Transdermal Estradiol Research Articles

Transdermal estradiol for the management of refractory uremic bleeding.

The efficacy and thrombogenicity of transdermal estradiol in the management of refractory uremic bleeding in adults are examined. Platelet dysfunction from chronic kidney disease may induce uremic bleeding. This type of bleeding may involve the skin, oral and nasal mucosa, gingivae, respiratory system, and gastrointestinal or urinary tract. While the mainstay of treatment for uremic bleeding primarily involves dialysis and use of prohemostatic agents such as desmopressin and erythropoiesis-stimulating agents, certain patients may experience bleeding refractory to these interventions. In this clinical scenario, a weak conditional recommendation (grade 2C) supporting transdermal estradiol as a therapy of last resort exists. Limited data suggest that transdermal estradiol may reduce bleeding time and transfusion requirements in dialysis patients with recurrent episodes of hematochezia, gastrointestinal telangiectasia, and hematomas. The management of uremic bleeding will require long-term therapy, and case reports have documented the safe use of transdermal estradiol for up to 25 months. Oral conjugated estrogens increase the risk of deep vein thrombosis in women; however, the transdermal route of administration has been associated with a lower incidence of venous thromboembolism and stroke relative to oral estrogen and, in some studies, its associated risk of thrombosis is not significantly different when compared with placebo. Patients who are refractory to routine interventions for uremic bleeding may benefit from transdermal estrogen despite the limited data. Extended therapy with low-dose transdermal estrogen (≤50 μg daily) may provide a hemostatic benefit that outweighs thrombotic risk.

Hormone therapy effective in preventing depressive symptoms in menopause transition

Transdermal estradiol plus intermittent micronized progesterone over 12 months was more effective than placebo in preventing the development of clinically significant depressive symptoms in perimenopausal and early postmenopausal women, a randomized trial has found. The benefits seen from hormonal therapy did not extend to women in later stages of the menopause transition, according to the researchers. Study results were published online Jan. 10 in JAMA Psychiatry.

Response to Diversity

Response to Diversity

Quantification of steroid hormones in plasma using a surrogate calibrant approach and UHPLC-ESI-QTOF-MS/MS with SWATH-acquisition combined with untargeted profiling

In spite of demonstrated lack of accuracy and consistency, quantification of steroid hormones is still most commonly executed via immunoassays. Mass spectrometric methods with triple quadrupole instruments are well established and, because of their proven robustness and sensitivity, best suited for targeted analysis. However, recent studies have shown that high-resolution mass spectrometers, like quadrupole time-of-flight instruments (QTOF), show comparable performance in terms of quantification and can generate additional sample information via untargeted profiling workflows. We demonstrate that adequate accuracy and selectivity for estradiol and testosterone can be achieved with a QTOF by data-independent acquisition with sequential window acquisition of all theoretical fragment-ion mass spectra (SWATH). Besides potential combination of targeted quantification and untargeted profiling, SWATH offers advantages with respect to sensitivity because the reduced total number of MS/MS experiments could be used to increase accumulation time without increasing cycle time. By applying a surrogate calibrant method leading to successful validation, a reliable method for absolute steroid quantification and high potential for steroid profiling has been developed. Linear calibration was achieved in the range from 10 to 1,000 pg mL−1 for 13C3-estradiol and from 20 to 15,000 pg mL−1 for 13C3-testosterone. Results for inter-day precision (13C3-estradiol: 4.5–10.2%; 13C3-testosterone: 5.1–7.8%) and inter-day accuracy (13C3-estradiol: 94.6–112.8%; 13C3-testosterone: 98.2–107.7%) were found to be well acceptable. Eventually, the method has been utilized to measure clinical samples of a study in which male volunteers obtained transdermal estradiol patches and sex hormone levels were quantified in plasma.

Short-term effects of transdermal estradiol in men undergoing androgen deprivation therapy for prostate cancer: a randomized placebo-controlled trial.

There is increasing recognition that, in men, some biological actions attributed to testosterone (TS) are mediated by estradiol (E2). This study used two low doses of daily transdermal E2 gel to assess the effects on circulating E2 concentrations in men with prostate cancer with suppressed endogenous E2 production arising from androgen deprivation therapy (ADT). Secondarily, we aimed to assess short-term biological effects of E2 add-back without increasing circulating TS. 28-day randomised, placebo-controlled trial. 37 participants were randomised to either 0.9 or 1.8 mg of 0.1% E2 gel per day or matched placebo gel. Fasting morning serum hormones, quality of life questionnaires, and treatment side effects were evaluated at baseline, days 14 and 28. Hot flush diaries and other biochemical measurements were completed at baseline and study end. Transdermal E2 significantly raised serum E2 from baseline to day 28 compared to placebo in the 0.9 mg dose group (median: 208 pmol/L; interquartile range: 157-332) and in the 1.8 mg dose group (median: 220 pmol/L; interquartile range: 144-660). E2 treatment reduced hot flush frequency and severity as well as beta carboxyl-terminal type 1 collagen telopeptide. In men with castrate levels of E2 and TS, daily transdermal E2: 0.9-1.8 mg increased median serum E2 concentrations into the reference range reported for healthy men, but with substantial variability. E2 treatment reduced hot flushes and bone resorption. Larger studies will be required to test whether low-dose E2 treatment can mitigate ADT-associated adverse effects without E2-related toxicity.

Transdermal estrogen gel and oral aspirin combination therapy improves fertility prognosis via the promotion of endometrial receptivity in moderate to severe intrauterine adhesion.

Intrauterine adhesion (IUA) is one of the most common gynecological diseases in women of reproductive age. IUA, particularlyin moderate to severe forms, accounts for a large percentage of infertility cases. Clinically, the first-line treatment strategy for IUA is transcervical resection of adhesion (TCRA), followed by adjuvant postoperative treatment. Estrogen is one of the classic chemotherapies used following TCRA and contributes to preventing re-adhesion following surgery. However, estrogen has limited effects in promoting pregnancy, which is the ultimate goal for IUA management. In the present study, a transdermal estrogen gel and oral aspirin combination therapy was used in patients with IUA following TCRA. Compared with in the control group (transdermal estrogen only therapy), the combination therapy significantly increased endometrial receptivity marker (αvβ٣ and laminin) expression in endometrium tissues. Additionally, ultrasonic examination revealed the pulsatility index and resistant index of the uterine artery were lower in the combination therapy group. Combination therapy promoted angiogenesis and prevented fibrosis following TCRA more effectively than estrogen-only therapy. Collectively, the evaluation indices, including American Fertility Society score, endometrial parameters and pregnancy rate, indicated that patients with combination therapy had better prognoses in endometrial repair and pregnancy. In conclusion, postoperative combination therapy with transdermal estrogen gel and oral aspirin may be more efficacious in enhancing endometrial receptivity by increasing uterine blood and angiogenesis, contributing to improved fertility prognosis. The findings of the present study may provide novel guidance to the clinical treatment of IUA.

Associations Between Type and Route of Hormone Use on Urinary Incontinence and Pelvic Organ Prolapse in Premenopausal and Postmenopausal Women.

The aim of this study was to evaluate the associations between type and route of hormone use and urinary incontinence (UI) and pelvic organ prolapse (POP) in premenopausal and postmenopausal women. The authors used the National Health and Nutritional Examination Survey database for data from 2005-2006, 2007-2008, 2009-2010, and 2011-2012. Seven thousand sixty-six of the women included were premenopausal, and 5387 were postmenopausal. Premenopausal women were younger than 51 years and reported menstrual periods in the last 12 months. Postmenopausal women reported being in natural or surgical menopause. Urinary incontinence was defined as experiencing urinary leakage "less than once a month" or more. Pelvic organ prolapse was defined as an affirmative response to "experience bulging in the vaginal area." Hormone route and use were stratified in years. Pearson χ and Pearson correlations were used, with P < 0.05 considered significant. In premenopausal women, birth control pills, estrogen/progestin pills, and estrogen-only patch use are associated with UI (P < 0.05). Birth control pills are associated with both UI and POP in premenopausal women (P < 0.05 for UI and POP). In postmenopausal women, estrogen-only pills, and estrogen/progestin pill use are associated with UI (P < 0.05). Birth control pill use is associated with POP in postmenopausal women (P = 0.029). Neither estrogen patch nor estrogen/progestin patch is associated with UI or POP in postmenopausal women. Type and route of hormone use have varied associations with UI and POP in premenopausal and postmenopausal women. Prospective studies are needed to further evaluate the effect of hormone type and route on UI and POP in premenopausal and postmenopausal women.

Transdermal oestradiol as a method of androgen suppression for prostate cancer within the STAMPEDE trial platform.

Transdermal oestradiol as a method of androgen suppression for prostate cancer within the STAMPEDE trial platform.

Late-Onset Puberty Induction by Transdermal Estrogen in Turner Syndrome Girls-A Longitudinal Study.

Estrogen replacement therapy (ERT) for Turner syndrome (TS) is a widely discussed topic; however, the optimal model of ERT for patients with delayed diagnosis and/or initiation of therapy is still unclear, mainly due to insufficient data. We present the results of a prospective observational single-center study in which the efficacy of late-onset puberty induction by one-regimen transdermal ERT in TS girls was evaluated. The analysis encompassed 49 TS girls (63.3% with 45,X) with hypergonadotropic hypogonadism in whom unified transdermal ERT protocol was used for puberty induction (first two months 12.5 μg/24 h, thereafter 25.0 μg/24 h until breakthrough bleeding). Clinical visits for examination and therapy modification took place every 3-6 months. Transabdominal pelvic ultrasound examinations were performed at least twice: at the beginning and at the end of follow-up. The mean (SD) age at ERT induction was 15.1 (1.3) years. The duration of follow-up was 2.4 (1.1) years. Half of all the patients had at least B2 after 0.57 years, B3 after 1.1 years, B4 after 1.97 years, and menarche after 1.82 years from ERT initiation. With earlier initiation of ERT (≤14 years), B2 (p = 0.059) was achieved faster and B4 (p = 0.018) significantly slower than with the later start of ERT. Thirty-four (94.4%) patients had at least stage B3 at menarche. The karyotype, initial weight, and body mass index had no impact on puberty tempo during ERT. The uterine volume increased significantly during ERT in all the study group (p < 0.0001), and in half of the patients, the increase was at least 12.4-fold. It did not correlate with the duration of treatment (p = 0.84) or the dose of estradiol per kilogram (p = 0.78), nor did it depend on karyotype (p = 0.71) or age at ERT initiation (p = 0.28). There were no differences in ΔhSDS during ERT (p = 0.63) between the two age groups (ERT ≤14 and >14 years). The presented easy-to-use fixed-dose regimen for late-onset puberty induction allowed for a satisfactory rate of achieving subsequent puberty stages and did not influence the growth potential.

Estrogen Replacement in Turner Syndrome: Literature Review and Practical Considerations.

Most girls with Turner syndrome (TS) have hypergonadotropic hypogonadism and need hormonal replacement for induction of puberty and then for maintaining secondary sex characteristics, attaining peak bone mass, and uterine growth. The optimal estrogen replacement regimen is still being studied. We conducted a systematic search of PubMed for studies related to TS and puberty. The goals of replacement are to mimic normal timing and progression of physical and social development while minimizing risks. Treatment should begin at age 11 to 12 years, with dose increases over 2 to 3 years. Initiation with low-dose estradiol (E2) is crucial to preserve growth potential. Delaying estrogen replacement may be deleterious to bone and uterine health. For adults who have undergone pubertal development, we suggest transdermal estrogen and oral progestin and discuss other approaches. We discuss linear growth, lipids, liver function, blood pressure, neurocognition, socialization, and bone and uterine health as related to hormonal replacement. Evidence supports the effectiveness of starting pubertal estrogen replacement with low-dose transdermal E2. When transdermal E2 is unavailable or the patient prefers, evidence supports use of oral micronized E2 or an intramuscular preparation. Only when these are unavailable should ethinyl E2 be prescribed. We recommend against the use of conjugated estrogens. Once progestin is added, many women prefer the ease of use of a pill containing both an estrogen and a progestin. The risks and benefits of different types of preparations, with examples, are discussed.

Associations among circulating colony-stimulating factor-1, estrogen, and bone mineral density in postmenopausal women: results from a randomized placebo-controlled trial.

This study addresses the relationship between circulating levels of colony-stimulating factor 1 (CSF-1) and rates of postmenopausal bone loss. The purpose was to test the hypothesis that CSF-1 levels would correlate with the rate of bone loss in estrogen-deficient woman. We further hypothesized that estrogen replacement would eliminate this association. This was an ancillary study to the parent Kronos Early Estrogen Prevention Study (KEEPS)-a 4-year randomized placebo-controlled study that evaluated the effects of estrogen therapy on cardiovascular endpoints. Women between of the ages of 42 and 58, who had been amenorrheic for ≥6 months and ≤36 months, were enrolled in KEEPS. Participants were randomized to conjugated equine estrogen 0.45 mg daily, transdermal estradiol 50 micrograms weekly, or placebo. There was no correlation between serum levels of CSF-1 and bone mineral density at the spine, hip, or femoral neck in estrogen-deficient women (correlation 0.0017, P = 0.99 for spine; correlation 0.0010, P = 0.0079 for hip, and correlation 0.0019, P = 0.99 for femoral neck). There was also no significant correlation in the treatment group (correlation 0.0015, P = 0.99; correlation -0.00024, P = 0.99; correlation 0.0011, P = 0.99 at spine, hip, and femoral neck respectively). This study did not demonstrate a meaningful relationship between circulating levels of CSF-1 and bone mineral density in either the placebo group or estrogen-treated group. Although CSF-1 is required for osteoclastic bone resorption, our data suggest that circulating levels of the cytokine may not reflect this process.

Trans dermal estrogen (oestrogel) for endometrial preparation in freeze embryo transfer cycle: An RCT

Estrogen and progesterone are two crucial factors for endometrial preparation in frozen embryo transfer (FET) cycles. Studies assessing different forms of estradiol in FET have published already but literature lacks enough surveys on transdermal estrogen application in reproductive medicine. To investigate the effects of trans dermal estrogen (Oestrogel) on pregnancy rates in patients that candidate for FET cycle. In this randomized clinical trial, 100 women undergoing FET cycles referred to Imam Khomeeini Hospital were enrolled in two groups, randomly. Group I received 8 mg/day estradiol valerate (E2 tablet) orally and group II were treated with 6 mg/day transdermal oestrogel gel after suppression with gonadotropin releasing hormone agonist. In both groups medication were started in the first day of menstruation cycle and continued until endometrial thickness reached 8 mm. Pregnancy rates (chemical, clinical, and ongoing), abortion rate, live birth rate, and frequency of complications were compared between two groups. Chemical and clinical pregnancy rates were not significantly different between two groups (p=0.384). The abortion rate was significantly lower in group II than group I (p=0.035). Ongoing pregnancy and the live birth rates were significantly higher in group II (p=0.035). The rate of complication was not different in two groups. Oestrogel seems to enhance ongoing pregnancy and live birth rates in comparison to estradiol valerate tablet.

Insulin and Estrogen Independently and Differentially Reduce Macronutrient Intake in Healthy Men.

Insulin administration to the central nervous system inhibits food intake, but this effect has been found to be less pronounced in female compared with male organisms. This sex-specific pattern has been suggested to arise from a modulating influence of estrogen signaling on the insulin effect. We assessed in healthy young men whether pretreatment with transdermal estradiol interacts with the hypophagic effect of central nervous insulin administration via the intranasal pathway. According to a 2×2 design, two groups of men (n = 16 in each group) received a 3-day transdermal estradiol (100 µg/24 h) or placebo pretreatment and on two separate mornings were intranasally administered 160 IU regular human insulin or placebo. We assessed free-choice ad libitum calorie intake from a rich breakfast buffet and relevant blood parameters in samples collected before and after breakfast. Estrogen treatment induced a 3.5-fold increase in serum estradiol concentrations and suppressed serum testosterone concentrations by 70%. Independent of estradiol administration, intranasal insulin reduced the intake of carbohydrates during breakfast, attenuating in particular the consumption of sweet, palatable foods. Estradiol treatment per se decreased protein consumption. We did not find indicators of eating-related interactions between both hormones. Results indicate that, in an acute setting, estrogen does not interact with central nervous insulin signaling in the control of eating behavior in healthy men. Insulin and estradiol rather exert independent inhibiting effects on macronutrient intake.

Efficacy of Transdermal Estradiol and Micronized Progesterone in the Prevention of Depressive Symptoms in the Menopause Transition

The menopause transition and early postmenopausal period are associated with a 2- to 4-fold increased risk for clinically significant depressive symptoms. Although a few studies suggest that hormone therapy can effectively manage existing depression during this time, to our knowledge, there have been no studies testing whether hormone therapy can prevent the onset of perimenopausal and early postmenopausal depressive symptoms. To examine the efficacy of transdermal estradiol plus intermittent micronized progesterone (TE+IMP) in preventing depressive symptom onset among initially euthymic perimenopausal and early postmenopausal women. A secondary aim was to identify baseline characteristics predicting TE+IMP's beneficial mood effects. Double-blind, placebo-controlled randomized trial at the University of North Carolina at Chapel Hill from October 2010 to February 2016. Participants included euthymic perimenopausal and early postmenopausal women from the community, aged 45 to 60 years. Transdermal estradiol (0.1 mg/d) or transdermal placebo for 12 months. Oral micronized progesterone (200 mg/d for 12 days) was also given every 3 months to women receiving active TE, and identical placebo pills were given to women receiving placebo. Scores on the Center for Epidemiological Studies-Depression Scale (CES-D), assessed at baseline and months 1, 2, 4, 6, 8, 10, and 12 after randomization, and the incidence of clinically significant depressive symptoms, defined as a CES-D score of at least 16. Of 172 participants, 130 were white (76%), and 70 were African American (19%), with a mean household income of $50 000 to $79 999. The mean age was 51 years, and 43 developed clinically significant depressive symptoms. Women assigned to placebo were more likely than those assigned to TE+IMP to score at least 16 on the CES-D at least once during the intervention phase (32.3% vs 17.3%; odds ratio [OR], 2.5; 95% CI, 1.1-5.7; P = .03) and had a higher mean CES-D score across the intervention period (P = .03). Baseline reproductive stage moderated the effect of treatment (β, -1.97; SEM, 0.80; P for the interaction = .03) such that mood benefits of TE+IMP vs placebo were evident among women in the early menopause transition (β, -4.2; SEM, 1.2; P < .001) but not the late menopause transition (β, -0.9; SEM, 0.3; P = .23) or among postmenopausal women (β, -0.3; SEM, 1.1; P = .92). Stressful life events in the 6 months preceding enrollment also moderated the effect of treatment on mean CES-D score such that the mood benefits of TE+IMP increased with a greater number of events (β, 1.22; SEM, 0.40; P = .003). Baseline estradiol levels, baseline vasomotor symptoms, history of depression, and history of abuse did not moderate treatment effects. Twelve months of TE+IMP were more effective than placebo in preventing the development of clinically significant depressive symptoms among initially euthymic perimenopausal and early postmenopausal women. clinicaltrials.gov Identifier: NCT01308814.

Appraising cervical mucus: a new approach to evaluating contraceptives

Purpose: Timing of sample collection represents a major source of variability in studies evaluating the effects of administered agents on cervical mucus in naturally-cycling women. We sought to create and validate an artificial model of the cervical mucus cycle using exogenous E2 and P4 replacement in ovarian suppressed women. Materials and methods: We conducted a prospective experiment (clinicaltrials.gov, NCT02969590) examining cervical mucus changes in six women during natural and artificial menstrual cycles [leuprolide acetate, estradiol transdermal patch (0.05–0.3 mg/day) and progesterone 200 mg/day]. We collected serum and mucus samples at each visit corresponding to early, mid and late follicular, ovulation and mid-luteal time points in the natural and artificial cycles. We evaluated mucus according to the modified Insler score described in the WHO laboratory Manual for the Examination and Processing of Human Semen. Results: We enrolled healthy women between 27 and 40 years of age. All of the subjects achieved a mucus score of ≥10 both in the natural cycle and during peak estradiol replacement levels (0.3 mg/day) in the artificial cycle. During the simulated luteal phase, all mucus scores were ≤5 (median 3.5; range 1–5), similar to scores seen in the luteal phase of natural cycles (median 1; range 1–3). Conclusions: Our artificial cycle model (leuprolide acetate suppression) and dose escalation with estradiol patches produced favourable cervical mucus with mucus scores similar to those in the periovulatory phase of natural menstrual cycles. Additional studies are needed to validate the model for evaluation of mucus effects of contraceptive agents.

Premature ovarian insufficiency - hormone replacement therapy and management of long-term consequences.

Premature ovarian insufficiency (POI) correlates with increased risk of cardiovascular diseases, osteoporosis, genitourinary syndrome, and other symptoms of prolonged oestrogen deprivation. Properly selected therapy improves the quality of women’s lives and reduces the risk of mortality. There is a wide spectrum of available oestrogen and progestogen formulations restoring proper levels of serum sex steroid hormones. The treatment should be implemented at recognition of the POI and continued to at least the age of natural menopause. Transdermal oestradiol and oral or vaginal progesterone administration provide the most physiological sex steroid replacement therapy. Patients’ views and individual preference according the route, dose, and regimen of hormonal treatment have to be taken into consideration in order to achieve high compliance rates. Women with POI should be managed by a multidisciplinary team, such as a gynaecologist, endocrinologist, dietitian, and psychologist.

Metabolic Syndrome in Hypopituitarism.

Prevalence of metabolic syndrome (MetS) and mortality rates from cardiovascular causes are increased in patients with hypopituitarism. Features of obesity, visceral adiposity, dyslipidemia, insulin resistance, and hypertension are common in these patients. Unreplaced growth hormone (GH) deficiency and inadequate replacement of other hormone insufficiencies may be responsible for the adverse body composition and metabolic profile associated with hypopituitarism. Recently, fatty liver disease was added to this unfavorable metabolic phenotype. Long-term treatment with low-dose GH replacement is considered safe and advantageous for metabolic profile and normalization of cardiovascular mortality rates in hypopituitary patients. Positive influence of optimal balance in replacement of other pituitary hormone deficiencies with doses of hydrocortisone (<20 mg/day), weight-adjusted T4 doses, and transdermal estrogen in women is also very important. Active screening and treatment of all cardiometabolic risk factors and comorbidities may further improve outcomes in patients with hypopituitarism.

Mammary Myofibroblastoma in a Transgender Patient on Feminizing Hormones: Literature Review and Case Report.

Purpose: Defining the risk of neoplasia associated with gender-affirming hormone therapy (GAHT) is a priority for transgender medical research. The purposes of this article are to present a unique case of breast neoplasia in a transgender individual and to review the existing evidence base on GAHT as a potential risk for breast pathology.Methods: We present the case of a 76-year-old transgender patient who developed an estrogen receptor-positive mammary myofibroblastoma (MFB) after 13 months of treatment on feminizing hormones. To our knowledge, this is the first reported case of MFB occurring in a transgender individual. A literature review was conducted to identify all reported cases of breast neoplasia among transgender individuals receiving feminizing GAHT. Information was abstracted from each of the included cases to describe the existing body of literature and to compare published cases to the case reported in this study.Results: We identified a total of 19 malignant and 3 benign cases of breast neoplasia among transgender women. Ours is the first reported case of MFB in a transgender individual receiving feminizing hormones and the first reported case of breast neoplasia associated with GAHT administered via the estradiol patch.Conclusion: This case reinforces the need for additional reporting of breast neoplasia presenting in transgender individuals treated with feminizing hormones. The relationship between estrogen exposure and breast neoplasia in the transgender population remains poorly defined, and additional research is needed to define risks and inform clinical practice.

Induction of the LH Surge in Premenarchal Girls Confirms Early Maturation of the Hypothalamic-Pituitary-Ovarian Axis.

To determine whether premenarchal girls exhibit positive estradiol feedback similar to regularly cycling adult women when given exogenous estradiol. This was a prospective clinical cohort study at 2 institutions. Nine girls and 6 women received a 7-day course of transdermal estradiol designed to produce physiologic, mid-cycle circulating estradiol levels. Participants collected daily morning urine for luteinizing hormone (LH), estradiol metabolites (E1c), and progesterone metabolites (Pdg), corrected for creatinine. Main outcomes were percentage increase in LH from nadir to peak and the absolute value of peak LH between the 2 groups, using t testing and linear mixed-effects modeling. All participants exhibited a positive feedback response to estradiol. Adult women had a 532.8% (95% confidence interval [CI]: 253.7-1119) increase in LH after estradiol exposure; premenarchal girls had a 497.9% increase (95% CI: 274.5-903.2; P = .86). The absolute value of the LH surge in women was 9.50 mLU/mgCr (95% CI: 2.59- 43 34.90) and in premenarchal girls was 2.57 mLU/mgCr (95% CI: 0.53-12.49; P = .15). Premenarchal girls can mount an LH surge proportionally similar to regularly cycling adults. This occurs earlier in puberty than previously believed, in contrast to current dogma that maturation of the hypothalamic-pituitary-ovarian axis occurs after menarche and is the rate-limiting step for the establishment of regular, ovulatory cycles. Failure to achieve regular cycles may instead be due to nutritional or ovarian factors. Young girls who fail to ovulate shortly after menarche may warrant further evaluation for endocrinopathies.

The effectiveness and safety of mht depending on the type, route of administration of estrogens, and the type of progestogen. Analysis of data from clinical trials and international recommendations

The hormone therapy remains the most effective method for treating of the vasomotor symptoms and genitourinary syndrome in menopause. The evidence available to date suggests that for women younger than 60 and with a postmenopause no more than 10 years without contraindications, the benefits of administering systemic hormone therapy for the treatment of vasomotor symptoms, sleep disorders and prevention of bone loss exceed possible risks. In addition, the data about statistically significant reduction in all-cause mortality in women who initiate hormone therapy before the age of 60 and/or 10 years after the onset of menopause have been obtained.Menopausal hormone therapy (MHT) includes a wide range of hormonal drugs and administration routes that potentially have different risks and benefits, and therefore the term “class effect” is misleading and inappropriate. The risks of menopausal hormone therapy vary depending on the composition, dose and route of administration of hormones, as well as the timing of the onset and duration of use of both estrogens and progesterone. The use of transdermal estrogens in combination with progesterone seems safer for venous thromboembolism, especially in high-risk women. The use of transdermal estrogen drugs in comparison with oral estrogens is associated with a lesser likelihood of developing thrombotic risk, and possibly the risk of developing stroke and coronary heart disease. If progesterone is needed, micronized progesterone is a safer alternative.MHT requires a periodic reassessment of the benefits and risks for deciding whether to continue or stop using it. The use of postmenopausal hormone therapy in women with menopausal disorders should be based on an assessment of all risk factors for cardiovascular disease, age and time from the onset of menopause. The duration of therapy should be motivated by the indications, and the decision should be taken in conjunction with the doctor.