The gonadotropic function of insulin.

We have reviewed the role of insulin in ovarian physiology. Clinical observations and experimental data strongly support the hypothesis that insulin possesses gonadotropic activity, when acting alone or with FSH or LH. This idea is further supported by the recent discovery of insulin in follicular fluid. The idea that insulin has gonadotropic function can explain a variety of clinical observations, which otherwise are difficult to understand. For example, manifestations of ovarian hypofunction (primary amenorrhea, late menarche, anovulation, low pregnancy rate, and early menopause) in IDDM can be understood if it is accepted that insulin is necessary for the ovary to reach its full steroidogenic potential. The idea that insulin affects ovarian steroidogenesis also helps to understand the observation that hyperandrogenism frequently accompanies each of the various insulin-resistant states, regardless of the latter's etiology (e.g. genetic deficiency in the number of insulin receptors, antiinsulin receptor antibodies, obesity, etc.). The explanation for this association is based on the idea that hyperinsulinemia intensifies ovarian steroidogenesis, which manifests clinically as hyperandrogenism. Continuous stimulation of the ovary by insulin over a long period of time possibly produces morphological ovarian changes, such as hyperthecosis or polycystic changes; these changes commonly are observed among women with insulin resistance. The effects of insulin on ovarian cells are mediated possibly through binding of the peptide to its own receptor or to the IGF-1 receptor (the specificity spillover phenomenon). The latter could be an important mechanism in cases of insulin resistance. Potential mechanisms underlying the gonadotropic activity of insulin include direct effects on steroidogenic enzymes, modulation of FSH or LH receptor number, synergism with FSH or LH, or nonspecific enhancement of cell viability. The gonadotropic function of insulin adds yet another note to what has been termed a symphony of insulin action. Further investigation into this new area may yield greater insights not only into normal ovarian physiology, but also into the pathogeneses of such diverse entities as PCO, obesity, diabetes mellitus, and the syndromes of insulin resistance and acanthosis nigricans.

Regulation of insulin receptors in the human ovary: in vitro studies.

The association between insulin resistance and ovarian hyperstimulation has led to a hypothesis that insulin stimulates ovarian steroidogenesis. This possible effect of insulin on the ovary could be mediated by either the insulin receptor or the type I insulin-like growth factor (IGF) receptor, both of which have been described in the human ovary. We examined the in vitro regulation of insulin receptors by LH, FSH, multiplication-stimulating activity (MSA), and insulin in ovarian stromal fragments from 24 women. [125I]Insulin binding was measured in the presence and absence of increasing concentrations of insulin, IGF-I, LH, and FSH. Neither LH nor FSH competed with [125I]insulin for binding sites, but preincubation with LH or FSH reduced [125I]insulin binding by 19-38%. Preincubation with MSA reduced [125I]insulin binding by 34-48%. The affinity of the insulin receptors, determined by Scatchard analysis, did not change (Ka = 3.3 X 10(8) mol-1). A concentration of 10 ng/mL insulin in the preincubation medium reduced [125I]insulin binding by 40%, whereas an insulin concentration of 50 or 500 ng/mL completely obliterated specific [125I]insulin binding. [125I]Insulin binding fully recovered, however, 4 h after termination of tissue exposure to insulin. The specificity of [125I] insulin binding was confirmed by studies with IGF-I. We conclude that of the hormones examined, insulin is the most potent regulator of human ovarian insulin receptors in vitro. Down-regulation of insulin receptors by insulin was reversed within 4 h after withdrawal of insulin. MSA, FSH, and LH also down-regulated the number of human ovarian insulin receptors in vitro, but were less potent. These phenomena, if also present in vivo, could be important factors in the regulation of ovarian function by insulin in normal and pathological states.

Hyporeninemic hypoaldosteronism associated with acquired immune deficiency syndrome.

Four patients with the acquired immune deficiency syndrome (AIDS) and persistent unexplained hyperkalemia were studied. Testing with cosyntropin (0.25 mg intravenously) revealed normal baseline and stimulated cortisol levels and adequate aldosterone stimulation. The baseline aldosterone level was low for the degree of hyperkalemia. Renin/aldosterone stimulation testing was performed by intravenous injection of 80 mg of furosemide followed by four hours of upright posture. This study showed low baseline renin and aldosterone levels and inadequate renin and aldosterone stimulation. Three patients were subsequently treated with fludrocortisone (0.1 to 0.2 mg per day), with normalization of serum potassium levels. It is concluded that hyporeninemic hypoaldosteronism is responsible for hyperkalemia in some patients with AIDS and that treatment with fludrocortisone is effective in these cases.

Sex hormones and coronary disease: a review of the clinical studies.

PIP: A male to female ration of coronary disease of 2:1 has been a consistent finding. This differential persists event when the classic risk factors for coronary disease--hypertension, smoking, obesity, diabetes, and hyperlipidemia--are controlled for gender. The most likely ultimate cause of this phenomenon is male-female differences in sex hormone patterns. Clinical studies in this area have either compared the sex hormone profiles of men and women with and without coronary disease or computed the relative prevalence of disease in populations that differ in their sex hormone patterns. In general, research findings have disputed the hypothesis that persons with coronary disease have low levels of a protective factor such as estrogen or progesterone and high levels of testosterone. Coronary disease patients actually have elevated estrogen levels and low testosterone levels; endogenous progesterone levels are normal before infarction but show a stress-mediated increase in the immediate postinfarction period. Findings of a low prevalence of coronary disease in premenopausal women, a loss of protection after menopause, and a low prevalence of coronary disease in men with cirrhosis-related hyperestrogenemia suggest that natural estrogens are antiatherogenic. The protective effect of pregnancy against myocardial infarction, despite concomitant potentially thrombogenic levels of estrogen at the time, seems to indicate that progesterone, whose levels are also extremely high during pregnancy, plays a major anti-infarction protective effect distinct from that of estrogen. Studies of women oral contraceptive (OC) users and men taking estrogens for brief periods have found that these exogenous hormones produce coronary thrombosis but not atherosclerosis. Finally, the finding of increased coronary disease risk in long-term OC users indicates that synthetic estrogens favor coronary atherosclerosis by suppressing natural estrogen and progesterone production.^ieng

Methadone medical maintenance (MMM): treating chronic opioid dependence in private medical practice--a summary report (1983-1998).

BACKGROUND: Methadone Medical Maintenance (MMM) was implemented in 1983 to enable socially rehabilitated methadone patients to be treated in the offices of private physicians rather than in the traditional clinic system. Over a period of 15 years, 158 methadone patients who fulfilled specific criteria within the clinic system entered this program in New York City. Participating patients reported to their physician once a month and received a one-month supply of methadone tablets rather than a one-day liquid dose in a bottle. METHOD: Of the 158 patients who entered this program, 132 (83.5%) were compliant with the regulations and proved to be treatable within the hospital-based private practices of internists participating in the program. Compliant MMM patients found it easier to improve their employment status and business situations, finish their educations, and normalize their lives in MMM as opposed to the traditional clinic system because they had simplified reporting schedules and fewer clinical restrictions. Twelve (8%) compliant patients were able to successfully withdraw from methadone after an average of 17.7 years of treatment in both the traditional clinics and MMM. Twenty compliant patients (13%) died from a variety of causes, 40% of which were related to cigarette smoking. None of the deaths were attributable to long-term methadone treatment. Other causes of death included hepatitis C, AIDS, cancer, homicide, complications of morbid obesity and meningitis. RESULTS: The 26 noncompliant patients (16.5%) were referred back to their clinics for continued treatment or were discharged for failure to report as directed. A major cause of failure in MMM was abuse of crack/cocaine. CONCLUSIONS: Stigma concerning enrollment in methadone treatment was a major social issue that patients faced. Many refused to inform employers, members of their families, friends, and other physicians who treated them for a various of conditions that they were methadone patients. The methadone medical maintenance physician, therefore, functions as a medical ombudsman for the patient, educating other physicians who treat the patient about methadone maintenance and its applicability to the patient. Our results can serve as a model for the expansion of office-based MMM treatment.

Inpatient intervention in an indigent, minority population with uncontrolled diabetes.

OBJECTIVE: To study whether a program of brief, intensive, inpatient intervention could improve glycemic control in an indigent, minority population with uncontrolled diabetes unresponsive to outpatient treatment. METHODS: Patients with uncontrolled diabetes unresponsive to treatment in our outpatient Diabetes Clinic were admitted to our inpatient Diabetes Unit, where their care was directed by the Diabetes Team (an attending diabetologist, an endocrinology fellow, two nurses, and two nutritionists). Of 108 patients admitted, data were available for 96. Patients from minority populations constituted 91.7% of the group. All patients were indigent. The mean duration of stay was 4.3 days. After dismissal, patients underwent follow-up again in our Diabetes Clinic. During the 540-day follow-up period, 25 patients were electively readmitted when satisfactory improvement in glycemic control was not achieved. Hemoglobin A1c levels were averaged and plotted for the group at defined time points up to 360 days before admission and up to 540 days after admission. RESULTS: During the year before admission, hemoglobin A1c increased slowly from 10.1 +/- 0.3% (mean +/- standard error) at day -360 to 10.3 +/- 0.2% at day -210 (F5 = 29; P<0.01) and then rapidly to 11.4 +/- 0.2% at admission (F7 = 1,541; P<0.001). After admission, hemoglobin A1c declined rapidly to 9.5 +/- 0.2% at day 90 (F4 = 121; P<0.005), plateaued at that level until day 240, and then declined again slowly to 9.0 +/- 0.3% at day 540, the end of the follow-up period (F10 = 70; P<0.01). All hemoglobin A1c levels 30 days or more after admission were significantly lower than the mean level at admission (P<0.05 at day 30 and P<0.001 from day 45 to day 540). CONCLUSION: Brief, intensive, inpatient intervention in an indigent, minority population with uncontrolled diabetes unresponsive to outpatient treatment produced and sustained a significant improvement in glycemic control. This mode of treatment is a practical approach to achieving the improvement in glycemic control that the Diabetes Control and Complications Trial demonstrated to be effective in delaying the onset and slowing the progression of diabetic retinopathy, nephropathy, and neuropathy.

Outcomes of treatment of socially rehabilitated methadone maintenance patients in physicians' offices (medical maintenance): follow-up at three and a half to nine and a fourth years.

OBJECTIVE: To determine whether selected socially rehabilitated former heroin addicts maintained on methadone can continue successful rehabilitation while maintained on methadone by primary care physicians rather than licensed clinics. This procedure has been termed "medical maintenance." DESIGN: Cohort study with 42-111 months of follow-up. SETTING: Offices of hospital staff physicians (internists or family practitioners). PATIENTS: The 100 patients met extensive entry criteria, including five or more years in conventional methadone maintenance treatment; stable employment or other productive activity; verifiable financial support; and no criminal involvement, use of illegal drugs, or excessive alcohol use within three or more years. MEASUREMENTS AND MAIN RESULTS: Outcome measures used were retention in treatment, discharge for one of several reasons, lost medication incidents, and substance abuse. At one, two, and three years of treatment, 98, 95, and 85 patients, respectively, remained in medical maintenance. Cumulative proportional survival in treatment was 0.735 +/- 0.048 at five years and 0.562 +/- 0.084 at nine years. After 42-111 months, 72 patients remained in good standing; 15 patients had unfavorable discharges (11 for cocaine use, three for misuse of medication, and one for administrative violations); seven voluntarily withdrew from methadone in good standing (after receiving it for 9.1-24.4 years); four died; one transferred to a chronic care facility; and one voluntarily left the program. CONCLUSIONS: Carefully selected methadone maintenance patients in medical maintenance have a high retention rate and a low incidence of substance abuse and lost medication. Voluntary withdrawal from methadone maintenance after one or two decades is possible. The authors believe that medical maintenance should be made available to appropriate patients in other localities.