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1.  Safety, efficacy, actions, and patient acceptability of drospirenone/ethinyl estradiol contraceptive pills in the treatment of premenstrual dysphoric disorder 
Premenstrual dysphoric disorder (PMDD) is estimated to affect 3%–8% of reproductive age women. Multiple therapeutic modalities have been evaluated with varying efficacy for the associated somatic and mood symptoms. The majority of older studies had shown that oral contraceptive pills (OCs) were most effective for the physical symptoms. However, newer OCs containing a novel progestin, drospirenone, have shown promise in alleviating both the somatic and affective/behavioral symptoms. This progestin, which is a derivative of spironolactone, has both antimineralocorticoid and antiandrogenic activity. A 24/4 formulation containing 20 μg of ethinyl estradiol has been found effective in randomized double-blind placebo-controlled trials utilizing established scales documenting symptoms associated with PMDD. Multiple studies have shown that drospirenone-containing OCs are safe without evidence of clinically adverse effects on carbohydrate metabolism, lipids, blood pressure, weight, serum potassium or increased thrombotic events compared to other low dose OCs. In addition, significant improvements have been demonstrated in acne, hirsutism, and fluid retention symptoms. Several open label studies demonstrated good patient compliance and reported satisfaction with the method. Because of the significant placebo effect demonstrated in the blinded placebo-controlled trials, additional large randomized placebo-controlled trials are needed to confirm the efficacy of the drospirenone OCs in the treatment of PMDD. However, this OC formulation appears to be a promising therapeutic modality.
PMCID: PMC2971718  PMID: 21072278
drospirenone; premenstrual dysphoric disorder; premenstrual syndrome; oral contraceptive pill
2.  Hormonal contraception in women with migraine: is progestogen-only contraception a better choice? 
A significant number of women with migraine has to face the choice of reliable hormonal contraception during their fertile life. Combined hormonal contraceptives (CHCs) may be used in the majority of women with headache and migraine. However, they carry a small, but significant vascular risk, especially in migraine with aura (MA) and, eventually in migraine without aura (MO) with additional risk factors for stroke (smoking, hypertension, diabetes, hyperlipidemia and thrombophilia, age over 35 years). Guidelines recommend progestogen-only contraception as an alternative safer option because it does not seem to be associated with an increased risk of venous thromboembolism (VTE) and ischemic stroke.
Potentially, the maintenance of stable estrogen level by the administration of progestins in ovulation inhibiting dosages may have a positive influence of nociceptive threshold in women with migraine. Preliminary evidences based on headache diaries in migraineurs suggest that the progestin-only pill containing desogestrel 75 μg has a positive effect on the course of both MA and MO in the majority of women, reducing the number of days with migraine, the number of analgesics and the intensity of associated symptoms. Further prospective trials have to be performed to confirm that progestogen-only contraception may be a better option for the management of both migraine and birth control. Differences between MA and MO should also be taken into account in further studies.
doi:10.1186/1129-2377-14-66
PMCID: PMC3735427  PMID: 24456509
Migraine with aura (MA); Migraine without aura (MO); Combined hormonal contraceptives (CHCs); Combined oral contraceptives (COCs); Progestogen-only contraception; Desogestrel-only pill; Venous thromboembolism (VTE); Stroke
3.  Hormonal Contraception and Metabolic Outcomes in Women with or at Risk for HIV Infection 
Introduction
The use of hormonal contraception (HC) is increasing in HIV-infected women. Both HC and HIV infection have been associated with adverse metabolic outcomes. We investigated the association of progestin-only and combined (estrogen/progestin) HC with disorders of glucose and lipid metabolism in HIV-infected and uninfected women.
Methods
Linear mixed models evaluated the association of HC type with fasting HDL, LDL, triglycerides, the homeostasis model assessment estimate of insulin resistance (HOMA-IR), and glucose in 885 HIV-infected and 408 HIV-uninfected women from the Women's Interagency HIV Study seen between October 2000 and September 2005.
Results
Compared to non-HC users, progestin-only HC was independently associated with lower HDL (-3mg/dL;95% confidence interval[CI]:-5,-1 in HIV-infected and -6mg/dL;95% CI:-9,-3 in HIV-uninfected women), greater HOMA (+0.86;95% CI:0.51,1.22 and +0.56;95% CI:0.12,1.01). Combined HC was associated with higher HDL(+5mg/dL;95% CI:2,7 and +5mg/dL;95% CI:3,7).
Conclusion
Progestin–only HC is associated with lower HDL and greater HOMA-IR than non-HC users. Combined HC may be preferred in HIV-infected women of reproductive age at risk for cardiovascular disease, but interactions with antiretroviral therapy that may impair contraceptive efficacy have been reported. Alternative HC methods that minimize adverse outcomes but maintain efficacy require further study.
PMCID: PMC2886798  PMID: 19950431
HIV/AIDS; hormonal contraception; Depo Provera®; HDL; triglycerides
4.  Breast cancer and specific types of combined oral contraceptives. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. 
British Journal of Cancer  1992;65(1):108-113.
Data on 2,754 cases and 18,565 controls from a multinational hospital-based, case-control study were analysed to determine whether observed associations between combined oral contraceptives and breast cancer are similar for oral contraceptives with varying types and doses of oestrogens and progestins. After stratifying on duration of use, risk was found to be increased in current and recent users, and to decline with time since last use. These associations, of similar strength, were observed for users of products that contain mestranol and ethinyl estradiol, for women who used preparations with progestins derived from 19-nortestosterone and 17-alpha-hydroxyprogesterone, and for those who took preparations with relatively higher and lower doses of oestrogen. When products with equal doses of the same oestrogen or progestin and varying doses of the other hormonal constituent were considered, slightly higher relative risks per year of use were estimated for users of products with relatively higher than lower doses of either the constituent oestrogen or progestin, but the differences in relative risk could readily have occurred by chance. This study provides no evidence that risk of breast cancer in users of oral contraceptives varies by the type of oestrogen or progestin consumed.
PMCID: PMC1977361  PMID: 1733433
5.  Drospirenone/ethinyl estradiol 3 mg/20 μg (24/4 day regimen): hormonal contraceptive choices – use of a fourth-generation progestin 
The combined oral contraceptive pill (COC) consisting of drospirenone 3 mg/ethinyl estradiol 20 μg (3 mg DRSP/20 μg EE-24/4) supplies 24 days of pills with hormones followed by 4 days of hormone-free pills. This regimen is called the 24/4 regimen. The progesterone component of this oral contraceptive pill (OCP), drospirenone (DRSP), is a fourth-generation progestin that has potent progestogenic, antimineralocorticoid, and antiandrogenic activity, which are unique characteristics compared with the other progestogens contained in most of the other OCPs currently marketed. This formulation, in addition to being an effective long-term OCP, has the additional medical benefit of providing a good parallel treatment for premenstrual dysphoric disorder and moderate acne. The effectiveness of 3 mg DRSP/20 μg EE-24/4, its tolerability and safety, and its additional non-contraceptive benefits are discussed.
PMCID: PMC2778416  PMID: 19936169
drospirenone; premenstrual dysphoric disorder; acne vulgaris; contraception; antimineralocorticoid activity; antiandrogenic activity
6.  The link between neurosteroids and syndromic/syndromal components of the mood spectrum disorders in women during the premenstrual phase 
Objectives
Females with a lifetime diagnosis of major mood disorder (Bipolar Disorder BD, Major Depressive Disorder MMD) investigated during the luteal phase of their menstrual cycle and in a condition of clinical well-being showed higher blood serum concentrations of progesterone and allopregnanolone compared to healthy controls. Women with BD presented even higher levels than those affected by MDD. This study attempted to verify, in line with a dimensional approach, if the possible differences in neurohormonal levels may be directly linked to some syndromal clusters (dimensions) of the mood spectrum disorders indipendently of diagnosis.
Methods
Premenstrual concentrations of allopregnanolone, THDOC, progesterone, and cortisol were measured in 3 groups of women: 17 BD and 14 MDD outpatients, and 16 control subjects. Psychiatric evaluation was performed with the SCID-I interview and the SCI-MOODS-SR questionnaire. The correlation between steroid levels and mood disorder syndromal cluster (SCI-MOODS-SR domains and sub-domains) was evaluated by means of analysis of main components with Varimax rotation and Kaiser's normalization (which provided for inclusion of all components with an Eigen value >1).
Results
Analysis of the main components evidenced the presence of 3 components: 1) mania, 2) depression both with mixed component 3) steroid + manic cognitivity and suicidal ideas.
Conclusion
Levels of allopregnanolone and progesterone do not correlate with the association of the depressive and manic syndromes, but rather with mixed symptomatological aspects, and in particular with cognitive manic and depressive (with suicidal thoughts) dimensions. Further studies should be carried out to confirm these findings.
doi:10.1186/1745-0179-4-3
PMCID: PMC2311299  PMID: 18302757
7.  The Influence of Menopausal Status and Postmenopausal Use of Hormone Therapy on Presentation of Major Depression in Women 
Menopause (New York, N.Y.)  2010;17(4):828-839.
Objective:
The purpose of this study was to determine whether there are differences in depression characteristics among premenopausal, perimenopausal, and postmenopausal women with major depressive disorder. This study also evaluated these differences between postmenopausal women with major depressive disorder who are taking and not taking hormone therapy.
Methods:
Analyses conducted with data from the Sequenced Treatment Alternatives to Relieve Depression study focused on female outpatients with non-psychotic major depressive disorder seeking treatment in 41 primary or psychiatric care settings across the United States. Baseline demographic and clinical characteristics were compared among women not taking hormone therapy who were premenopausal (N=950), perimenopausal (N=380), or postmenopausal (N=562). These comparisons were also made between postmenopausal women (n=768) taking (N=171) or not taking (N=562) hormone therapy.
Results:
After adjusting for sociodemographic and clinical baseline differences, premenopausal women were more likely to present with irritability than either peri- or postmenopausal women, and were more likely to have decreased appetite and less likely to have early morning insomnia than perimenopausal women. Postmenopausal women were more likely to have suicidal ideation and poorer physical functioning than either of the other groups, and were more likely to have sympathetic arousal and gastrointestinal symptoms than premenopausal women. After adjusting for baseline differences, postmenopausal women taking hormone therapy had better physical functioning, fewer melancholic features, less sympathetic arousal, and more lack of involvement in activities than women not taking hormone therapy.
Conclusions:
Menopausal status and postmenopausal use of hormone therapy may influence the clinical presentation of major depressive episodes in women.
doi:10.1097/gme.0b013e3181d770a8
PMCID: PMC2949279  PMID: 20616669
menopause; hormone therapy; depression; major depressive disorder
8.  ORAL CONTRACEPTIVES DECREASE THE PREVALENCE OF OVARIAN CANCER IN THE HEN 
Ovarian cancer is the leading cause of reproductive cancer death in U.S. women. This high mortality rate is due to the lack of early detection methods and ineffectiveness of therapy for advanced disease. Until more effective screening methods and therapies are developed, chemoprevention strategies are warranted. The hen has a high spontaneous prevalence of ovarian cancer and has been used as a model for studying ovarian cancer chemoprevention. In this study, we used the hen to determine the effect of progestin alone, estrogen alone, or progestin and estrogen in combination (as found in oral contraceptives) on ovarian cancer prevalence. We found that treatment with progestin alone and in combination with estrogen decreased the prevalence of ovarian cancer. A significant risk reduction of 91% was observed in the group treated with progestin alone (risk ratio 0.0909: 95% confidence interval 0.0117-0.704) and an 81% reduction was observed in the group treated with progestin plus estrogen (risk ratio 0.1916: 95% confidence interval 0.043-0.864). Egg production was also significantly reduced in these treatment groups compared to control. We found no effect of progestin, either alone or in combination with estrogen, on apoptosis or proliferation in the ovary, indicating that this is not the likely mechanism responsible for the protective effect of progestin in the hen. Our results support the use of oral contraceptives to prevent ovarian cancer and suggest that ovulation is related to the risk of ovarian cancer in hens and that other factors, such as hormones, more than likely modify this risk.
doi:10.1158/1940-6207.CAPR-11-0344
PMCID: PMC3273612  PMID: 22135044
ovarian cancer; animal models of cancer; hen; oral contraceptives; ovulation
9.  Neonatal testosterone partially organizes sex differences in stress-induced emotionality in mice 
Neurobiology of Disease  2012;46(2):486-496.
Major depressive disorder (MDD) is a debilitating disorder of altered mood regulation. Despite well established sex differences in MDD prevalence, the mechanism underlying the increased female vulnerability remains unknown. Although evidence suggests an influence of adult circulating hormone levels on mood (i.e. activational effects of hormones), MDD prevalence is consistently higher in women across life stages (and therefore hormonal states), suggesting that additional underlying structural or biological differences place women at higher risk. Studies in human subjects and in rodent models suggest a developmental origin for mood disorders, and interestingly, a developmental process also establishes sex differences in the brain. Hence, based on these parallel developmental trajectories, we hypothesized that a proportion of the female higher vulnerability to MDD may originate from the differential organization of mood regulatory neural networks early in life (i.e. organizational effects of hormones). To test this hypothesis in a rodent system, we took advantage of a well-established technique used in the field of sexual differentiation (neonatal injection with testosterone) to masculinize sexually dimorphic brain regions in female mice. We then investigated adult behavioral consequences relating to emotionality by comparing neonatal testosterone-treated females to normal males and females. Under baseline/trait conditions, neonatal testosterone treatment of female mice did not influence adult emotionality, but masculinized adult locomotor activity, as revealed by the activational actions of hormones. Conversely, the increased vulnerability of female mice to develop high emotionality following unpredictable chronic mild stress (UCMS) was partially masculinized by neonatal testosterone exposure, with no effect on post-UCMS locomotion. The elevated female UCMS-induced vulnerability did not differ between adult hormone treated groups. These results demonstrate that sex differences in adult emotionality in mice are partially caused by the organizational effects of sex hormones during development, hence supporting a developmental hypothesis of the human adult female prevalence of MDD.
doi:10.1016/j.nbd.2012.02.014
PMCID: PMC3323718  PMID: 22394611
depression; emotionality; testosterone; unpredictable chronic mild stress; sex difference; development
10.  Does Comorbid Posttraumatic Stress Disorder Affect the Severity and Course of Psychotic Major Depression? 
Background
Major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) are commonly comorbid conditions that result in greater severity, chronicity, and impairment compared with either disorder alone. However, previous research has not systematically explored the potential effects of the psychotic subtyping of MDD and comorbid PTSD.
Method
The sample consisted of psychiatric outpatients diagnosed with psychotic MDD with PTSD, psychotic MDD without PTSD, and nonpsychotic MDD with PTSD presenting for clinic intake. Clinical indices of severity, impairment, and history of illness were assessed by trained diagnosticians using the Structured Clinical Interview for DSM-IV supplemented by items from the Schedule for Affective Disorders and Schizophrenia.
Results
In terms of current severity and impairment, the psychotic MDD with PTSD and psychotic MDD only groups were similar to each other, and both tended to be more severe than the nonpsychotic MDD with PTSD group. In terms of history of illness, the psychotic MDD with PTSD group tended to show greater severity and impairment relative to either the psychotic MDD only or nonpsychotic MDD with PTSD groups. Furthermore, the psychotic MDD with PTSD patients had an earlier time to depression onset than patients with either psychotic MDD alone or nonpsychotic MDD with PTSD, which appeared to contribute to the poorer history of illness demonstrated in the former group.
Conclusions
Future research should explore the possibility of a subtype of psychotic depression that is associated with PTSD, resulting in a poorer course of illness. The current findings highlight the need for pharmacological and psychotherapeutic approaches that can be better tailored to psychotic MDD patients with PTSD comorbidity.
doi:10.4088/JCP.08m04794gre
PMCID: PMC3671375  PMID: 20021993
major depression; posttraumatic stress disorder; psychosis; comorbidity; psychiatric outpatients; onset of illness
11.  The effect of combined oral contraception on testosterone levels in healthy women: a systematic review and meta-analysis 
Human Reproduction Update  2013;20(1):76-105.
BACKGROUND
Combined oral contraceptives (COCs) reduce levels of androgen, especially testosterone (T), by inhibiting ovarian and adrenal androgen synthesis and by increasing levels of sex hormone-binding globulin (SHBG). Although this suppressive effect has been investigated by numerous studies over many years, to our knowledge no systematic review concerning this issue had been performed. This systematic review and meta-analysis was performed to evaluate the effect of COCs on concentrations of total T, free T and SHBG in healthy women and to evaluate differences between the various types of COCs (e.g. estrogen dose, type of progestin) and the assays used to assess total T and free T.
METHODS
A review of the literature was performed using database searches (MEDLINE, EMBASE and the Cochrane Central Register of Clinical Trials) and all publications (from inception date until July 2012) investigating the effect of COCs on androgen levels in healthy women were considered eligible for selection. Three reviewers were involved in study selection, data extraction and critical appraisal. For the meta-analysis, data on total T, free T and SHBG were extracted and combined using random effects analysis. Additional subgroup analyses were performed to evaluate differences between the various types of COCs (e.g. estrogen dose, type of progestin) and the assays used to assess total T or free T.
RESULTS
A total of 151 records were identified by systematic review and 42 studies with a total of 1495 healthy young women (age range: 18–40 years) were included in the meta-analysis. All included studies were experimental studies and 21 were non-comparative. Pooling of the results derived from all the included papers showed that total T levels significantly decreased during COC use [mean difference (MD) (95% confidence interval, CI) −0.49 nmol/l (−0.55, −0.42); P < 0.001]. Significantly lower levels of free T were also found [relative change (95% CI) 0.39 (0.35, 0.43); P < 0.001], with a mean decrease of 61%. On the contrary, SHBG concentrations significantly increased during all types of COC use [MD (95% CI) 99.08 nmol/l (86.43, 111.73); P < 0.001]. Subgroup analyses revealed that COCs containing 20–25 µg EE had similar effects on total and free T compared with COCs with 30–35 µg EE. In addition, suppressive effects on T levels were not different when comparing different types of progestins. However, subgroup analyses for the estrogen dose and the progestin type in relation to changes in SHBG levels did show significant differences: COCs containing second generation progestins and/or the lower estrogen doses (20–25 µg EE) were found to have less impact on SHBG concentrations.
CONCLUSIONS
The current literature review and meta-analysis demonstrates that COCs decrease circulating levels of total T and free T and increase SBHG concentrations. Due to the SHBG increase, free T levels decrease twice as much as total T. The estrogen dose and progestin type of the COC do not influence the decline of total and free T, but both affect SHBG. The clinical implications of suppressed androgen levels during COC use remain to be elucidated.
doi:10.1093/humupd/dmt038
PMCID: PMC3845679  PMID: 24082040
combined oral contraception; androgens; testosterone; SHBG; systematic review
12.  Hormonal Contraception and Thrombotic Risk: A Multidisciplinary Approach 
Pediatrics  2011;127(2):347-357.
Heightened publicity about hormonal contraception and thrombosis risk and the publication of new guidelines by the World Health Organization in 2009 and the Centers for Disease Control and Prevention in 2010 addressing this complex issue have led to multidisciplinary discussions on the special issues of adolescents cared for at our pediatric hospital. In this review of the literature and new guidelines, we have outlined our approach to the complex patients referred to our center. The relative risk of thrombosis on combined oral contraception is three- to fivefold, whereas the absolute risk for a healthy adolescent on this therapy is only 0.05% per year. This thrombotic risk is affected by estrogen dose, type of progestin, mechanism of delivery, and length of therapy. Oral progestin-only contraceptives and transdermal estradiol used for hormone replacement carry minimal or no thrombotic risk. Transdermal, vaginal, or intrauterine contraceptives and injectable progestins need further study. A personal history of thrombosis, persistent or inherited thrombophilia, and numerous lifestyle choices also influence thrombotic risk. In this summary of one hospital's approach to hormone therapies and thrombosis risk, we review relative-risk data and discuss the application of absolute risk to individual patient counseling. We outline our approach to challenging patients with a history of thrombosis, known thrombophilia, current anticoagulation, or family history of thrombosis or thrombophilia. Our multidisciplinary group has found that knowledge of the guidelines and individualized management plans have been particularly useful for informing discussions about hormonal and nonhormonal options across varied indications.
doi:10.1542/peds.2010-2221
PMCID: PMC3025417  PMID: 21199853
contraception; thrombosis; thrombophilia; hormone
13.  Efficacy and safety of combined ethinyl estradiol/drospirenone oral contraceptives in the treatment of acne 
Acne is a common disorder affecting the majority of adolescents and often extends into adulthood. The central pathophysiological feature of acne is increased androgenic stimulation and/or end-organ sensitivity of pilosebaceous units leading to sebum hypersecretion and infundibular hyperkeratinization. These events lead to Propionibacterium acnes proliferation and subsequent inflammation. Hormonal therapy, including combined oral contraceptives (OCs), can attenuate the proximate androgenic trigger of this sequence. For many women, hormonal therapy is a rational option for acne treatment as it may be useful across the spectrum of severity. Drospirenone (DRSP) is a unique progestin structurally related to spironolactone with progestogenic, antimineralocorticoid, and antiandrogenic properties. It is available in 2 combined OC preparations (30 μg EE/3 mg DRSP; Yasmin® in a 21/7 regimen; and 20 μg EE/3 mg DRSP; Yaz® in a 24/4 regimen). These preparations are bereft of the fluid retentional side effects typical of other progestins and their safety has been demonstrated in large epidemiological studies in which no increased risk of vascular thromboembolic disease or arrhythmias was observed. In acne, the efficacy of DRSP-containing OCs has been shown in placebo-controlled superiority trials and in active-comparator non-inferiority trials.
PMCID: PMC2971705  PMID: 21072290
acne vulgaris; combined oral contraceptives; drosperinone; ethinyl estradiol; efficacy; safety; treatment
14.  Premenstrual mood symptoms: study of familiality and personality correlates in mood disorder pedigrees 
Archives of women's mental health  2009;12(1):10.1007/s00737-008-0043-4.
We sought to determine whether premenstrual mood symptoms exhibit familial aggregation in bipolar disorder or major depression pedigrees. Two thousand eight hundred seventy-six women were interviewed with the Diagnostic Interview for Genetic Studies as part of either the NIMH Genetics Initiative Bipolar Disorder Collaborative study or the Genetics of Early Onset Major Depression (GenRED) study and asked whether they had experienced severe mood symptoms premenstrually. In families with two or more female siblings with bipolar disorder (BP) or major depressive disorder (MDD), we examined the odds of having premenstrual mood symptoms given one or more siblings with these symptoms. For the GenRED MDD sample we also assessed the impact of personality as measured by the NEO-FFI. Premenstrual mood symptoms did not exhibit familial aggregation in families with BP or MDD. We unexpectedly found an association between high NEO openness scores and premenstrual mood symptoms, but neither this factor, nor NEO neuroticism influenced evidence for familial aggregation of symptoms. Limitations include the retrospective interview, the lack of data on premenstrual dysphoric disorder, and the inability to control for factors such as medication use.
doi:10.1007/s00737-008-0043-4
PMCID: PMC3845804  PMID: 19137238
Premenstrual; Bipolar; Major depression; Genetics
15.  Oral contraceptives modify DNA methylation and monocyte-derived macrophage function 
Background
Fertile women may be encouraged to use contraception during clinical trials to avoid potential drug effects on fetuses. However, hormonal contraception interferes with pharmacokinetics and pharmacodynamics and modifies internal milieus. Macrophages depend on the milieu to which they are exposed. Therefore, we assessed whether macrophage function would be affected by the use of combined oral contraceptives (OCs) and if this influence depended on the androgenic or non-androgenic properties of progestin.
Methods
Healthy adult women were enrolled and stratified into two groups: women who did not use OCs (Fs) and women treated with OCs (FOCs). FOCs were further stratified as a function of androgenic (FOCA+) and non-androgenic (FOCA-) properties of progestins. Routine hematological, biochemical, inflammatory and endothelial dysfunction parameters were measured. Monocyte-derived macrophages (MDMs) were evaluated for the expression and activity of estrogen receptors and androgen receptors, and release of tumor necrosis factor α (TNFα) was measured from unstimulated and lipopolysaccharide-stimulated cells.
Results
As is already known, the use of OCs changed numerous parameters: the number of lymphocytes, iron levels, total iron-binding capacity of transferrin, triglycerides, high-density lipoprotein, total cholesterol, and C-reactive protein increased, while prothrombin time and alkaline phosphatase decreased. Hormonal levels also varied: cortisol was higher in FOCs, while luteinizing hormone, follicle-stimulating hormone, and testosterone were lower in FOCs. Asymmetric dimethylarginine, an index of endothelial function, was lower in FOC than in Fs, as were cysteine and bilirubin. The androgenic properties of progestins affected the activity of OCs: in particular, white blood cell count, hemoglobin, high-density lipoprotein and calcium were higher in FOCA- than in FOCA+, whereas percentage oxygen saturation and γ-glutamyl transpeptidase were lower in FOCA- than in FOCA+. Importantly, FOCs had a lower global DNA methylation, indicating that OC may have epigenetic effects on gene expression. OC did not modify the expression of androgen receptor but increased estrogen receptor α expression, more considerably in FOCA+, and decreased estrogen receptor β, more considerably in FOCA-. Importantly, the activation state of estrogen receptor β in FOCs was decreased, while estrogen receptor α was not active in either Fs or FOCs. Unstimulated MDMs obtained from FOCs showed higher release of TNFα in comparison with Fs. After lipopolysaccharide stimulation, the release of TNFα was significantly higher in Fs than in FOCs.
Conclusions
OC use induced many changes in hematological and plasmatic markers, modifying hormonal levels, endothelial function, inflammation index and some redox state parameters, producing a perturbation of the internal milieu that impacted macrophagic function. In fact, different levels of estrogen receptor expression and release of TNFα were observed in macrophages derived from OC users. Some of the above activities were linked to the androgenic properties of progestin. Even though it is not known whether these effects are reversible, the results indicate that to avoid potential skewing of results only a single type of OC should be used during a single clinical trial.
doi:10.1186/2042-6410-3-4
PMCID: PMC3298494  PMID: 22284681
androgenic and non-androgenic progestin; combined oral contraceptive; estrogen receptors; global DNA methylation; monocyte-derived macrophages; TNFα
16.  Types of combined oral contraceptives used by U.S. women 
Contraception  2012;86(6):659-665.
Background
We sought to estimate the prevalence of types of combined oral contraceptives (COC) used among U.S. women.
Study Design
We analyzed interview-collected data from 12,279 women ages 15–44 years participating in the National Survey of Family Growth, 2006–2010. Analyses focused on COC use overall, by pill type, across sociodemographics and health factors.
Results
The prevalence of current COC use (88 different brands) was 17%. The majority of COC-users used earlier formulation COCs: ≥30 mcg (67%) versus <30 mcg estrogen (33%), monophasic (67%) versus multiphasic (33%) dosages, and traditional 21/7 (88%) versus extended/other cycle regimens (12%) regimens; Norgestimate (32%) and norethindrone (20%) were the most commonly used progestins. Sociodemographic, gynecological and health risk factors were associated with type of COC use.
Conclusion
Further investigation of specific COC use and of the factors associated with types of pills used among U.S. women at the population level is needed.
doi:10.1016/j.contraception.2012.05.017
PMCID: PMC3469779  PMID: 22770787
combined oral contraceptives; estrogen dosage; progestin generation; formulation
17.  The association of contraceptive methods and depression 
Background
None of the contraceptive methods are fully side-effect free. One of the side effects that commonly causes discontinuation is mood changes and depression. The present study aimed to compare the depression between contraceptive methods including low-dose estrogen (LD) combined pills, condom and intrauterine devices (IUD).
Materials and Methods:
In a cross-sectional study, 216 women were selected through systematic random sampling from 10 health care center sin Isfahan in 2011. Beck Depression Inventory II was used and individual productivity characteristics were asked. Validity and reliability of Beck depression inventory have been repeatedly confirmed in Iran. Content validity the productivity characteristics questionnaire was confirmed and its reliability was measured through Cronbach’s alpha correlation coefficient (calculated as 0.71). ANOVA, covariance analysis and logistic regression were used to analyze the data.
Findings:
Depression was observed in 47.8% of participants; however, there was no difference between mean score of depression in the users of three contraceptive methods.
Conclusions:
The findings of this study showed that depression is not correlated with family planning type and fear of depression should not be an obstacle to choose between these methods. Depression is a multifactor issue. This study showed that type of family planning method in itself cannot be the cause of depression and family planners and consultants should consider this.
PMCID: PMC3696218  PMID: 23833619
Contraceptive methods; depression; family planning; mood; side effects
18.  A combined oral contraceptive containing 30 mcg ethinyl estradiol and 3.0 mg drospirenone does not impair endothelium-dependent vasodilation 
Contraception  2010;82(4):366-372.
Background
Ethinyl estradiol (EE) increases endothelium-dependent vasodilation in young women, but certain progestins paired with EE in combination OCPs have been shown to antagonize the vasodilatory effects of EE. Therefore, the purpose of this study was to investigate how endothelial function, serum biomarkers, and resting blood pressures change across an OCP cycle in women using a monophasic OCP formulation containing the progestin drospirenone.
Study Design
Twelve women were studied during two hormone phases of their OCP cycle; once at the end of three weeks of active pills (30 mcg EE and 3.0 mg drospirenone), and once at the end of a week of placebo pills (no exogenous hormones).
Results
Endothelium-dependent vasodilation was greater during the active phase compared to the placebo phase (p < 0.001). In contrast, there was no difference in endothelium-independent dilation between hormone phases.
Conclusion
These data suggest that the combination of 30 mcg EE and 3.0 mg drospirenone used in the active phase of this OCP increases endothelium-dependent vasodilation compared to a placebo phase.
doi:10.1016/j.contraception.2010.03.009
PMCID: PMC2943430  PMID: 20851231
progestin; estrogen; vasodilation; birth control pills; drospirenone; blood pressure
19.  The Role of Genetic Sex in Affect Regulation and Expression of GABA-Related Genes Across Species 
Although circulating hormones and inhibitory gamma-aminobutyric acid (GABA)-related factors are known to affect mood, considerable knowledge gaps persist for biological mechanisms underlying the female bias in mood disorders. Here, we combine human and mouse studies to investigate sexual dimorphism in the GABA system in the context of major depressive disorder (MDD) and then use a genetic model to dissect the role of sex-related factors in GABA-related gene expression and anxiety-/depressive-like behaviors in mice. First, using meta-analysis of gene array data in human postmortem brain (N = 51 MDD subjects, 50 controls), we show that the previously reported down-regulation in MDD of somatostatin (SST), a marker of a GABA neuron subtype, is significantly greater in women with MDD. Second, using gene co-expression network analysis in control human subjects (N = 214; two frontal cortex regions) and expression quantitative trait loci mapping (N = 170 subjects), we show that expression of SST and the GABA-synthesizing enzymes glutamate decarboxylase 67 (GAD67) and GAD65 are tightly co-regulated and influenced by X-chromosome genetic polymorphisms. Third, using a rodent genetic model [Four Core Genotypes (FCG) mice], in which genetic and gonadal sex are artificially dissociated (N ≥ 12/group), we show that genetic sex (i.e., X/Y-chromosome) influences both gene expression (lower Sst, Gad67, Gad65 in XY mice) and anxiety-like behaviors (higher in XY mice). This suggests that in an intact male animal, the observed behavior represents the outcomes of male genetic sex increasing and male-like testosterone decreasing anxiety-like behaviors. Gonadal sex was the only factor influencing depressive-like behavior (gonadal males < gonadal females). Collectively, these combined human and mouse studies provide mechanistic insight into sexual dimorphism in mood disorders, and specifically demonstrate an unexpected role of male-like factors (XY genetic sex) on GABA-related genes and anxiety-like behaviors.
doi:10.3389/fpsyt.2013.00104
PMCID: PMC3775314  PMID: 24062698
GABA; genetic sex; mood; somatostatin; anxiety; depression
20.  Cross-Disorder Genomewide Analysis of Schizophrenia, Bipolar Disorder, and Depression 
The American journal of psychiatry  2010;167(10):10.1176/appi.ajp.2010.09091335.
Background
Family and twin studies indicate substantial overlap of genetic influences on psychotic and mood disorders. Linkage and candidate gene studies have also suggested overlap across schizophrenia (SCZ), bipolar disorder (BPD), and major depressive disorder (MDD). The objective of this study was to apply genomewide association study (GWAS) analysis to address the specificity of genetic effects on these disorders.
Method
We combined GWAS data from three large effectiveness studies of SCZ (CATIE, genotyped n = 741), BPD (STEP-BD, n = 1575) and MDD (STAR*D, n= 1938) and psychiatrically-screened controls (NIMH-GI controls, n = 1204). We applied a two-stage analytic procedure involving an omnibus test of allele frequency differences among case and control groups followed by a model selection step to identify the best-fitting model of allelic effects across disorders.
Results
The strongest result was seen for a single nucleotide polymorphism near the adrenomedullin (ADM) gene (rs6484218, p = 3.93 × 10−8), with the best-fitting model indicating that the effect is specific to bipolar II disorder. We also observed evidence suggesting that several genes may have effects that transcend clinical diagnostic boundaries including variants in NPAS3 that showed pleiotropic effects across SCZ, BPD, and MDD.
Conclusions
This study provides the first genomewide significant evidence implicating variants near the ADM gene on chromosome 11p15 in psychopathology, with effects that appear to be specific to bipolar II disorder. Although we do not detect genomewide significant evidence of cross-disorder effects, our study provides evidence that there are both pleiotropic and disorder-specific effects on major mental illness and illustrates an approach to dissecting the genetic basis of mood and psychotic disorders that can inform future large-scale cross-disorder GWAS analyses.
doi:10.1176/appi.ajp.2010.09091335
PMCID: PMC3880556  PMID: 20713499
21.  Hormonal Approaches to Male contraception 
Current opinion in urology  2010;20(6):520-524.
Purpose of review
Condoms and vasectomy are male controlled family planning methods but suffer from limitations in compliance (condoms) and limited reversibility (vasectomy); thus many couples desire other options. Hormonal male contraceptive methods have undergone extensive clinical trials in healthy men and shown to be efficacious, reversible and appear to be safe.
Recent Findings
The success rate of male hormonal contraception using injectable testosterone alone is high and comparable to methods for women. Addition of progestins to androgens improved the rate of suppression of spermatogenesis. Supported by government or non-government organizations, current studies aim to find the best combination of testosterone and progestins for effective spermatogenesis suppression and to explore other delivery methods for these hormones. Translation of these advances to widespread use in the developed world will need the manufacturing and marketing skills of the pharmaceutical industry. Availability of male contraceptives to the developing world may require commitments of governmental and non-governmental agencies. In a time when imbalance of basic resources and population needs are obvious, this may prove to be a very wise investment.
Summary
Male hormonal contraception is efficacious, reversible and safe for the target population of younger men in stable relationships. Suppression of spermatogenesis is achieved with a combination of an androgen and a progestin. Partnership with industry will accelerate the marketing of a male hormonal contraceptive. Research is ongoing on selective androgen and progesterone receptor modulators that suppress spermatogenesis, minimize potential adverse events while retaining the androgenic actions.
doi:10.1097/MOU.0b013e32833f1b4a
PMCID: PMC3078035  PMID: 20808223
androgens; progestins; selective androgen receptor modulators; suppression of spermatogenesis
22.  Progress and prospects in male hormonal contraception 
Purpose of review
Testosterone functions as a contraceptive by suppressing the secretion of luteinizing hormone and follicle-stimulating hormone from the pituitary. Low concentrations of these hormones deprive the testes of the signals required for spermatogenesis and results in markedly decreased sperm concentrations and effective contraception in a majority of men. Male hormonal contraception is well tolerated and acceptable to most men. Unfortunately, testosterone-alone regimens fail to completely suppress spermatogenesis in all men, meaning that in some the potential for fertility remains.
Recent findings
Because of this, novel combinations of testosterone and progestins, which synergistically suppress gonadotropins, have been studied. Two recently published testosterone/progestin trials are particularly noteworthy. In the first, a long-acting injectable testosterone ester, testosterone decanoate, was combined with etonogestrel implants and resulted in 80–90% of subjects achieving a fewer than 1 million sperm per milliliter. In the second, a daily testosterone gel was combined with 3-monthly injections of depot medroxyprogesterone acetate producing similar results.
Summary
Testosterone-based hormone combinations are able to reversibly suppress human spermatogenesis; however, a uniformly effective regimen has remained elusive. Nevertheless, improvements, such as the use of injectable testosterone undecanoate, may lead to a safe, reversible and effective male contraceptive.
doi:10.1097/MED.0b013e3282fcc30d
PMCID: PMC2664382  PMID: 18438174
etonogestrel; medroxyprogesterone acetate; progestogens; spermatogenesis; testosterone; testosterone decanoate; testosterone undecanoate
23.  Prefrontal Brain Asymmetry and Pre-Menstrual Dysphoric Disorder Symptomatology 
Journal of affective disorders  2010;128(1-2):178-183.
Background
Premenstrual dysphoric disorder (PMDD), a dysphoric form of premenstrual syndrome, is included as a diagnosis for further study in the DSM-IV-TR (APA, 2000). The present study investigated whether a marker of risk for Major Depressive Disorder (MDD), prefrontal brain asymmetry, also characterizes women with PMDD.
Methods
In a sample of 25 college women with PMDD symptomatology and 25 matched controls, resting frontal electroencephalographic (EEG) activity was assessed on four occasions within a two-week span.
Results
Across several frontal sites women with PMDD had relatively less left than right prefrontal brain activity, consistent with a diathesis-stress model for menstrual-related dysphoria.
Conclusions
The findings suggest an overlap in the risk profile for MDD and PMDD.
doi:10.1016/j.jad.2010.07.017
PMCID: PMC2994967  PMID: 20833433
EEG asymmetry; premenstrual dysphoria; risk; diathesis
24.  Newborn neurobehavioral patterns are differentially related to prenatal maternal Major Depressive Disorder and Serotonin Reuptake Inhibitor treatment 
Depression and Anxiety  2011;28(11):1008-1019.
Background
Prenatal serotonin reuptake inhibitor (SRI) exposure has been related to adverse newborn neurobehavioral outcomes; however these effects have not been compared to those that may arise from prenatal exposure to maternal major depressive disorder (MDD) without SRI treatment. This study examined potential effects of MDD with and without SRI treatment on newborn neurobehavior.
Methods
This was a prospective, naturalistic study. Women were seen at an outpatient research center twice during pregnancy (26–28 and 36–38 weeks gestational age (GA)). Psychiatric diagnoses were assessed using the Structured Clinical Interview for the DSM-IV; medication use was measured with the Timeline Follow-Back instrument. Three groups were established based upon MDD diagnosis and SRI use: Control (N=56), MDD (N=20) or MDD+SRI (N=36). Infants were assessed on a single occasion within 3 weeks of birth with the NICU Network Neurobehavioral Assessment Scale (NNNS). Generalized Linear Modeling was used to examine neurobehavioral outcomes by exposure group and infant age at assessment.
Results
Full-term infants exposed to MDD+SRIs had a lower GA than CON or MDD-exposed infants and, controlling for GA, had lower quality of movement and more central nervous system stress signs. In contrast, MDD-exposed infants had the highest quality of movement scores, while having lower attention scores than CON and MDD+SRI-exposed infants.
Conclusion
MDD+SRI-exposed infants appear to have a different neurobehavioral profile than MDD-exposed infants in the first three weeks after delivery; both groups may have different neurobehavioral profiles with increasing age from birth.
doi:10.1002/da.20883
PMCID: PMC3215845  PMID: 21898709
infant; motor quality; central nervous system; depression; pregnancy; treatment
25.  Update on Research and Treatment of Premenstrual Dysphoric Disorder 
Harvard review of psychiatry  2009;17(2):120-137.
Many women in their reproductive years experience some mood, behavioral. or physical symptoms in the week prior to menses. Variability exists in the level of symptom burden in that some women experience mild symptoms, whereas a small minority experience severe and debilitating symptoms. For an estimated 5%–8% of premenopausal women, work or social functioning are affected by severe premenstrual syndrome. Many women in this group meet diagnostic criteria for premenstrual dysphoric disorder (PMDD). Among women who suffer from PMDD, mood and behavioral symptoms such as irritability, depressed mood, tension, and labile mood dominate. Somatic complaints, including breast tenderness and bloating, also can prove disruptive to women's overall functioning and quality of life. Recent evidence suggests that individual sensitivity to cyclical variations in levels of gonadal hormones may predispose certain women to experience these mood, behavioral, and somatic symptoms. Treatments include: antidepressants of the serotonin reuptake inhibitor class, taken intermittently or throughout the menstrual cycle; medications that suppress ovarian cyclicity; and newer oral contraceptives with novel progestins. (Harv Rev Psychiatry 2009;17:120–137.)
doi:10.1080/10673220902891836
PMCID: PMC3098121  PMID: 19373620
mood disorders; premenstrual dysphoric disorder; premenstrual syndrome

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