium after aspirin administration. However, aspirin therapy could not significantly add to the endometrial thickness and the resistance of uterine and ovarian flow.
Comment: Use of aspirin to improve implantation or prevent miscarriage has been bantered about for a number of years. Theoretically, aspirin could improve circulation by its action on prostacyclin/thromboxane pathways, but its anti-inflammatory action could equally blunt the prerequisite inflammatory response necessary for implantation. The mere fact that most do not use it can be taken as an indication of its lack of effectiveness. I wish someone would perform a definitive well-designed and controlled study to put this issue to rest.


Metformin and adrenal function

Title: Effects of metformin on adrenal steroidogenesis in women with polycystic ovary syndrome 
Author: A. la Marca, et al. Address:Siena, Italy Source: Fertility and Sterility 72: 985-989 (December) 1999

Summary: This prospective trial was conducted to determine whether the administration of metformin, an insulin-sensitizing agent, is followed by changes in adrenal steroidogenesis in women with polycystic ovary syndrome (PCOS). Participants were 14 women with PCOS. Blood samples were obtained before and after the administration of ACTH (250 µg). Metformin was then given at a dosage of 500mg 3 times a day for 30-32 days, at which time the pretreatment study was repeated. Ovulation occurred in 2 women in response to metformin treatment. A significant reduction in basal concentrations of free testosterone and a significant increase in concentrations of sex hormone-binding globulin were observed. The administration of metformin was associated with a significant reduction in the response of 17 a-hydroxyprogesterone, which indicates 17,20-lyase activity, were significantly lower after a month of metformin treatment, indicating a reduction in the activities of these enzymes. The administration of metformin to unselected women with PCOS led to a reduction in the adrenal steroidogenesis response to ACTH. This finding supports the hypothesis that high insulin levels associated with PCOS may cause an increase in plasma levels of adrenal androgens.
Comment: Insulin can be thought of as very similar to LH in its capacity to stimulate ovarian androgen production. This is a curious finding in that it has a similar affect on adrenal steroidogenesis. 


St. John’s Wort

Title: Second thoughts about safety of St. John’s wort 
Author: E. Ernst
Address: Exeter, UK
Source: The Lancet 354: 2014-2015 (December) 1999

Summary: Several reports have raised the possibility of important interactions between hypericum extracts and various prescribed drugs. At least 8 cases have been reported that suggest that hypericum extracts are potent inducers of hepatic enzymes. In all cases the patients were women (this may be a coincidence since women use hypericum extracts more frequently than men do), plasma concentrations of the concomitant medication were reduced, and all the comedications are metabolized by hepatic cytochrome P450 microsomal oxidase enzymes. Two recent preclinical studies confirm that hypericum extracts are hepatic enzyme inducers in humans. Other important interactions have been reported. Concomitant use of hypericum extracts in 5 patients while they were on a stable dose of serotonin-reuptake inhibitors has resulted in symptoms characteristic of central serotonin excess. Given the widespread use of hypericum extracts, the implications of the emerging evidence of adverse reactions are potentially serious. Even though the interaction data are preliminary, attention to 3 precepts seem prudent. Doctors should be aware that administration (or discontinuation) of hypericum extracts may significantly affect blood concentrations or many prescribed medicines. Patients must be encouraged to discuss their use of herbal remedies with their physician, and the prevalent misconception that natural always equates with harmless must be effectively refuted. Finally, regulatory bodies should take a fresh look at whether herbal medicines need regulation, since the perception of “risk free” may reflect incomplete understanding.

Liver disease and insulin altering drugs

Title: Frequency of liver disease in type 2 diabetic patients treated with oral antidiabetic agents 
Author: S. Jick, et al.
Address: UK
Source: Diabetes Care 22: 2067-2071 (December) 1999

Summary: Researchers evaluated liver disease in conventionally treated type 2 diabetic patients to provide a reference against which reports of liver disease related to novel oral antidiabetic treatment could be compared. Patients with type 2 diabetes who were treated with oral antidiabetic agents were identified and were followed to determine whether they developed liver disease. Among 44,406 type 2 diabetic patients, 605 had a computer diagnosis of liver disease (incidence rate of 53.2/10,000 person-years). Of these, 186 had nonsymptomatic, mild and transient liver disorders; 249 had a predisposing condition; and 113 had another cause for the disease. A total of 57 cases were possibly drug induced (incidence rate 5.0/10,000person-years). Of the cases, 11 were attributed to other drugs, 8 to fatty liver disease of diabetes, and the remaining cases to uncertain causes. Oral antidiabetic agents were continued in 51 of these 57 cases, and researchers could not rule out oral antidiabetic agents as a cause of liver disease in 2 cases (incidence rate of 0.2/10,000 person-years). In this population, the background incidence of liver disease was high. Most cases involved other systemic diseases that may cause liver disease. The background rate of relatively mild liver disease (not due to oral antidiabetic treatment) in a population of type 2 diabetic patients is not uncommon and should be considered when evaluating spontaneous reports of liver disease in patients.

Comment: There has been considerable concern over liver disease in patients treated with insulin altering drugs such as troglitazone (Rezulen). This complication seems quite rare and to exclude these medications from therapy because of this potential complication may be unwarranted. A specific indication for therapy is needed and close monitoring is mandated.


 Oral Contraceptives and glucose tolerance

Title: Oral contraceptive use and glucose metabolism in a national sample of women in the United States
Author: R. Troisi, et al.
Address: Bethesda, Maryland
Source: American Journal of Obstetrics and Gynecology 183:389-395 (August) 2000
Summary: Researchers wanted to determine whether users of oral contraceptives had elevated levels of measures of glucose metabolism. Postchallenge glucose levels and the incidence of impaired glucose tolerance were found to be higher among oral contraceptive users than among nonusers in studies during the 1980s. In the current study, researchers examined hemoglobin A1c levels and fasting glucose, insulin, and C-peptide levels. Means were compared among women who had never used oral contraceptives, current users of oral contraceptives, and former users of oral contraceptives, with and without adjustment for potential confounders. Most of the current users of oral contraceptives were using low-dose estrogen formulations. These subjects did not have elevated values for any of the four measures of glucose metabolism. Hemoglobin A1c level and fasting glucose, insulin, and C-peptide levels were not related to duration of current use, age at which use began, or major formulation type. Among women who were former users of oral contraceptives, there was no evidence of higher values among those who had recently ceased use. Researchers concluded that oral contraceptive formulations currently available in the US are not associated with an adverse glucose metabolic profile. 
Comment: I like their conclusions, but I am not sure that the patients were intensively investigated enough to fully support the above findings. Medical endocrinologists often decry OC as having adverse actions on glucose metabolism and advise against their use, especially in PCOS. I believe the non-contraceptive benefits of OCs far outweigh what at best seems to be laboratory more than clinical concerns. Besides, the earlier studies on more potent preparations may be invalid for comparison with newer preparations. 

The pill lessens osteoporosis risk 

Title: Oral contraceptive and bone mineral density: A population-based study 
Author: J. Pasco, et al.
Address: Geelong, Australia
Source: American Journal of Obstetrics & Gynecology 182: 265-269 (February) 2000

Summary: Multiple regression techniques were used to analyze data for a random sample of 710 women to test the hypothesis that exposure to oral contraceptives protects the skeleton. Bone mineral density (BMD) was measured at the lumbar spine, proximal femur, whole body, and distal forearm. Oral contraceptive exposure was assessed via a questionnaire. Researchers discovered that women exposed to oral contraceptives had a 3.3% greater mean BMD adjusted for body mass index and age at the lumbar spine (partial r2=0.009). Adjusted mean vertebral BMD was 3.3% greater for premenopausal women (partial r2=0.008), but the effect did not reach significance among postmenopausal women. Higher BMD was associated with increased duration of exposure, with a mean increase of 3.2% associated with the first 5 years and a further 0.2% with >5 years exposure. No association was detected at other sites.

Comment: Good to know. The results theoretically could have gone the other way.


Gonal F vs. Puregon

Title: Comparison of two recombinant follicle-stimulating hormone preparations in in-vitro fertilization: a randomized clinical study
Author: M. Tulppala, et al.
Address: Helsinki, Finland
Source: Human Reproduction 14: 2709-2715 (November) 1999

Summary: A randomized comparison of Gonal-F and Puregon in ovarian stimulation for in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) was carried out on 348 women aged 22-43 years who were suffering from infertility due to miscellaneous causes. The subjects underwent stimulation using equal starting doses (150 IU/day: Gonal-F n-164, Puregon n=158 or 300 IU/day: Gonal-F n=8, Puregon n=14) after down-regulation with intranasal buserelin from the mid-luteal phase. Similar clinical pregnancy rates were achieved with both preparations; 33.5& per cycle and 37.4% per embryo transfer with Gonal-F (150 IU/day) and 32.9% per cycle and 36.4% per embryo transfer with Puregon (150 IU/day). The ongoing cumulative pregnancy rates after frozen-thawed embryo transfer were 35.4% with Gonal-F and 37.7% with Puregon. Similar numbers of oocytes were obtained in both groups. The fertilization and cleavage rates and the incidence of moderate or severe ovarian hyperstimulation syndrome were also similar. Researchers concluded that Gonal-F and Puregon were equally and highly effective in stimulation for IVF and ICSI.


Metformin, insulin and weight loss

Title: Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome
Author: R. Pasquali, et al.
Address: Bologna, Italy
Source: The Journal of Clinical Endocrinology & Metabolism 85:2767-2774 (August) 2000

Summary: This study was conducted to evaluate the effects of combined hypocaloric diet and metformin on body weight, fat distribution, the glucose-insulin system, and hormones. Participants were a group of 18 obese PCOS women with the central abdominal obesity, and an appropriate control group of 17 obese women without PCOS who were comparable for age and pattern of body fat distribution. While continuing dietary treatment (1200-1400 kcal/day), PCOS women and obese controls were subsequently placed, in a random order, on metformin or placebo for six months. In the PCOS group, metformin therapy improved hirsutism and menstrual cycles significantly more than placebo. In both PCOS and control women, metformin treatment reduced body weight and BMI significantly more than placebo. Metformin also decreased SAT values in both groups, although only in the control group were SAT changes significantly greater than those observed during the placebo treatment. Fasting insulin significantly decreased in both PCOS women and controls, regardless of treatment, whereas glucose-stimulated insulin significantly decreased only in PCOS women and controls treated with metformin. Testosterone concentrations decreased only in PCOS women treated with metformin. Researchers concluded that PCOS women with abdominal obesity, long-term treatment with metformin added to hypocaloric diet induced, in comparison with placebo, a greater reduction of body weight and abdominal fat, particularly the visceral depots, and a more consistent decrease of serum insulin, testosterone, and leptin concentrations.

Comment: The authors conclude that hyperinsulinemia and abdominal obesity are complementary in the pathogenesis PCOS. I agree

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