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PubMed2003

A review of treatment of premenstrual syndrome and premenstrual dysphoric disorder.

Severe premenstrual syndrome (PMS) and, more recently, premenstrual dysphoric disorder (PMDD) have been studied extensively over the last 20 years. The defining criteria for diagnosis of the disorders according to the American College of Obstetricians and Gynecologists (ACOG) include at least one moderate to severe mood symptom and one physical symptom for the diagnosis of PMS and by DSM IV criteria a total of 5 symptoms with 1 severe mood symptom for the diagnosis of PMDD. There must be functional impairment attributed to the symptoms. The symptoms must be present for one to two weeks premenstrually with relief by day 4 of menses and should be documented prospectively for at least two cycles using a daily rating form. Nonpharmacologic management with some evidence for efficacy include cognitive behavioral relaxation therapy, aerobic exercise, as well as calcium, magnesium, vitamin B(6) L-tryptophan supplementation or a complex carbohydrate drink. Pharmacologic management with at least ten randomized controlled trials to support efficacy include selective serotonin reuptake inhibitors administered daily or premenstrually and serotonergic tricyclic antidepressants. Anxiolytics and potassium sparing diuretics have demonstrated mixed results in the literature. Hormonal therapy is geared towards producing anovulation. There is good clinical evidence for GnRH analogs with addback hormonal therapy, danocrine, and estradiol implants or patches with progestin to protect the endometrium. Oral contraceptive pills prevent ovulation and should be effective for the treatment of PMS/PMDD. However, limited evidence does not support efficacy for oral contraceptive agents containing progestins derived from 19-nortestosterone. The combination of the estrogen and progestin may produce symptoms similar to PMS, such as water retention and irritability. There is preliminary evidence that a new oral contraceptive pill containing low-dose estrogen and the progestin drospirenone, a spironolactone analog, instead of a 19-nortestosterone derivative can reduce symptoms of water retention and other side effects related to estrogen excess. The studies are in progress, however, preliminary evidence suggests that the drospirenone-containing pill called Yasmin may be effective the treatment of PMDD.

Androstenes↗
PubMed1998

Ovarian activity in the scimitar-horned oryx (Oryx dammah) determined by faecal steroid analysis.

Ultrasonography and radioimmunoassay (RIA) of serum oestradiol-17beta, luteinizing hormone (LH) and progesterone, and faecal oestrogen and progestin was used to assess ovarian activity in the scimitar-horned oryx (Oryx dammah). Ovarian examination using ultrasonography revealed maximal follicle and corpus luteum (CL) diameters of 15 and 32 mm, respectively. Steroid hormone metabolite distribution among individual faecal pellets within the same defaecation was relatively homogeneous with coefficients of variation averaging 10.2+/-1.8% and 16.2+/-4.6% for oestrogens and progestins, respectively. Elevated faecal oestrogen concentrations were associated with large (> 10 mm) antral follicles detected by ultrasonography. Periovulatory peaks in faecal oestrogen excretion, coincident with nadirs in progestin excretion, were detected in three females. Faecal progestin excretion exhibited a similar temporal pattern to serum progesterone concentrations, with a time lag of approximately 16 h. Faecal progestin concentrations corresponded with the presence of functional CL and proved useful for monitoring luteal function, spontaneous and prostaglandin-F2alpha analogue-induced luteolysis and anovulation. In summary, faecal steroid monitoring is a practical, noninvasive method for characterising ovarian steroid excretion and has potential for facilitating the application of assisted reproductive technologies in scimitar-horned oryx.

Animals↗
PubMed1997

Adiposity and androstenedione production in relation to delayed ovulation in the Indian bat, Scotophilus heathi.

Observations on body weight, circulating androstenedione concentrations and morphology of ovarian stroma were made in Scotophilus heathi during the period of delayed ovulation to make a comparison with polycystic ovarian syndrome in women. Body weight of bats increased from a level of 31.00 +/- 0.30 g in August and reached a peak of 45.00 +/- 0.46 g in November. This increase in body weight was due to accumulation of adipose tissue. The body weight declined gradually from December onwards and finally reached a basal level in March. The circulating androstenedione concentration showed a gradual increase from 36.80 +/- 15.54 ng/ml in August and reached a peak level of 220.50 +/- 50.10 ng/ml in November. Androstenedione concentration reached the lowest level in the March, just before ovulation. Morphological study showed extensive distribution of luteinized stromal cells or interstitial cells (ICs). Morphometric study showed that during the period of ovulatory delay, more than 75% area of the ovary was occupied by the ICs. Hyperandrogenism, anovulation, obesity (fat deposition) and stromal hyperthecosis present during delayed ovulation in S. heathi may serve as an experimental model for some aspects of the polycystic ovarian condition in women.

Adipose Tissue↗
PubMed1998

Effects of lifestyle and body composition on the ovary.

Reduction of metabolic fuel availability below the critical level by food restriction or increased expenditure is appropriately accompanied by activations of multiple neuroendocrine-metabolic changes resulting in anovulation and amenorrhea, an important device for endogenous hypothalamic contraception. This reproductive strategy in women is required because of the enormous nutritional demand for reproductive success.

Amenorrhea↗
PubMed1999

The epidemiology of polycystic ovary syndrome. Prevalence and associated disease risks.

Polycystic ovary syndrome is a common problem affecting approximately 5% of women of reproductive age when defined by clinical features of anovulation and hyperandrogenism. Metabolic derangements associated with this condition may predispose to a range of diseases with attendant morbidity and mortality risks. In general, available data support significantly increased rates of type II diabetes mellitus, dyslipidemia, and endometrial cancer in PCOS that are not completely explained by obesity; data also suggest that rates of hypertension, gestational diabetes, and pregnancy-induced hypertension may likewise be increased, although the extent to which obesity mediates these risks is not clear. The increased prevalence of several cardiovascular risk factors in PCOS and limited cross-sectional data suggest that cardiovascular disease should be more likely in PCOS, but prospective data are lacking to confirm this supposition. Limited data have suggested an association between PCOS and ovarian cancer risk and require further study. The present data do not support an increased risk for breast cancer in this condition. Long-term prospective data are clearly needed to better delineate the nature and magnitude of disease risks associated with PCOS, with appropriate adjustment for associated obesity. Such information is a necessary background for understanding the role of established and emerging PCOS therapies, including oral contraceptives, intermittent progesterone, ovulation induction agents, and insulin sensitizers, in modifying such risks. In the meantime, close follow-up of women with PCOS and encouragement of lifestyle practices likely to reduce disease risks, such as regular exercise and weight control, should be standard practice.

Cardiovascular Diseases↗
PubMed1999

Neuroendocrine aspects of polycystic ovary syndrome.

A series of investigations have emphasized the heterogeneous nature of the clinical condition known as PCOS and have delineated several factors that may contribute to the hyperandrogenemia and anovulation in this condition. Currently, it remains unclear whether intrinsic abnormalities of ovarian steroidogenesis, the effects of hyperinsulinemia in augmenting LH stimulation of ovarian androgen production, and the persistent rapid frequency of LH/GnRH secretion are primary factors in all patients. Indeed, these factors may have variable roles in different patients, all of whom present with the clinical syndrome of PCOS. A consensus has emerged that abnormalities in the neuroendocrine control of GnRH secretion exist in a significant subset of patients and lead to persistent hypersecretion of LH, which seems to be an important component of the syndrome, particularly in nonobese patients. The relative frequency of primary abnormalities in the regulation of GnRH secretion versus secondary changes reflecting altered circulating concentrations of ovarian steroid remains uncertain. No clear evidence exists for an underlying neuroendocrine abnormality of GnRH regulation in all patients. The recent data showing insensitivity of the hypothalamic GnRH pulse generator to E2 progesterone feedback have suggested potential mechanisms that may explain the abnormalities of GnRH secretion seen in adolescent girls in whom the clinical syndrome of PCOS is destined to develop. Further studies are required in adolescents to establish whether GnRH regulation is impaired during puberty or whether data in adults simply reflect the long-term effects of elevated androgens, estrogens, or other hormones on the hypothalamus. Studies in carefully delineated subgroups of patients with PCOS are needed to establish these points, with a long-term goal of providing patients with improved methods of inducing ovulation and reducing hyperandrogenemia.

Adolescent↗
PubMed1999

Cardiovascular consequences of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS), a syndrome of hyperandrogenism and anovulation with numerous associated derangements, is typified by a substantially increased incidence of type 2 diabetes mellitus and coronary disease in mid-adult life. A marker of the disorder, and a potential determinant of the macroangiopathy, is insulin resistance. Thus, in addition to altered lipid metabolism, hypertension, hormonal derangements, obesity, and altered coagulation--all of which may contribute to the development of vascular disease--the insulin resistance and dysinsulinemia may underlie impaired fibrinolysis and related derangements within the vessel walls that may be modifiable by attenuation of insulin resistance and amelioration of hyperinsulinemia.

Blood Coagulation Disorders↗
PubMed2001

Hypothalamic amenorrhea. The effects of environmental stresses on the reproductive system: a central effect of the central nervous system.

Although the treatment of anovulation has become significantly more specialized and complex in the centuries since Hippocrates, a complete understanding of the causes and mechanisms of hypothalamic amenorrhea has not been achieved. Even the best research on hypothalamic amenorrhea is plagued by the lack of longitudinal studies, the use of different exercise models, the difficulty of controlling for caloric intake, and the fact that genetics may have a role in the disorder. Continuing research on metabolic rate, leptin, and other factors will ultimately answer many of the outstanding questions and will help to create better tools for treating this disorder.

Amenorrhea↗
PubMed2000

Abnormal uterine bleeding in adolescents.

Irregular bleeding is a common complaint of adolescents and is responsible for approximately 50% of gynecologic visits in that age group. Most abnormal bleeding in adolescents is caused by immaturity of the hypothalamic-pituitary-ovarian axis resulting in anovulation. Approximately 20% of adolescents have an underlying disorder requiring targeted diagnostic testing. A thorough history and physical examination and laboratory findings will often reveal the source of abnormal bleeding. Appropriate treatment is then directed to the underlying cause.

Adolescent↗
PubMed2002

Contraceptive needs of the perimenopausal woman.

Although there are many definitions of the perimenopause, all include the concept of transition from physiologic ovulatory menstrual cycles to hyperestrogenic anovulation and ultimately to hypoestrogenic ovarian shutdown. With this comes a transition from childbearing, and its requirement for contraception, to the infertility of menopause. There is no contraceptive method that is contraindicated merely by age. The contraceptive needs of the perimenopausal woman, however, may be better suited to some methods over others. This article explores various methods of contraception for the perimenopausal woman, including female sterilization, barrier methods, intrauterine devices, injectables, implants, and oral contraceptives.

Climacteric↗
PubMed2003

Treatment of the adolescent patient with polycystic ovary syndrome.

Frequently, a multidisciplinary approach is needed in the management of the adolescent with PCOS. Treatment must be provided in a supportive environment. Because adolescent females are concerned about their appearance any image, short-term treatment goals are usually directed toward the amelioration of hirsutism, acne, and irregular menstruation. Although not immediately concerning to the adolescent, the prevention of long-term sequelae from anovulation and hyperinsulinemia is also important. Multiple concomitant therapies are often necessary to address the variety of symptoms and achieve better results. Recent studies have investigated the role of the insulin-sensitizing agent, metformin, in the treatment of PCOS. Although most studies show a benefit, the conclusions are limited owing to the small numbers of select patients, observational designs, and short durations of follow-up. In addition, there are few data comparing insulin-sensitizing drugs with traditional therapies for PCOS. More long-term, randomized controlled trials are needed to determine the utility of insulin-sensitizing agents, their long-term benefits, and the ideal patient population for their use.

Acne Vulgaris↗
PubMedDate not supplied

Neurobehavioral actions of coumestrol and related isoflavonoids in rodents.

Isoflavonoids are plant estrogens that are increasingly advocated as a natural alternative to estrogen replacement therapy (ERT) and are available as dietary supplements. As weak estrogen agonists/antagonists with a range of other enzymatic activities, the isoflavonoids provide a useful model for the actions of endocrine disruptors. This paper reviews the responses of rodents to diets containing coumestrol or an isoflavone supplement in comparison to animals fed the phytoestrogen-free AIN76A diet. Neural mechanisms were investigated by examining isoflavonoid effects on ER(alpha)-dependent (regulation of oxytocin receptor [OTR] binding in the ventromedial nucleus of the hypothalamus [VMN]) and ERbeta-dependent (regulation of ERbeta mRNA in the paraventricular nucleus [PVN]) endpoints. Activational as well as organizational effects on sexual behavior and gonadotropin secretion were observed for coumestrol. Treatment of rat dams with a 100-ppm coumestrol diet from birth to postnatal day (PND) 21 induced premature anovulation in female offspring, and treatment from birth to PND 10 suppressed sexual behavior in male offspring. One-week treatment of ovariectomized (OVX) female rats with the same coumestrol diet increased ERbeta mRNA expression in the PVN, an effect opposite to that of estradiol. Ten days of treatment with a 200-ppm coumestrol diet increased LH secretion in OVX wild-type mice, an effect opposite to the normal negative feedback effects of estradiol. No effects were observed in ER(alpha) knockout (ER(alpha)KO)-OVX females, indicating that coumestrol's action on LH was mediated through ER(alpha). Similar activational effects were observed for the isoflavone diet. The lordotic response to estrogen was significantly reduced by 2 days of treatment of OVX adult females with an isoflavone diet providing 13 ppm genistein and 33 ppm daidzein. One week of treatment with the same isoflavone diet produced an effect opposite to that of estradiol in the PVN, increasing ERbeta mRNA expression above control levels. These investigations show that, in spite of their preferential affinity for ERbeta, isoflavonoids act through both ER(alpha) and ERbeta. Moreover, their neurobehavioral actions were antiestrogenic, either antagonizing or producing an action in opposition to that of estradiol. This work demonstrates that even small, physiologically relevant exposure levels can alter estrogen-dependent gene expression in the brain and complex behavior.

Animals↗
PubMed1998

Adverse lipid and coronary heart disease risk profiles in young women with polycystic ovary syndrome: results of a case-control study.

Polycystic ovary syndrome (PCOS), a disorder of hyperandrogenism and chronic anovulation affects 5%-10% of all women. Women with PCOS often have elevated cardiovascular risk factors. A total of 244 PCOS cases were identified through the Division of Reproductive Endocrinology at Magee-Womens Hospital and were age-matched to 244 neighborhood controls. The average age of cases and controls was 35.3 +/- 7.4 and 36.7 +/- 7.7. Women with PCOS compared to controls had substantially higher LDL-C and total cholesterol levels at each age group under 45 years after adjustment for body mass index, hormone use, and insulin levels. In the over 40-year age group, little difference was noted between cases and controls. Among cases and controls (<40), PCOS predicted LDL-C, total cholesterol and triglycerides, but did not have a significant effect on lipid levels in older cases and controls after controlling for the other variables. The primarily pre- to perimenopausal PCOS cases > or =40 years of age have similar LDL-C and total cholesterol levels as their age-matched controls, probably reflecting the LDL-C increase with age among controls.

Adult↗
PubMed2003

Higher androgens and weight gain with valproate compared with lamotrigine for epilepsy.

BACKGROUND: Valproate is used widely for the treatment of epilepsy but has been associated with hyperandrogenism, hyperinsulinemia, and dyslipidemia. The mechanism for these associations is unknown, but they have been hypothesized to be secondary to valproate-associated weight gain. This study was conducted to test the hypothesis that the antiepileptic drug lamotrigine, which also has a broad spectrum of anti-seizure efficacy, would not be associated with endocrine abnormalities and would not cause weight gain. OBJECTIVE AND METHODS: This open-label, cross-sectional study compared (1) endocrine and lipid measures during the early follicular phase of the menstrual cycle; (2) prevalence of menstrual disorders (from patient diaries recorded over three cycles); and (3) body weight of women with epilepsy on lamotrigine monotherapy (n=119) with those on valproate monotherapy (n=103) for <5 years. RESULTS: Mean total serum testosterone and androstenedione levels were higher (P<0.02) in the valproate group compared with the lamotrigine group. More lamotrigine patients (87%) than valproate patients (77%) reported regular menstrual cycles at the Screening Visit. The prevalence of anovulation did not differ between lamotrigine and valproate. Mean HDL cholesterol levels were higher (P<0.01) with lamotrigine compared with valproate as were LDL and total cholesterol levels (P<0.05). Mean total insulin levels did not significantly differ between the groups. Whereas mean body weight in lamotrigine patients did not differ between the time lamotrigine treatment was initiated and the Study Visit, mean weight in valproate patients increased by 3.7 kg. CONCLUSIONS: Compared with lamotrigine monotherapy, valproate monotherapy was associated with weight gain and higher androgen levels in women with epilepsy. These data suggest that the hyperandrogenism observed in some women using valproate for epilepsy may be secondary to drug therapy. Lamotrigine monotherapy may be more appropriate than valproate for women in whom reproductive endocrine or metabolic abnormalities are potential concerns, i.e. women with concerns about weight gain, diabetes, hirsutism, polycystic ovary syndrome, menstrual dysfunction or infertility.

Adult↗
PubMed2000

[Menstrual cycle disorders in adolescents].

Long cycles and excessive uterine bleeding are the most common menstrual disorders in adolescents. Long cycles usually result from a benign transitory functional disorder which spontaneously resolves within two to three years after menarche; however, this diagnosis can only be retained in the absence of hirsutism or galactorrhea as revealing symptoms of functional ovarian hyperandrogenism, polycystic ovary syndrome, late form of congenital adrenal hyperplasia or hyperprolactinemia; ovarian failure will be considered in case of isolated long cycles persisting more than two years after menarche. Excessive uterine bleeding usually occurs early after menarche. Although the main cause is functional, resulting from anovulation and the related absence of progesterone, coagulation disorders must always be excluded. Management of these disorders are described.

Adolescent↗
PubMed1987

Physical exercise and the neuroendocrine control of reproduction.

Reproductive change during conditioning exercise (physical training provides a model of hypothalamic adaptation to alterations in the external and internal environment. Parallels exist between the reproductive changes with exercise and those occurring with physical illness, undernutrition and psychological trauma. Although menstrual cyclicity may be disrupted in younger women, luteal phase shortening, anovulation and decreased premenstrual symptoms within normal ovulatory cycles are the most frequent observations noted. Baseline LH, prolactin and oestradiol tend to be lower, and other hormones unchanged, in trained women. Testosterone may be decreased within the normal range in men. Recent evidence shows that LH pulse frequency, amplitude and area under the LH curve are decreased in both female and male runners. Interrelationships between increases in central dopamine, endorphin and probably some hypothalamic message(s) relating to nutritional state appear to modulate these reproductive changes. The clinical and therapeutic response to reproductive alterations in the context of exercise differs when these are seen as adaptive and not as disease processes (Prior and Vigna, 1985b).

Energy Metabolism↗
PubMed1996

Neuroendocrinology of the polycystic ovary syndrome.

The clinical and biochemical heterogeneity of the PCOS is mirrored by the range of neuroendocrine disturbances described in women with PCOS. An increased serum LH concentration is a common, although not ubiquitous, feature and occurs primarily as a result of an increase in the amplitude of pulsatile LH, and presumably GnRH, secretion. The frequency of pulsatile GnRH secretion may, however, be increased in certain patients and may conceivably increase LH bioactivity by altering glycosylation of the molecule. Vigorous debate continues as to whether the observed changes in gonadotrophins are a primary abnormality or occur secondary to alterations in peripheral steroid concentrations. The proponents of the frequency hypothesis point to the discordant changes in gonadotrophin secretion that may be induced by rapid frequency exogenous GnRH stimulation in patients with hypogonadotrophic hypogonadism. Those who believe that the inappropriate gonadotrophin secretion is a secondary phenomenon argue that manipulation of peripheral steroid levels, by either administration of oestrogen/progesterone, induced ovulation or ovarian diathermy, may correct the disturbance of gonadotrophin secretion, which is therefore presumably a consequence of changes in ovarian steroid feedback signals. The weight of evidence at present suggests that the inappropriate gonadotrophin secretion is usually a secondary abnormality, although there may be groups of patients with a primary increase in GnRH pulsatility. The search for a unifying neuroendocrine disturbance in PCOS has been frustrated by the inability to find consistent evidence of disordered central dopaminergic, opioidergic, noradrenergic or serotoninergic pathways. Those abnormalities which have been uncovered appear to be secondary to chronic anovulation rather than of primary pathological import, and emphasize the central importance of the ovary as culprit rather than victim in PCOS.

Female↗
PubMed1993

The differential effects of FSH and LH on the human ovary.

The basic foundation for normal puberty and adult reproductive function is established during fetal life with the adequate development of the hypothalamus, pituitary and gonads. Further maturation and differentiation of the hypothalamic-pituitary-gonadal axis continues throughout childhood, puberty, adult life and senescence. Pituitary FSH and LH play a central role in the cascade of events in the hypothalamic-pituitary-gonadal axis by mediating between the brain and hypothalamus on one hand and the end-organ, the ovary, on the other. Absent or low pituitary secretion of FSH and LH, as occurs in hypothalamic/pituitary hypogonadism, leads in women to anovulation, amenorrhoea and absent ovarian follicular development. The ability of gonadotrophins to modulate ovarian function depends on their rate of synthesis by the pituitary gonadotrophs, on their circulating concentrations (which vary throughout life and throughout the menstrual cycle), on the relative abundance of the multiple forms of gonadotrophins that have varying biological activity, on the presence of their receptors on the different cell types of the ovary, on the intracellular adenylate cyclase enzyme that causes the production of cAMP, and on the extra- and intragonadal factors that are able to modulate the effects of gonadotrophins in the ovary. Recent clinical and basic research with recombinant gonadotrophins, molecular biological studies on the localization, function and regulation of the long sought after gonadotrophin receptors, as well as research on the interaction between gonadotrophins and local intragonadal factors have widened our knowledge about the function and role of FSH and LH in the ovary and have provided new insights into previously unanswered questions of ovarian physiology and pathophysiology and will provide the basis for the design of new treatment strategies to overcome ovulatory gonadotrophin-dependent dysfunction in the future.

Animals↗