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PCOS Research Review

Sam Thatcher MD, PhD
Center for Applied Reproductive Science

The Polycystic Ovarian Syndrome Association is pleased to have Samuel Thatcher, MD, PhD, from the Center for Applied Reproductive Science contributing reviews about PCOS research findings to the PCOSupport web site.

The information contained in this communication is compiled from a survey of the recent publications and proceedings in reproductive medicine. It is intended as general information for both health care consumers and providers. Information is chosen due to its importance to clinical management of PCOS, their newsworthiness, or as a topic of controversy. The summary is intended to represent an unbiased synopsis of the original author’s work, to be informative and impartial. The comment is an opinion offered by Dr. Thatcher alone and is intended to stimulate thought. The information provided is not intended to replace, define, or dictate medical practice.

Testosterone levels in PCOS fall as menopause nears

Title: Serum testosterone levels decrease in middle age in women with the polycystic ovary syndrome

Author: S. Winters, et al.

Address: Pittsburgh, Pennsylvania

Source: Fertility and Sterility 73:724-729 (April) 2000

Summary: This cross-sectional study of women with PCOS was conducted to determine whether testosterone levels change, as women with PCOS grow older. Subjects were 84 women with PCOS, 20-57 years, and 37 age-matched. Total and non-SHBG-bound testosterone levels were similar in women with PCOS who were 20-42 years of age but were reduced by approximately 50% among women 42-47 years of age and remained stable in women older than 47 years. Testosterone levels were increased in younger and older women with PCOS compared with controls but were similar to controls in women 42-47 years. Researchers concluded that hyperandrogenism partly resolves before menopause in women with PCOS.

Comment: It seems that PCOS patients begin to have more regular cycles as they approach menopause. An interesting question is whether PCOS reduces the symptoms of menopause and lessens its consequences. How does PCOS affect the need for hormone replacement therapy? Certainly, with PCOS there is a higher bone density at menopause, thus reducing fracture risk.

Prenatal corticosteroid exposure

Title: Antenatal dexamethasone and the growth hormone-insulin-like growth factor axis

Author: O. Ogueh, et al.

Address: London, UK

Source: Human Reproduction 15:1403-1406 (June) 2000

Summary: The purpose of this longitudinal study was to examine the premise that giving antenatal dexamethasone to pregnant women is associated with reduced activity of the GH-IGF axis. Blood samples were taken from 12 pregnant women before administration and at 24 hours and 48 hours after dexamethasone administration. Researchers measured GH, IGF-I, IGF bioactivity, IGF binding protein (IGFBP)-3 protease activity, and glucose and insulin concentrations. There were no significant differences between the concentrations of GH, IGF-I, IGF bioactivity and IGFBP-3 protease activity before and after dexamethasone. The concentrations of glucose and insulin were significantly higher at 24 hours, but not 48 hours post-dexamethasone. Researchers concluded that a single antenatal course of dexamethasone does not alter the GH-IGF-I axis in pregnant women at the time points studied.

Comment: Corticosteroids are frequently used to aid fetal lung maturation when there is a danger of pre-term delivery. There has been a suggestion that fetal exposure to dexamethasone could cause growth restriction, insulin resistance or PCOS at puberty in the exposed children. This needs to be confirmed. The above study is reassuring in that no lasting alteration in the growth hormone axis occurs.

PCOS may not be a risk factor for vascular disease

Title: Normal endothelial function despite insulin resistance in healthy women with the polycystic ovary syndrome

Author: K. Mather, et al.

Address: Alberta, Canada

Source: The Journal of Clinical Endocrinology & Metabolism 85:1851-1856 (May) 2000

Summary: Researchers completed a cross-sectional evaluation of endothelium-dependent and -independent vascular function using brachial artery ultrasound. They studied 18 healthy women with evidence of PCOS and 19 age-matched controls. Subjects weren’t taking any anti-hypertensive, cholesterol-lowering, or hormonal therapies. Despite differences in glucose/insulin ratio (6.1 + 1.1 mmol/pmol in the PCOS group vs. 9.9 + 0.6 in the controls), researchers didn’t find evidence of impaired endothelial function in the PCOS patients. Both endothelium-dependent and -independent vascular responses were normal, and practically identical to the responses seen in the control group. The PCOS women were more obese, but baseline brachial arterial diameters were not different between groups. There was no correlation between degree of insulin resistance or hyperandrogenism and the brachial response. This group of healthy obese young women with insulin resistance and hyperandrogenism due to PCOS had normal endothelium-dependent and -independent vascular responses compared to age-matched controls. Researchers concluded that the factors resulting in preservation of these responses are unclear and warrant further investigation.

Comment: It has been proposed that those with PCOS have a higher incidence of cardiovascular disease, heart attacks, and strokes. Judging by their obesity, insulin resistance and lipid profiles, this would seem to be the case. Those with PCOS also have higher levels of VEGF (vascular endothelial growth factor), which has positive effects on blood vessel health. This is very positive news for those with PCOS. We need much more information to draw a conclusion.

Suppressed LH in IVF cycles related to miscarriage

Title: Increased risk of early pregnancy loss by profound suppression of luteinizing hormone during ovarian stimulation in normogonadotrophic women undergoing assisted reproduction.

Author: L. Westergarrd, et al.

Address: Odense, Denmark

Source: Human Reproduction 15:1003-1008 (May) 2000

Summary: A retrospective study of 200 consecutive, normogonadotrophic women was conducted to assess the impact of suppressed concentrations of circulating LH during ovarian stimulation on the outcome of in vitro fertilization or intracytoplasmic sperm injection treatment. Low concentrations of LH on stimulation day 8 (S8) (less than 0.5 IU/I) were found in 49% of the women. This group was comparable with the normal LH group with regard to pre-treatment clinical parameters, and to the parameters characterizing the stimulation protocol. An exception of serum estradiol concentration, which on S8 was significantly lower than in the normal LH group, was noted. The ratio of positive pregnancy tests was comparable in the 2 groups (30% vs. 34% per started cycle), but the final clinical treatment outcome was significantly different, with a five-fold higher risk of early pregnancy loss (45% vs. 9%) in the low LH group. Thus there was a significantly poorer chance of delivery than in the normal LH group. Researchers concluded that a substantial proportion of normogonadotrophic women treated with the GnRH agonist down-regulation in combination with FSH, devoid of LH activity, experience LH suppression, which compromises the treatment outcome. Whether these women would benefit from supplementation with recombinant LH or human menopausal gonadotrophin during ovarian stimulation remains to be proven in the future by prospective randomized trials.

Comment: Normal follicular function, and therefore oocyte health, is related to the presence of both LH and FSH. Many with PCOS have abnormally elevated LH levels, but occasionally a PCOS patient may have lower levels. Most of the studies have been directed toward too much LH rather than too little. Too much LH has been related to poor success with IVF and increased miscarriage rate. Stimulation regimens should be individualized.

Insurance coverage for infertility

Title: Hidden costs of infertility treatment in employee health benefits plans

Author: R. Blackwell, et al.

Address: Birmingham, Alabama

Source: American Journal of Obstetrics and Gynecology 182:891-895 (April) 2000

Summary: Infertility treatment is often provided under other diagnoses or in association with therapy rendered for other disease processes. This 1-year retrospective analysis was conducted to estimate the hidden costs from specific medical claims gathered from a large representative employer with no infertility benefit and to determine what the costs would be of providing coverage for infertility treatment. Data were analyzed in the context of the claims experience of a health plan covering about 28,000 employees. Clinical practice experience was used to set boundaries regarding the likelihood of a given treatment being associated with infertility. This was compared with 100% covered charges to generate claims per employee per month. Procedures covered operative, diagnostic, and laboratory services. Forty-one ICD codes indicated the possibility of infertility treatment and 35 CPT codes were involved in claims highly indicative of infertility services. According to the CPT codes, $603,807.95 would have been paid if 100% of the charges had been covered Computed cost figures per member/month showed the hidden costs of infertility to range between $0.27 and $0.50. On the basis of various cost studies, rate filings, and employee data, the cost of providing coverage for infertility treatment has previously been shown to vary between $0.20 and $2.00 per member/month. Through appropriate cost sharing, managed care, and algorithms, infertility coverage can be offered at a cost of $0.40 to $0.50 per member/month. This analysis indicates that at least some employers already pay this much even when infertility is specifically excluded under the plan.

Comment: One can argue whether infertility is a disease. Personally, I think it is a symptom, but a symptom that can have profound consequences. A fever is also a symptom, but that does not mean that high fevers are not dangerous. As I sit writing this comment with a chest cold so bad I can hardly breathe, it is hard for me to think of symptoms as elective. For there not to be insurance coverage for family building is as unconscionable as prohibiting contraception. Both the social and financial logic of this stand continues to escape me.

HRT and blood clots

Title: Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and estrogen/progestin replacement study.

Author: D. Grady, et al.

Address: San Francisco, California

Source: Annals of Internal Medicine 132:689-696 (May) 2000

Summary: Researchers conducted this study to determine whether women who take postmenopausal HRT are at a greater risk of developing blood clots than women who do not. Participants were 2763 women who were known to have heart disease and were past menopause but were younger than 80 years old, had not had a hysterectomy, and had never had a blood clot. Women received either HRT with estrogen and progestin or a placebo tablet that was identical in appearance to the hormone tablet. The follow-up period was 4.1 years. Thirty-four of 1380 women taking the hormone had experienced a blood clot compared to 13 out of 1383 women taking the placebo. Women with lower-extremity fractures, cancer, and for 90 days after inpatient surgery or non-surgical hospitalization were more likely to develop a blood clot than women without these conditions were. Women taking aspirin and those taking certain cholesterol-lowering medications were less likely to develop clots than women not taking these medications. Note that all women in this study had heart disease and these results might not apply to women without heart disease.

Comment: Although large doses of estrogen may increase the risk of clot formation, the use of low doses of natural estrogens is usually reported to improve coagulation profile. I wonder if this is the progestin component of the HRT regimen in the above study. Presently, the water is being muddied about HRT and cardiovascular health.

No increased cancer in IVF children

Title: Incidence of cancer in children born after in-vitro fertilization

Author: F. Bruinsma, et al.

Address: Victoria, Australia

Source: European Society of Human Reproduction and Embryology 15:604-607 (June) 2000

Summary: Researchers wanted to investigate findings of case-control studies and case reports that suggested that children who had been conceived using fertility drugs might be at an increased risk of neuroblastoma. This study used a record-linkage cohort design to investigate the incidence of cancer in children born after IVF. Included were all conceptions at two clinics in Victoria, Australia using assisted reproductive technologies between 1979 and 1995 that resulted in a live birth. The data on births were linked with a population-based cancer registry to determine the number of cases of cancer that occurred. The final cohort included 5249 births resulting from 4357 pregnancies. The median length of follow-up was 3 years, 9 months. In all, 4.33 cases of cancer were expected and six were observed, giving a standardized incidence ratio of 1.39. This study found that children conceived using IVF and related procedures did not have a significantly increased incidence of cancer in comparison to the general population.

Comment: Reassuring

Sleep apnea, visceral obesity and insulin resistance

Title: Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia

Author: A. Vgontzas, et al.

Address: Hershey, Pennsylvania

Source: The Journal of Clinical Endocrinology & Metabolism 85: 1151-1158 (March) 2000

Summary: This study tested 3 hypotheses: 1) Does sleep apnea contribute to the previously reported changes of plasma cytokine and leptin levels independently of obesity? 2) Among obese patients, is it generalized or visceral obesity that predisposes to sleep apnea? 3) Is apnea a factor independent from obesity in the development of insulin resistance? Obese middle-aged men with sleep apnea were first compared with nonapneic age- and body mass index-matched obese and age-matched lean men. The sleep apneic men had higher plasma concentrations of the adipose tissue-derived hormone, leptin, and of the inflammatory, fatigue-causing, and insulin resistance-producing cytokines tumor necrosis factor-a and interleukin-6 than nonapneic obese men, who had intermediate values, or lean men, who had the lowest values. The sleep apnea patients had a significantly greater amount of visceral fat compared to obese controls and indexes of sleep disordered breathing were positively correlated with visceral fat, but not with BMI or total subcutaneous fat. There was a higher degree of insulin resistance in the group of apneics than in BMI-matched nonapneic controls. Researchers concluded that there is a strong independent association among sleep apnea, visceral obesity, insulin resistance and hypercytokinemia, which may contribute to the pathological manifestations and somatic sequelae of this condition.

Comment: Confirms other studies about obesity and sleep apneas. It may be risk factors rather than sex that accounts for the male/female differences.

Bone density after contraceptives

Title: Steroid hormone contraception and bone mineral density: a cross-sectional study in an international population

Author: D. Petitti, et al.

Address: Geneva, Switzerland

Source: Obstetrics & Gynecology 95:737-744 (May) 2000

Summary: Researchers evaluated relationships between bone mineral density and use of steroid hormonal contraceptives. This was a multi-center cross-sectional study conducted in seven centers in three regions of the developing world from April 1994 to June 1997. Subjects included 2474 women aged 30-34 years attending family planning clinics, with at least 24 months of lifetime use of combined oral contraceptives (OC), depot medroxyprogesterone acetate (DMPA), or levonorgestrel implants, or no or only short-term use of steroid hormonal contraceptives. Subjects had bone mineral density measured at the distal radius and the mid-shaft of the ulna using single-photon x-ray absorptiometry. For OC use, adjusted mean BMD was significantly higher in short-term, current users compared with women who never use hormonal contraceptives. For DMPA and levonorgestrel implants, adjusted mean BMD was statistically significantly lower in short-term current users compared with those who never used hormonal contraceptives. For all 3 hormonal methods, there were no significant differences in BMD between past users of hormonal contraceptives and never users, even among those who had used the methods for 4 or more years. This study suggests that hormonal contraceptive use by young adult women is associated with small changes in BMD that occur early after initiation of use and are reversible.

Comment: One previous study has shown an improvement in bone density with OC's and one study has shown a marked decrease in density with Depo-Provera. This one is very "middle-of-the- road."

You will never get pregnant — a reassuring statement?

Title: Spontaneous conception after a successful attempt at in vitro fertilization/intracytoplasmic sperm injection

Author: B. Hennely, et al.

Address: Dublin, Ireland

Source: Fertility and Sterility 73:774-778 (April) 2000

Summary: This retrospective postal questionnaire was sent to 530 people to study the incidence of spontaneous pregnancy in women who were not actively undergoing therapy after a successful attempt at IVF/ICSI and to characterize its pattern of occurrence. The rate of spontaneous conception among the 513 respondents was 20.7%. Younger women (less than 34) had a higher rate of spontaneous conception, as did those with a shorter duration of infertility. Women with unexplained infertility and endometriosis also were more likely to conceive. Few of those who had undergone ICSI conceived, whereas 21.6% of those whose partners had had sperm quality sufficient for IVF later conceived spontaneously. These pregnancies may be related to the ovarian stimulation given in the past or to the physiologic effects of pregnancy on the pituitary and endocrine systems.

Comment: It is amazing how many stories I hear from those who have been told they would never be pregnant, only subsequently to have several children. I am not sure why a couple would be ever told this or what purpose this comment would serve. Very few are absolutely infertile — sterile. The ‘tincture of time’ is powerful therapy. I would not exclude relief of stress as the authors put forth as a possibility, but I would favor a resetting of the endocrine axis and mostly just their number coming up. Look also at the remaining 80% or so that may never have been pregnant without technology.

PCOS increases risk of diabetes and cardiovascular disease

Title: Increased risk on non-insulin dependent diabetes mellitus, arterial hypertension and coronary artery disease in perimenopausal women with a history of the polycystic ovary syndrome

Author: D. Cibula, et al.

Address: Czech Republic

Source: Human Reproduction 15:785-789 (April) 2000

Summary: Prevalence of non-insulin dependent diabetes mellitus (NIDDM), arterial hypertension, coronary artery disease and risk factors in perimenopausal women with a history of PCOS treatment was studied. Subjects were 28 women who had undergone wedge ovarian resection. Controls were 752 women selected from a random population sample. Prevalence of NIDDM and coronary artery disease was significantly higher in PCOS. There was no difference in the 2 groups in BMI, waist circumference or waist-hip ratio. Both groups had identical family histories for NIDDM, hypertension, and coronary artery disease and identical smoking habits. There was no difference between the mean concentrations of lipids and fasting glucose and they did not differ in the proportions of women with elevated lipid concentrations. Researchers determined that women in the general population have the same level of risk factors at perimenopausal age as PCOS women. Patients with markedly expressed clinical symptoms of PCOS made up a subgroup in the general population at high risk for developing NIDDM and coronary artery disease.

Comment: It is difficult to make a statement about 28 patients. It is also very difficult to make a statement about PCOS from only those who have had ovarian wedge resection. This is a subgroup and others may have either higher or lower risks. This study still highlights that PCOS women of reproductive age may be the metabolic syndrome of the peri- and post-menopausal.

Puberty -- some new thoughts

Title: Rapid maturation of the reproductive axis during perimenarche independent of body composition

Author: R. Legro, et al.

Address: Hershey, PA

Source: The Journal of Clinical Endocrinology & Metabolism 85:1021-1025 (March) 2000

Summary: Researchers sought to identify the natural history of menarche in a large, healthy cohort of young women studied at 6-month intervals over a 4-year period beginning at premenarche. Subjects were 112 premenarchal Caucasian females. Researchers quantified reproductive hormones in 24-hour urine collections as a measure of daily output and measured body composition biometrically and with the use of dual energy x-ray absorptiometry scans. Sex steroid and gonadotropin levels changed exponentially in the year approaching menarche. FSH levels peaked at menarche and then progressively declined thereafter. Estradiol output increased rapidly in the year approaching menarche and then plateaus thereafter. The frequency of menstrual bleeding increased rapidly and plateaued at 1 year postmenarche. At 1 year, 65% had established a pattern of 10 or more menstrual episodes/yr, and by 3 years postmenarche this figure exceeded 90%. Researchers concluded that menarche occurs as a result of rapid maturation of the reproductive axis, independent of changes in body fat, and heralds the reestablishment of a negative sex steroid feedback loop that parallels the adult threshold.

Puberty-more thoughts about its origin

Title: A randomized trial of oral contraceptive and hormone replacement therapy on bone mineral density and coronary heart disease risk factors in postmenopausal women

Author: N. Taechakraichana, et al.

Address: Bangkok, Thailand

Source: The Journal of Clinical Endocrinology & Metabolism 84: 3936-3944 (November) 1999

Summary: Researchers longitudinally investigated individual changes in body mass index (BMI) and urinary 24-h excretion rates of dehydroepiandrosterone sulfate (DHEAS) in a pre-puberty (11 boys and 11 girls) and a puberty (10 boys and 10 girls) cohort of healthy children. Almost 3-fold higher median increases in urinary DHEAS excretion rates were observed during highest rises in BMI. No consistently significant associations were found between urinary DHEAS output and BMI from simple cross-sectional correlations at defined age points. These findings provide the first in vivo evidence that a change in the nutritional status, measurable in the form of Æ-BMI, is an important physiological regulator of adrenarche regardless of individual adrenal androgen excretion level, age, and developmental stage.

Comment: Some tidbits. It now appears that the best way to think about puberty is the typical growth curve that starts slowly, goes through a logarithmic growth phase and then slows. Puberty is an orderly continuous adaptive process and not as explosive as many with teenagers might imagine. The old theory of "critical weight" is only valid as an association not causative factor. An evaluation would be started if there is no evidence of puberty by age 13. The total span of puberty is about 41/2 years. At menarche 95% of the adult height has been obtained. Oral contraceptives at anytime after menarche should not hamper growth. While irregular bleeding patterns (variable 21-45 days) are often normal within a year, consistent cycle lengths above 45 days is strongly predictive of PCOS.

Polycystic "appearing" ovaries

Title: Normal ovulatory women with polycystic ovaries have hyperandrogenic pituitary-ovarian responses to gonadotropin-releasing hormone-agonist testing

Author: P. Chang, et al.

Address: New York, NY

Source: The Journal of Clinical Endocrinology & Metabolism 85: 995-1000 (March) 2000

Summary: Researchers examined whether ovulatory women without clinical/biochemical hyperandrogenism but with polycystic appearing ovaries (PAO) have subclinical features of PCOS. They characterized 26 PAO women and matched them to 25 ovulatory women with normal appearing ovaries (NAO) and to 22 women with PCOS. All had baseline endocrine and metabolic assessments. A subset of each group underwent GnRH-agonist testing, ACTH stimulation, and an insulin tolerance test (ITT). At baseline, PAO and NAO women had similar endocrine profiles (LH, LH:FSH, androstenedione, and DHEAS). Compared with NAO, 31% of PAO women had reduced glucose responses after insulin, suggesting mild insulin resistance, and 35% had HDL levels below 35 mg/dL, a level considered to represent significant cardiovascular risk. After GnRH-agonist, PAO women had response patterns in LH, total testosterone, and 17-hydroxyprogesterone that were intermediate between NAO and women with PCOS. Ovarian responses were above the normal range in 30-40% of women with PAO. Researchers concluded that occult biochemical ovarian hyperandrogenism may be uncovered using GnRH-agonist in ovulatory women with PAO, while adrenal responses remain normal. It was also stated that up to one third of women with PAO might have subtle findings consistent with PCOS.

Comment: This is from the leader who has made much on the distinction between PCOS and PAO. At least 20% of women have polycystic ovaries on ultrasound. Most will have subtle endocrine imbalances. These may be fertile or infertile, and they may be fat or thin. Ultrasound is the most sensitive indicator of PCOS. With PCOS we always seem to be dealing with shades of gray. As medicine moves from pathology to physiology, from disease to disease prevention, lighter shades of gray take on new meaning.

No more Rezulin

Summary: On Tuesday, March 21, 2000, following additional reports of hepatic and other toxicity of Rezulin (troglitazone), the Food and Drug Administration (FDA) asked Warner-Lambert to withdraw the drug from the market. In the interest of patient safety, The Endocrine Society supports the actions of the FDA and Warner-Lambert in withdrawing Rezulin.

Comment: Rezulin is a member of the thiazolidinediones ("glitazone") class of drugs. In the case of Rezulin, the FDA has found that the risks outweigh the benefits for patients and that alternatives existed that have the same positive effects, but lack the liver disease risks. The other FDA-approved thiazolidinediones, Avandia (rosiglitazone) and Actos (pioglitazone), provide similar efficacy as Rezulin in the treatment of diabetes and should be equally effective for PCOS. I generally consider them as a second line behind metformin (Glucophage™) for management of insulin resistance and hyperinsulinemia. In my experience they are more effective than metformin for reducing insulin, but do not offer the benefit of weight loss that many using metformin experience. Gastrointestinal side-effects are usually minimal with the "glitazones." While there is no evidence of liver toxicity and pending further safety studies, it has been recommend that all patients taking thiazolidinediones interact closely with their physicians to monitor their liver function.

ASRM Bulletin- VIAGRA™ for fertility enhancement

From the ASRM Bulletin, Volume 2, Number 9, March 21, 2000

ASRM Statement on Use of Viagra to Treat Female Infertility Statement Attributable to R. Jeffrey Chang, M.D., President American Society for Reproductive Medicine WASHINGTON, D.C.

Summary: The April issue of Human Reproduction contains an experiment conducted on four patients by Dr. Geoffrey Sher showing that Viagra improves the thickness of the lining, enabling previously infertile patients to become pregnant and carry children to term. Dr. Sher has already appeared on the Today Show and has been interviewed by a number of other media outlets. Following is the statement we released on this experiment:

Viagra is widely recognized as the first effective oral medication for treatment of erectile dysfunction in men. While the use of Viagra to increase the depth of the uterine lining of female patients suffering from the disease of infertility may be proven effective, this treatment is still experimental. Under no circumstance should a woman consider trying Viagra to improve her chances of a successful pregnancy without consulting her doctor and understanding the risks involved for both her and her potential child. Known side effects for women include high levels of nitrous oxide in the womb, which can be both dangerous for the mother and toxic to developing embryos.

Comment: ASRM is very supportive of research that will lead to improved treatments for our patients. However, such research should only be conducted as part of approved protocols under the careful oversight of an institutional review board and only after informed consent that explains the experimental nature of the study and the risks and benefits involved have been obtained.

Thyroid disease underestimated and under (mis)treated

Title: The Colorado thyroid disease prevalence study

Author: G. Canaris, et al.

Address: Omaha, Nebraska

Source: Archives of Internal Medicine 160:526-534 (February) 2000

Summary: Because the prevalence of abnormal thyroid function and the significance of thyroid dysfunction remain controversial, researchers conducted this cross-sectional study of 25,862 subjects to determine the prevalence of abnormal thyroid function and the relationship between abnormal thyroid function and lipid levels and abnormal thyroid function and symptoms. They used modern and sensitive thyroid tests (serum thyrotropin and total thyroxine concentrations, serum lipid levels) and responses to a hypothyroid symptoms questionnaire. The prevalence of elevated TSH levels in this population was 9.5%, and the prevalence of decreased TSH levels was 2.2%. Forty percent of patients taking thyroid medications had abnormal TSH levels. Lipid levels increased in a graded fashion as thyroid function declined. Also, the mean total cholesterol and low-density lipoprotein cholesterol levels of subjects with TSH values between 5.1 and 10 mlU/L were significantly greater than the corresponding mean lipid levels in euthyroid subjects. Symptoms were reported more often in hypothyroid vs. euthyroid individuals. Among patients taking thyroid medication, only 60% were within the normal range of TSH. These results confirm that thyroid dysfunction is common, may often go undetected, and may be associated with adverse health outcomes that can be avoided by serum TSH measurement.

Comment: It is very common for women with thyroid disorders to be seen in gynecology offices seeking care for abnormal uterine bleeding. Others just do not feel good; they have gained weight and energy level is low. It would be great to have a reason for feeling this way, and some do--thyroid disease. All women should be screened for thyroid disease at age 40, or sooner if the clinical situation warrants.

Most abnormalities of thyroid function often result from an underlying disorder of the thyroid gland itself. The most common etiology of hyperthyroidism is Graves' Disease, while most hypothyroidism is secondary to autoimmune thyroiditis (Hashimoto's Disease), or as a result of ablative treatment of hyperthyroidism. Autoimmune thyroid disease is five times more prevalent in women and is seen very commonly in individuals with other autoimmune conditions. There appears to be a strong genetic predisposition to thyroid autoimmune disease, making a family history useful in determining the individual at risk.

The tests for thyroid stimulating hormone (TSH) are now widely available and this measurement is usually all that is necessary to screen for both hyperthyroidism (overactive) and hypothyroidism (under active). The so-called "thyroid panel" is a dinosaur. If the TSH level is abnormal, the test should be repeated, together with a test for thyroid hormone, free thyroxine (free T4). A low TSH with a high free thyroxine indicates hyperthyroidism. All cases of hyperthyroidism warrant full investigation. A low TSH and low free thyroxine indicates the relatively uncommon disorder of central suppression. By far the most common problem is hypothyroidism. If the TSH is elevated and the free thyroxine is normal this has been called "subclinical" hypothyroidism. In my experience, there is often nothing subclinical about this and these individuals often have a number of symptoms. Most cases of subclinical hypothyroidism will progress to overt thyroid disease over time. A trial of low dose replacement may be tried in all substantiated cases of subclinical hypothyroidism, but reevaluation of its usefulness and TSH level are essential.

TSH is the method of choice to monitor thyroid replacement therapy. It should be noted that there is a 4-6 week period necessary for equilibrium to be reached and checking more often than this may lead to false conclusions and abrupt changes in therapy. Thyroid therapy should be started at low doses and slowly increased. Replacement therapy should be modified to keep TSH levels firmly in the mid-normal range. Too much replacement can significantly increase the risk for osteoporosis and heart disease. With too little replacement, many will start to have a decreased feeling of well-being. Often there is a noticeable difference with even minute changes in therapy. It is recommended that the same brand name therapy always be used.

Whether thyroid diseases have a relationship to PCOS is not known. On the surface both are common problems and therefore may be seen together in many. That does not mean that there is no association or that we should stop looking.

Obesity and depression

Title: Relationships between obesity and DSM-IV major depressive disorder, suicide ideation, and suicide attempt: results from a general population study

Author: K. Carpenter, et al.

Address: New York, NY

Source: American Journal of Public Health 90: 251-257 (February) 2000

Summary: To test the relationships between relative body weight and clinical depression, suicide ideation, and suicide attempts, researchers conducted a cross-sectional study of more that 40,000 men and women. The results of the study indicated that the psychological effects of obesity were different in women compared with men. In women, obesity increased the risk of being diagnosed with major depression by 37%, but in men, obesity decreased this risk by 37%. A 10-unit increase in body mass index increased the risks of both suicidal ideation and suicide attempts in the past year by 22% in women, while decreasing these risks by 26% and 55%, respectively, in men. However, in men, being underweight was associated with substantially increased risks of depression (25% increase), suicidal ideation (81% increase) and suicide attempts (77% increase) in the past year. Researchers also noted that the study did not indicate whether being underweight causes depression in men, or whether depression causes men to lose weight. The study also leaves unclear the temporal relationship between overweight and depression in women.

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 500 mg 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.

Progestins and breast cancer

Title: Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk

Author: C. Schairer, et al.

Address: Rockville, MD

Source: JAMA 283: 485-491 (January) 2000

Summary: A total of 46,355 postmenopausal women were studied to determine if the increased risk of breast cancer associated with the estrogen-progestin regimen is greater than those associated with estrogen alone. The average age of participants was 58 years and the average length of follow-up was 10.2 years. During the time period studied, 2082 cases of breast cancer were identified. Increases in risk with estrogen only and estrogen-progestin only were restricted to use within the previous 4 years with relative risk (RR) 1.2 for estrogen only and 1.4 for estrogen-progestin only. The RR increased by 0.01 with each year of estrogen only use and by 0.08 with each year of estrogen-progestin. Risk in heavier women did not increase with use of estrogen only or estrogen-progestin only. Researchers concluded that their data indicated that the estrogen-progestin regimen increases breast cancer risk beyond that associated with estrogen alone.

Comment: A relative risk of 1 suggests that there is neither an increase nor decrease in an event happening. A RR of 1.2 indicates a 20% increase, or in this study, from about 4% to about a 5% chance of developing breast cancer. Most studies thus far have hovered around RR of 1, most very slightly above 1. In evaluating the value of estrogen replacement, a useful comparison is that there are 4 times as many women who die as a result of a hip fracture than breast cancer. The above adds data; still, total benefit versus total risk should be considered.

Treatment of hirsutism

Title: Comparison of spironolactone, flutamide, and finasteride efficacy in the treatment of hirsutism: a randomized, double blind, placebo-controlled trial

Author: P. Moghetti, et al.

Address: Verona, Italy

Source: The Journal of Clinical Endocrinology & Metabolism 85: 89-94 (January) 2000

Summary: The vast majority of the published work concerning hirsutism treatment shows considerable shortcomings, such as lack of a control group, assessment of results only by subjective methods, or too short a duration in relation to the physiology of hair growth. The present study is the first to evaluate the efficacy on hirsutism of three different drugs, spironolactone, flutamide, and finasteride, by a rigorous clinical trial methodology of a double blind, placebo-controlled, randomized study. The most interesting finding of the study is that, in a population of unselected women with moderate to severe hirsutism, the clinical efficacies of these drugs were similar despite their differing mechanisms of action. The tolerability of anti-androgen drugs examined was good, with the noticeable exception of polymenorrhea in 50% of subjects given spironolactone. Researchers also observed occasional mild, transient liver toxicity in women given low doses of flutamide (375-500 mg/day). As a whole, these observations suggest that the use of this compound for the treatment of hirsutism should be carefully challenged in each subject. At the doses used in this study the retail costs of a 1-month course of therapy are $21.3, $95.4, and $56.1, respectively for spironolactone, flutamide, and finasteride.

Comment: Good study. Spironolactone remains the drug of choice, but 30% of patients using it will have irregular bleeding. OC's also have a positive effect and control bleeding.

Hyperinsulinemia and cardiovascular risk

Title: Hyperinsulinemia in polycystic ovary syndrome correlates with increased cardiovascular risk independent of obesity

Author: K. Mather, et al.

Address: Alberta, Canada

Source: Fertility and Sterility 73: 150-156 (January) 2000

Summary: Researchers studied 57 women with clinically defined polycystic ovarian syndrome (PCOS) and 45 unselected healthy age-matched controls to assess the role of insulin resistance, independent of obesity, in determining cardiovascular risk among women with the PCOS. They studied the relationships between hyperinsulinemia, composite cardiovascular risk scores, and prevalence of individual risk factors. Hyperinsulinemic women with PCOS carried more cardiovascular risk than their normoinsulinemic counterparts, who in turn had more risk than the control women. In addition to the lipid changes expected with insulin resistance, there was an excess of LDL cholesterol among the women with PCOS. Across the range of body mass index, women with PCOS had greater insulin resistance than controls, suggesting that PCOS itself and body mass index both contribute to the observed insulin resistance. Researchers concluded that insulin resistance in PCOS is a determinant of overall cardiovascular risk independent of obesity. However, the mechanism of this relationship remains uncertain.

Treatment of abnormal bleeding with destruction of the uterine lining

Title: Thermal balloon ablation versus endometrial resection for the treatment of abnormal uterine bleeding

Author: A. Gervaise, et al.

Address: Bourg-La-Reine, France

Source: Human Reproduction 14: 2743-2747 (November) 1999

Summary: This study was conducted to compare the clinical efficiency and safety of a thermal uterine balloon system with hysteroscopic endometrial resection in the treatment of dysfunctional uterine bleeding in 147 women. From Nov. 1994 - April 1998, 73 women were enrolled in a prospective study of a thermal uterine balloon system. The control group was chosen from analysis of the records of patients undergoing resection and treated during the same period by endometrial ablation for abnormal uterine bleeding. Inclusion in the study required that women be > 40 years of age, with the exception of 2 patients in each group who had a serious medical contraindication for pregnancy in addition to menorrhagia. The indication for treatment in both groups was excessive menstrual blood loss. The premenopausal women had either unsuccessful medical therapy with progestins or were unwilling or unable to continue with medical treatment. The post-menopausal patients were not willing to discontinue HRT. Researchers found the operative time to be reduced significantly with the uterine balloon technique. There were no intra-operative complications in either group and postoperative morbidities were not statistically different. Multivariate analysis noted 2 prior factors associated with failures: retroverted uterus with thermal balloon ablation and age less than 43 years with endometrial resection. The overall success rate was not significantly different among the two groups, making uterine balloon ablation appear to be as effective as endometrial resection. The former is much easier to perform, making the technique readily reproducible, especially by those with limited expertise in hysteroscopic surgery, and thus more widely applicable and safer.

Comment: In many cases uterine bleeding is of endocrine (hormonal) origin rather than anatomic (structural). If this cannot be controlled by medical therapy, destruction of the uterine lining may be preferable to hysterectomy. No study has addressed this in PCOS, a relatively common cause of abnormal bleeding.

Blood vessels, diabetes and HRT

Title: The effect of hormonal replacement therapy on the vascular reactivity and endothelial function of healthy individuals and individuals with type 2 diabetes

Author: S. Lim, et al.

Address: Boston, MA

Source: The Journal of Clinical Endocrinology & Metabolism 84: 4159-4164 (November) 1999

Summary: Researchers studied the effects of HRT on the microvascular reactivity and endothelial function of women with and without diabetes. Participants included 28 healthy premenopausal women, 16 premenopausal women with type 2 diabetes, 12 healthy postmenopausal women, 17 postmenopausal women with diabetes, 13 healthy postmenopausal women on HRT, and 11 postmenopausal women with diabetes on HRT. Laser Doppler flowmetry was used to measure forearm cutaneous vasodilatation in response to iontophoresis of 1% acetylcholine and 1% sodium nitroprusside. The endothelium-dependent vasodilation was significantly higher in premenopausal healthy women compared to premenopausal diabetic women. Endothelium-dependent vasodilation was also higher in postmenopausal healthy women on HRT compared with postmenopausal diabetic women on HRT, postmenopausal healthy women without HRT, and postmenopausal diabetic women without HRT. A similar pattern of responses was observed in the endothelium-independent vasodilation. Soluble intercellular adhesion molecule (sICAM) was also measured among all the women with diabetes. Premenopausal women with diabetes and postmenopausal women with diabetes on HRT had lower sICAM levels compared with the postmenopausal diabetic women without HRT.

Comment: Researchers concluded that menopausal status and type 2 diabetes are associated with impaired microvascular reactivity. HRT substantially improves microvascular reactivity in postmenopausal healthy women. In contrast, the effect of HRT on the microvascular reactivity of postmenopausal diabetic women is less apparent in body fat distribution and insulin resistance.

Regional fat distribution and insulin sensitivity

Title: Relation of regional fat distribution to insulin sensitivity in postmenopausal women

Author: C. Sites, et al.

Address: Burlington, Vermont

Source: Fertility and Sterility 73: 61-65 (January) 2000

Summary: This study of 27 women in the early stages of menopause was conducted to study the relation between insulin sensitivity and total and regional body fat in non-obese postmenopausal women. None of the participants were taking HRT, and all had an FSH level of >35mIU/mL, a body mass index of less than 30 kg/m2, and a waist circumference of less than 94cm. The natural log of insulin sensitivity correlated significantly with intraabdominal fat, subcutaneous fat, and sagittal diameter. After adjusting for total fat, sagittal diameter remained significantly related to insulin sensitivity. Central abdominal fat is inversely and independently related to insulin sensitivity after adjusting for total fat in women in the early postmenopausal period. Efforts to reduce either subcutaneous abdominal fat or intraabdominal fat should be helpful in reducing the risk of non insulin-dependent diabetes mellitus in postmenopausal women.

Comment: Identification of risk factors may allow intervention that can significantly alter life quality and expectancy. The question remains as to whether we can alter obesity. Just to say to patients or ourselves, "lose weight," seldom works. We know what we should do; we just can't do it.