Vaginal progesterone and the vaginal first-pass effect.

Vaginal progesterone is an effective alternative to systemic administration by oral or intramuscular use. The first-pass effect is reviewed, as are the most common uses for this route of delivery. This includes use in hormone replacement therapy, luteal support particularly in assisted reproduction, and avoidance of side-effects of oral progestins and progesterone. Vaginal progesterone represents a unique therapeutic solution to a number of clinical problems.

In Vitro Detection of Caries Around Amalgam Restorations Using Four Different Modalities.

OBJECTIVE: The aim of this study was to evaluate the ability of PTR-LUM (The Canary System, CS), laser fluorescence (DIAGNOdent, DD), LED fluorescence (Spectra), and visual inspection (ICDAS II) to detect natural decay around bonded amalgam restorations in vitro. METHODS: Seventeen extracted human molars and premolars, consisting of visually healthy (n=5) and natural cavitated (n=12) teeth were selected. For the carious teeth, caries was removed leaving some decayed tissue on the floor and or wall of the preparation. For sound teeth, 3 mm. deep cavity preparations were made and teeth were restored with bonded-amalgam restorations. Thirty-six sites (13 sound sites; 23 carious sites) were selected. CS and DD scans were performed in triplicate at 2, 1.5, 0.5, and 0 mm away from the margin of the restoration (MOR). Spectra images were captured for the entire surface, and dentists blinded to the samples provided ICDAS II scoring. RESULTS: Canary Numbers (Mean±SE) for healthy and carious sites at 2, 1.5, 0.5, and 0 mm from the MOR ranged from 12.9±0.9 to 15.4±0.9 and 56.1±4.0 to 56.3±2.0, respectively. DD peak values for healthy and carious sites ranged from 4.7±0.5 to 13.5±2.99, and 16.7±3.7 to 24.5±4.4, respectively. For CS and DD, sensitivity/specificity for sites at 2.0, 1.5, 0.5, 0 mm ranged from 0.95-1.0/0.85-1.0, and 0.45-0.74/0.54-1.0, respectively. For ICDAS II, sensitivity and specificity were 1.0 and 0.17, respectively. For Spectra, data and images were inconclusive due to signal intereference from the amalgam restoration. CONCLUSIONS: Using this in-vitro model, CS and DD were able to differentiate between sound and carious tissue at the MOR, but larger variation, less reliability, and poorer accuracy was observed for DD. Therefore, CS has the potential to detect secondary caries around amalgam restorations more accurately than the other investigated modalities.

Correlation with Caries Lesion Depth of The Canary System, DIAGNOdent and ICDAS II.

INTRODUCTION: The aim of this study was to correlate lesion depth of natural caries, measured with Polarized Light Microscopy (PLM), to Canary Numbers (CN) derived from The Canary System™ (CS), numerical readings from DIAGNOdent (DD), and lesion scores from ICDAS II. METHODS: A total of 20 examination sites on extracted human molars and premolars were selected. The selected examination sites consisted of healthy and enamel caries on smooth and occlusal surfaces of each tooth. Two blinded dentists ranked each examination site using ICDAS II and the consensus score for each examined site was recorded. The same examination sites were scanned with CS and DD, and the CN and DD readings were recorded. After all the measurements were completed, the readings of the three caries detection methods were validated with a histological method, Polarized Light Microscopy (PLM). PLM performed by blinded examiners was used as the 'gold standard' to confirm the presence or absence of a caries lesion within each examined site and to determine caries lesion depth. RESULTS: Pearson's coefficients of correlation with caries lesion depth of CNs, DD readings and ICDAS scores were 0.84, 0.21 and 0.77, respectively. Mean ± SD CN for sound sites (n=3), caries lesion depths <800 µm (n=11), and caries lesion depths >800 µm (n=6) were 11±1, 55±15, and 75±22, respectively. Mean ± SD DD readings for sound sites, caries lesion depths <800 µm, and caries lesion depths >800 µm were 1±1, 7±11, and 8±9, respectively. Mean ± SD ICDAS II scores for sound sites, caries lesion depths <800 µm, and caries lesion depths >800 µm were 0±0, 2±1, and 2±1, respectively. The intra-operator repeatability for the Canary System was .953 (0.913, 0.978). CONCLUSION: This study demonstrated that the CS exhibits much higher correlation with caries lesion depth compared to ICDAS II and DD. CS may provide the clinician with more information about the size and position of the lesion which might help in monitoring or treating the lesion.The present extracted tooth study found that The Canary System correlates with caries lesion depth more accurately that ICDAS II and DIAGNOdent.

Food fortification for bone health in adulthood: a scoping review.

Food fortification can deliver essential micronutrients to large population segments without modifications in consumption pattern, suggesting that fortified foods may be formulated for populations at risk for fragility fractures. This scoping review determined the extent to which randomized controlled studies have been carried out to test the impact of fortified foods on bone outcomes, searching PubMed for all studies using the terms 'fortified AND bone', and 'fortification AND bone'. Studies were restricted to English language, published between 1996 and June 2015. From 360 articles, 24 studies met the following criteria: human study in adults ⩾18 years (excluding pregnancy or lactation); original study of a fortified food over time, with specific bone outcomes measured pre- and post intervention. Six studies involved adults <50 years; 18 involved adults ⩾50 years. Singly or in combination, 17 studies included calcium and 16 included vitamin D. There were 1 or 2 studies involving either vitamin K, magnesium, iron, zinc, B-vitamins, inulin or isoflavones. For adults <50 years, the four studies involving calcium or vitamin D showed a beneficial effect on bone remodeling. For adults ⩾50 years, n=14 provided calcium and/or vitamin D, and there was a significant bone turnover reduction. No consistent effects were reported in studies in which addition of vitamin K, folic acid or isoflavone was assessed. Results from this scoping review indicate that up to now most studies of fortification with bone health have evaluated calcium and/or vitamin D and that these nutrients show beneficial effects on bone remodeling.

Missed symptoms of menopause.

OBJECTIVE: This review examines the available data on the efficacy of selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs) for treating the commonly missed climacteric symptoms of menopause. DISCUSSION: Although some women may pass through the menopausal transition phase with few or no symptoms, the majority experience one or more symptoms serious enough to be disruptive to their lives. The most common are vasomotor symptoms (VMS; hot flushes and night sweats), but they are not the only climacteric symptoms that can negatively affect quality of life. The 'missed symptoms' of menopause -- symptoms with high prevalence and an impact on quality of life that nonetheless receive less attention than do VMS -- include mood changes, sleep disturbances and somatic complaints. These symptoms are reported by approximately half of menopausal women, with numbers varying by region and ethnic background. As with VMS, the effects of declining oestrogen levels on serotonin/noradrenaline pathways could play a role in their development. CONCLUSIONS: Results from pilot studies of several SSRIs and SNRIs suggest that they may improve menopausal mood and sleep symptoms, but few studies have demonstrated significant improvement compared with placebo. One SNRI (venlafaxine) improved menopausal mood symptoms and two SSRIs (citalopram and paroxetine) improved sleep, each in a single placebo-controlled trial of women with VMS. Additional placebo-controlled trials are needed to determine whether SSRIs or SNRIs are effective treatment options for women who cannot or choose not to use hormone therapy.

The genetics, diagnosis and treatment of amenorrhea.

The menstrual cycle is regulated by complex feedback interactions between the ovaries, pituitary and hypothalamus. A disruption at any point in one of these pathways may lead to irregularities in the menstrual cycle. In particular, amenorrhea, the cessation of menstrual functioning, serves as an indicator of ovarian, pituitary and/or hypothalamic dysfunction. Historically, diagnosing and treating amenorrhea presented medical professionals with numerous practical difficulties. In recent years, however, studies of amenorrhea have yielded new understandings and new treatments of the disorder. This paper synthesizes these current methodologies for diagnosing, treating and understanding both primary and secondary amenorrhea.

Effects of a triphasic combination oral contraceptive containing norgestimate/ethinyl estradiol on biochemical markers of bone metabolism in young women with osteopenia secondary to hypothalamic amenorrhea.

This multicenter, double-blind, placebo-controlled, randomized study of 45 patients evaluated the short-term effects of an oral contraceptive [Ortho Tri-Cyclen, 180-250 micro g of norgestimate (NGM) and 35 microg of ethinyl estradiol (EE)] on biochemical markers of bone resorption, formation, and osteoprotegerin in young women (mean age +/- SD, 26.5 +/- 6.3 yr) with hypothalamic amenorrhea and osteopenia. Body fat, endocrine, and cognitive function were evaluated as secondary endpoints. Biomarkers of bone metabolism were measured at baseline and after three cycles of NGM/EE or placebo. There were significant decreases in mean values of N-telopeptide [mean (SD), -13.4 (13.4) vs. 1.2 (23.8) nmol bone collagen equivalents (BCE)/mmol creatinine (Cr); P = 0.001] and deoxypyridinoline [-1.2 (2.9) vs. -0.5 (1.5) nmol deoxypyridinoline/mmol Cr; P = 0.021] as well as significant decreases in bone specific alkaline phosphatase [-5.1 (3.5) vs. 0.4 (3.1) ng/ml; P < 0.001], osteocalcin [-5.9 (3.6) vs. -2.9 (3.7); P = 0.016], and procollagen of type I propeptide [-35.2 (44.6) vs. -0.2 (30.0) ng/ml; P = 0.025], but not osteoprotegerin [0.39 (1.46) vs. -0.2 (0.49) pmol/liter; P = 0.397] in the NGM/EE vs. placebo group. There were no significant differences between groups with respect to changes in cognitive function, mood, body weight, body mass index, body fat, percentage of body fat, and all endocrine levels except FSH, [-3.7 (3.8) vs. -0.6 (2.1) IU/liter; P < 0.001, NGM/EE vs. placebo]. No serious adverse events were reported in either group. These results suggest that NGM/EE decreases bone turnover in osteopenic premenopausal women with hypothalamic amenorrhea. Further studies are needed to determine whether estrogen will increase bone density in this population.

Exercise-induced endocrine pathologies.

There has been a substantial increase in women practicing sports over the past 30 yr. While exercise provides many health benefits, there appears to be a unique set of risks associated with intense exercise for the female athlete. The female athlete triad encompasses these risks, including amenorrhea, osteoporosis and eating disorders. The incidence of menstrual irregularities including primary and secondary amenorrhea and shortened luteal phases is much higher among women partaking in athletics, specifically in sports requiring low body weight for performance and aesthetics. The hormone pattern seen in these amenorrheic athletes includes a decrease in GnRH pulses from the hypothalamus, which results in decreased pulsatile secretion of LH and FSH and shuts down stimulation of the ovary. The recently discovered hormone leptin may also play a large role as a significant mediator of reproductive function. The prevalence of eating disorders is high among female athletes who practice sports which emphasize leanness. Consequently, the cause of menstrual irregularities is not due to the exercise alone, but to chronic inadequate or restrictive caloric intake that does not compensate for the energy expenditure. The most dangerous risk associated with amenorrhea for the female athlete is the impact on the skeleton. Complications associated with amenorrhea include compromised bone density, failure to attain peak bone mass in adolescence and increased risk of stress fractures. The diagnosis of exercise-associated menstrual dysfunctions is one of exclusion. The most effective treatment is to decrease the intensity of the exercise and increase the nutritional intake. Hormone replacement has also been under investigation as a possible treatment.

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.

Temporomandibular disorders and hormones in women.

Temporomandibular disorders (TMD) are loosely defined as an assorted set of clinical conditions, characterized by pain and dysfunction of the masticatory system. Pain in the masticatory muscles, in the temporomandibular joint (TMJ), and in associated hard and soft tissues, limitation in jaw function, and sounds in the TMJ are common symptoms. That women make up the majority of patients treated for TMD is extensively hypothesized and documented in numerous epidemiological studies. Certain contradictory studies exist which propose that there are no statistically significant gender differences in the actual incidence of changes in joint morphology. Nonetheless, extensive literature suggests the disorder is 1.5-2 times more prevalent in women than in men, and that 80% of patients treated for TMD are women. The severity of symptoms is also related to the age of the patients. Pain onset tends to occur after puberty, and peaks in the reproductive years, with the highest prevalence occurring in women aged 20-40, and the lowest among children, adolescents, and the elderly. The gender and age distribution of TMD suggests a possible link between its pathogenesis and the female hormonal axis. In this review, we will use the hypothesis that the overwhelming majority of patients treated for temporomandibular disorders are women and use the available literature to examine the role of hormones in TMD.

The effects of intense exercise on the female reproductive system.

Women have become increasingly physically active in recent decades. While exercise provides substantial health benefits, intensive exercise is also associated with a unique set of risks for the female athlete. Hypothalamic dysfunction associated with strenuous exercise, and the resulting disturbance of GnRH pulsatility, can result in delayed menarche and disruption of menstrual cyclicity. Specific mechanisms triggering reproductive dysfunction may vary across athletic disciplines. An energy drain incurred by women whose energy expenditure exceeds dietary energy intake appears to be the primary factor effecting GnRH suppression in athletes engaged in sports emphasizing leanness; nutritional restriction may be an important causal factor in the hypoestrogenism observed in these athletes. A distinct hormonal profile characterized by hyperandrogenism rather than hypoestrogenism is associated with athletes engaged in sports emphasizing strength over leanness. Complications associated with suppression of GnRH include infertility and compromised bone density. Failure to attain peak bone mass and bone loss predispose hypoestrogenic athletes to osteopenia and osteoporosis. Metabolic aberrations associated with nutritional insult may be the primary factors effecting low bone density in hypoestrogenic athletes, thus diagnosis should include careful screening for abnormal eating behavior. Increasing caloric intake to offset high energy demand may be sufficient to reverse menstrual dysfunction and stimulate bone accretion. Treatment with exogenous estrogen may help to curb further bone loss in the hypoestrogenic amenorrheic athlete, but may not be sufficient to stimulate bone growth. Treatment aimed at correcting metabolic abnormalities may in fact prove more effective than that aimed at correcting estrogen deficiencies.

Natural vaginal progesterone is associated with minimal psychological side effects: a preliminary study.

The objective of this study was to evaluate the psychological side effects of a transvaginal natural progesterone gel in hormone replacement therapy (HRT). This 3-month preliminary study was part of a multicenter study previously performed in our center. We enrolled 49 women (ages 18-45 years) with hypothalamic amenorrhea (HA) (n = 40) and premature ovarian failure (POF) (n = 9). Estrogenized patients applied vaginal progesterone gel (4% or 8%) every other day for six doses per month. The Hopkins Symptom Checklist (HSCL), a psychometric profile test, was administered at baseline, day 13 of cycle 2, day 24 of cycle 2, and day 24 of cycle 3. Application of the progesterone gel caused no significant change in HSCL total scores or individual symptom scores for somatization, obsession-compulsion, interpersonal sensitivity, depression, and anxiety. Natural vaginal progesterone gel can be an effective alternative to oral progesterone for women on HRT.

The female athlete.

Over the past 30 years, the number of women participating in organized sports has grown dramatically. Several forms of menstrual irregularities have been described in the female athlete: primary and secondary amenorrhoea, oligomenorrhoea, short luteal phases and anovulation. The incidence of menstrual irregularities is much higher in activities where a thin body is required for better performance. The hormonal pattern seen in these athletes is a hypothalamic amenorrhoea profile. There appears to be a decrease in gonadotrophin-releasing hormone (GnRH) pulses from the hypothalamus, which in turn decreases the pulsatile secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and shuts down stimulation of ovary. Recently, another type of amenorrhoea has been described in swimmers which is characterized by mild hyperandrogenism. Athletes with low weight are at risk of developing the female athletic triad, which includes amenorrhoea, osteoporosis and disordered eating. Athletes with this triad are susceptible to stress fractures. Other issues include the pregnant athlete. Intensive exercise during pregnancy can cause bradycardia. Safe limits of aerobic exercise in pregnancy depend on previous exercise habits. Infertility, which may develop with exercise, is probably reversible with reduction of exercise or weight gain. High impact sports activities may produce urinary incontinence. Oestrogen replacement therapy is often prescribed in amenorrhoeic athletes, but bone loss may not be completely reversible.

Exercise and female adolescents: effects on the reproductive and skeletal systems.

It is generally accepted that exercise is beneficial for young women, since it increases cardiovascular fitness and reduces adiposity. Too much exercise can have negative effects on the reproductive and skeletal systems, however, including primary and secondary amenorrhea thought to be caused by several factors including low body weight and improper nutrition. Primary and secondary amenorrhea present similar patterns of luteinizing hormone and follicle stimulating hormone suppression, probably involving the hypothalamic-pituitary-gonadal axis and possibly also the hypothalamic-pituitary-adrenal axis. Recent research has also suggested that leptin (a hormone made by the fat cell) is a possible link between menstrual cycles and fat and energy levels. The female athletic triad consists of three interrelated problems: eating disorders, amenorrhea, and osteopenia. The most serious aspect of hypoestrogenism is its effect on bone growth of elite athletes; those with delayed menarche show a higher incidence of scoliosis, stress fractures, and osteopenia than do girls with normal menarche. The higher incidence of bone problems may be linked to a lower rate of bone accretion, which may lead to lower peak bone mass. Unfortunately, the loss may be irreversible. In addition to decreasing training and gaining weight, treatment for menarcheal delay may include oral contraceptive therapy.

Uses of progesterone in clinical practice.

Progesterone is the natural progestagen produced by the corpus luteum during the luteal phase. It is absorbed when administered orally, but is greater than 90% metabolized during the first hepatic pass. This greatly limits the efficacy of once-daily administration and also results in unphysiologically high levels of progesterone metabolites, particularly those reduced at the 5-a position. These metabolites can cause dizziness and drowsiness to the point of preventing the operation of a motor vehicle. Synthetic progestins, such as medroxyprogesterone acetate and norethindrone acetate (NETA), have been specifically designed to resist enzymatic degradation and remain active after oral administration. However, these compounds exert undesirable effects on the liver and often cause severe psychological side effects. The permeability of the skin does not allow for administration of progesterone in the quantities normally produced by the corpus luteum, i.e., up to 25 mg/day during the mid-luteal phase. To avoid this problem, synthetic progestins such as NETA have been administered transdermally. These compounds, though, just like synthetic estrogens administered non-orally, retain undesirable hepatic effects even when administered transdermally. Transvaginal administration of progesterone is a practical non-oral route available for administering progesterone. Early experience was gained with vaginal suppositories, which lack manufacturing controls. Recently, a new progesterone gel formulation has been designed for vaginal use. The clinical acceptability of this product has been enhanced by the bioadhesive characteristics of its polycarbophil-based gel, which conveys controlled and sustained-released properties. Investigations have shown that because of local direct vagina-to-uterus transport, which results in a preferential uterine uptake of progesterone, this formulation given in conjunction with physiological amounts of estradiol produces endometrial changes similar to those seen in the luteal phase, despite plasma progesterone levels that remain subphysiologic. Studies in infertility show that vaginal progesterone in this form allows secretory transformation of the endometrium and the development of pregnancy despite providing low systemic progesterone concentrations. Fewer side effects occur when used for hormone replacement than typically encountered with progestins and oral progesterone. Uses in patients with infertility and hypoestrogenism and secondary amenorrhea are reviewed.

Functional hypothalamic amenorrhea: hypoleptinemia and disordered eating.

Because the exact etiology of functional, or idiopathic, hypothalamic amenorrhea (FHA) is still unknown, FHA remains a diagnosis of exclusion. The disorder may be stress induced. However, mounting evidence points to a metabolic/nutritional insult that may be the primary causal factor. We explored the thyroid, hormonal, dietary, behavior, and leptin changes that occur in FHA, as they provide a clue to the etiology of this disorder. Fourteen cycling control and amenorrheic nonathletic subjects were matched for age, weight, and height. The amenorrheic subjects denied eating disorders; only after further, detailed questioning did we uncover a higher incidence of anorexia and bulimia in this group. The amenorrheic subjects demonstrated scores of abnormal eating twice those found in normal subjects (P < 0.05), particularly bulimic type behavior (P < 0.01). They also expended more calories in aerobic activity per day and had higher fiber intakes (P < 0.05); lower body fat percentage (P < 0.05); and reduced levels of free T4 (P < 0.05), free T3 (P < 0.05), and total T4 (P < 0.05), without a significant change in rT3 or TSH. Cortisol averaged higher in the amenorrheics, but not significantly, whereas leptin values were significantly lower (P < 0.05). Bone mineral density was significantly lower in the wrist (P < 0.05), with a trend to lower BMD in the spine (P < 0.08). Scores of emotional distress and depression did not differ between groups. The alterations in eating patterns, leptin levels, and thyroid function present in subjects with FHA suggest altered nutritional status and the suppression of the hypothalamic-pituitary-thyroid axis or the alteration of feedback set-points in women with FHA. Both lower leptin and thyroid levels parallel changes seen with caloric restriction. Nutritional issues, particularly dysfunctional eating patterns and changes in thyroid metabolism, and/or leptin effects may also have a role in the metabolic signals suppressing GnRH secretion and the pathogenesis of osteopenia despite normal body weight. These findings suggest that the mechanism of amenorrhea and low leptin in these women results mainly from a metabolic/nutritional insult.