Estrogen doses. Comprehensive Guide to Estrogen Therapy: Uses, Dosages, and Effects

07.07.197220.08.2021 by alexxlab

What are the primary uses of estrogen therapy. How does estrogen therapy affect menopausal symptoms. What are the recommended dosages for estrogen replacement. How does estrogen therapy impact bone health. What are the potential risks and side effects of estrogen therapy. How does estrogen therapy influence cardiovascular health. What are the different forms and administration routes for estrogen therapy.

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Understanding Estrogen Therapy: Purposes and Applications

Estrogen therapy, also known as hormone replacement therapy (HRT), serves various medical purposes, primarily in managing menopausal symptoms and addressing hormonal imbalances. This treatment approach has been a subject of extensive research and clinical application, offering relief to many individuals experiencing hormonal fluctuations.

Primary Uses of Estrogen Therapy

Alleviating menopausal symptoms
Preventing osteoporosis
Managing urogenital symptoms
Addressing mood and cognitive changes
Inducing puberty in cases of hormonal deficiency

Estrogen therapy plays a crucial role in mitigating the effects of hormonal changes, particularly during menopause. It helps in managing a range of symptoms that can significantly impact quality of life.

Estrogen Therapy for Menopausal Symptom Management

Menopausal symptoms can be challenging for many women, affecting their daily lives and overall well-being. Estrogen therapy has shown remarkable efficacy in addressing these symptoms, providing relief and improving quality of life.

Key Menopausal Symptoms Addressed by Estrogen Therapy

Hot flashes and night sweats
Vaginal dryness and discomfort
Mood swings and irritability
Sleep disturbances
Reduced libido

How effective is estrogen therapy in managing hot flashes? Studies have shown that estrogen therapy can reduce the frequency and intensity of hot flashes by up to 75% in many women, offering significant relief from this common menopausal symptom.

Dosage Guidelines for Estrogen Replacement Therapy

Determining the appropriate dosage for estrogen therapy is crucial for maximizing benefits while minimizing potential risks. Healthcare providers typically follow established guidelines while tailoring the treatment to individual patient needs.

Factors Influencing Estrogen Dosage

Age and overall health of the patient
Severity of symptoms
Presence of other medical conditions
Individual response to treatment

What is the recommended starting dose for estrogen therapy? For most women, a low-dose regimen is initially prescribed, typically 0.3 mg to 0.45 mg of conjugated estrogens or equivalent. This dose can be adjusted based on the patient’s response and symptom control.

Impact of Estrogen Therapy on Bone Health

Estrogen plays a vital role in maintaining bone density, and its decline during menopause can lead to an increased risk of osteoporosis. Estrogen therapy has demonstrated significant benefits in preserving bone health and reducing fracture risk.

Bone Health Benefits of Estrogen Therapy

Increased bone mineral density
Reduced risk of osteoporotic fractures
Improved bone metabolism
Enhanced calcium absorption

How does estrogen therapy reduce the risk of osteoporosis? Estrogen therapy helps maintain bone density by slowing bone resorption and promoting bone formation. Studies have shown that it can reduce the risk of hip fractures by up to 30% in postmenopausal women.

Potential Risks and Side Effects of Estrogen Therapy

While estrogen therapy offers numerous benefits, it’s essential to be aware of potential risks and side effects. Healthcare providers carefully weigh these factors against the benefits when prescribing treatment.

Common Side Effects of Estrogen Therapy

Breast tenderness
Nausea and bloating
Headaches
Mood changes
Vaginal bleeding or spotting

What are the more serious risks associated with estrogen therapy? Long-term use of estrogen therapy, especially when combined with progestin, has been associated with an increased risk of breast cancer, blood clots, and stroke in some women. However, these risks are generally low and should be discussed individually with a healthcare provider.

Estrogen Therapy and Cardiovascular Health

The relationship between estrogen therapy and cardiovascular health has been a subject of extensive research and debate. While earlier studies suggested potential cardiovascular benefits, more recent findings have provided a more nuanced understanding.

Cardiovascular Effects of Estrogen Therapy

Potential improvement in lipid profiles
Effects on blood pressure
Impact on blood clotting factors
Influence on arterial function

Does estrogen therapy reduce the risk of heart disease? The cardiovascular effects of estrogen therapy appear to be age-dependent. In younger postmenopausal women (under 60), it may offer some cardioprotective benefits. However, in older women or those with existing cardiovascular disease, the risks may outweigh the benefits.

Forms and Administration Routes of Estrogen Therapy

Estrogen therapy is available in various forms and can be administered through different routes, allowing for personalized treatment approaches based on individual needs and preferences.

Common Forms of Estrogen Therapy

Oral tablets
Transdermal patches
Topical gels and creams
Vaginal rings
Intravaginal creams and tablets

Which form of estrogen therapy is most effective? The effectiveness of estrogen therapy depends on individual factors and treatment goals. Transdermal forms, such as patches and gels, are often preferred as they bypass first-pass liver metabolism, potentially reducing the risk of blood clots and providing more stable hormone levels.

Estrogen Therapy in Special Populations

While estrogen therapy is primarily associated with menopausal symptom management, it also plays crucial roles in other medical contexts, particularly in addressing hormonal deficiencies in younger individuals.

Estrogen Therapy for Turner Syndrome

Turner Syndrome (TS) is a genetic condition affecting females, characterized by the absence of one X chromosome. Estrogen therapy plays a vital role in the management of TS, particularly in inducing puberty and maintaining hormonal balance.

At what age should estrogen therapy be initiated in girls with Turner Syndrome? Recent studies suggest that initiating low-dose estrogen therapy as early as 11 to 12 years of age in girls with TS is safe and effective. This approach aims to mimic physiological puberty and has been associated with improved quality of life and psychological well-being in adulthood.

Benefits of Early Estrogen Therapy in Turner Syndrome

Age-appropriate pubertal maturation
Improved bone density
Enhanced cognitive function
Better psychosocial outcomes

How does estrogen therapy affect growth in girls with Turner Syndrome? When coordinated with growth hormone therapy, low-dose estrogen does not interfere with linear growth. This integrated approach allows for simultaneous management of both growth and pubertal development.

Optimizing Estrogen Therapy: Dosage and Administration

The effectiveness of estrogen therapy largely depends on proper dosing and administration. Healthcare providers aim to tailor the treatment to individual needs while adhering to established guidelines.

Principles of Estrogen Dosing

Start with the lowest effective dose
Gradually increase dosage if needed
Regular monitoring and assessment
Consideration of combination therapy

How often should estrogen therapy be reassessed? The efficacy of HRT should be assessed after 4 to 6 weeks of treatment initiation. Doses can be adjusted upward until symptoms are adequately relieved. Thereafter, the need for continued therapy should be evaluated every 4 to 6 months.

Combination Therapy Considerations

For women with an intact uterus, estrogen therapy is typically combined with progesterone to prevent endometrial hyperplasia. This approach, known as combined hormone replacement therapy (HRT), requires careful consideration of dosing and administration schedules.

What are the different schedules for combined HRT? Combined HRT can be administered in either continuous or cyclical schedules. Continuous schedules involve daily administration of both hormones, while cyclical schedules alternate periods of estrogen-only and combined hormone administration.

Monitoring and Managing Side Effects of Estrogen Therapy

While estrogen therapy offers significant benefits, it’s crucial to monitor for and manage potential side effects. Proper management can enhance treatment adherence and overall outcomes.

Common Side Effects and Management Strategies

Breast tenderness: May resolve spontaneously or with dose adjustment
Nausea: Often improves with time or by taking medication with food
Headaches: May require dose adjustment or alternative formulations
Vaginal bleeding: Requires prompt evaluation, especially if unexpected

How can premenstrual-like symptoms be managed in women on HRT? Symptoms such as breast tenderness, bloating, mood swings, and headaches often resolve spontaneously within a few months. If persistent, lowering the progesterone dose or switching from cyclical to continuous HRT may help alleviate these symptoms.

Advanced Considerations in Estrogen Therapy

As research in hormone therapy continues to evolve, new insights and approaches are emerging, offering more refined and personalized treatment options.

Emerging Trends in Estrogen Therapy

Bioidentical hormone formulations
Tissue-selective estrogen complexes
Combination therapies with other hormones or supplements
Personalized dosing based on genetic profiles

What are the potential advantages of transdermal estrogen therapy? Recent studies suggest that transdermal estradiol may be the most physiological form of estrogen therapy commercially available. It results in more stable hormone levels and may have a lower risk of certain side effects compared to oral formulations.

Long-term Considerations in Estrogen Therapy

The duration of estrogen therapy remains a topic of ongoing research and discussion. While short-term use for symptom management is well-established, the long-term use of HRT requires careful consideration of individual risk factors and potential benefits.

How long should estrogen therapy be continued? The duration of therapy should be individualized based on the patient’s health status, risk factors, and treatment goals. Regular reassessment is crucial to ensure that the benefits continue to outweigh the risks.

Estrogen Therapy and Quality of Life

Beyond symptom management, estrogen therapy can have profound effects on overall quality of life for many individuals. Understanding these broader impacts is essential for comprehensive patient care.

Quality of Life Improvements with Estrogen Therapy

Enhanced mood and emotional well-being
Improved sexual function and satisfaction
Better sleep quality
Increased energy and vitality
Preservation of cognitive function

How does estrogen therapy affect cognitive function in postmenopausal women? While research is ongoing, some studies suggest that estrogen therapy, particularly when initiated close to menopause, may help maintain cognitive function and potentially reduce the risk of certain types of dementia.

Future Directions in Estrogen Therapy Research

The field of hormone therapy continues to evolve, with ongoing research aimed at refining treatment approaches and understanding long-term outcomes. Several areas of investigation hold promise for future advancements in estrogen therapy.

Emerging Research Areas in Estrogen Therapy

Precision medicine approaches to hormone therapy
Novel delivery systems for improved efficacy and reduced side effects
Combination therapies with other hormones or supplements
Long-term effects on cardiovascular and cognitive health
Potential applications in other medical conditions

What role might genomics play in the future of estrogen therapy? Advances in genomic research may lead to more personalized approaches to hormone therapy, allowing for tailored treatment based on individual genetic profiles and risk factors.

As our understanding of hormonal processes and their impacts on health continues to grow, estrogen therapy remains a dynamic field with significant potential for improving the lives of many individuals. Ongoing research and clinical experience continue to refine our approaches, offering hope for even more effective and personalized treatment options in the future.

Premarin Oral: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing

Straight to the Point: Menopause and hormone-replacement therapy

It is important to review the goals of hormone-replacement therapy (HRT)—for example, treatment of menopausal symptoms vs prevention of osteoporosis—with the patient before initiating therapy (table 1)

Table 1

Summary of hormone-replacement treatment effects^*

*Condition*	*Estrogen alone*	*Estrogen plus progestin*	*Raloxifene HCl*	*Estrogen plus testosterone*	*Biphosphonates*
Hot flashes and urogenital symptoms	++	++	–	++	00
Mood, cognitive libido changes	+	+	00	+	00
Osteoporosis	++	++	++	++	++
Coronary artery disease	+/-	+/-	0	0	00
Stroke	00	–	0	0	00
Breast cancer	–	–	++	0	00
Endometrial cancer	– –	00	00	0	00
Deep venous thrombosis or pulmonary embolus	– –	– –	– –	0	00
HCl = hydrochloride.

^*++ = proven benefit; + = possible benefit; – – = proven risk; – = possible risk; 00 = no effect; and 0 = no data.

Efficacy of HRT should be assessed after 4 to 6 weeks; doses can be titrated upward until symptoms are relieved. The need for continued therapy can be evaluated every 4 to 6 months

HRT may be given orally, transdermally, or intravaginally in either continuous or cyclical schedules

Progesterone is usually given with estrogen for women with a uterus to prevent endometrial hyperplasia

Women without a uterus do not require progesterone

Uterine bleeding that is excessive, prolonged, or in any way different from the expected bleeding of the prescribed regimens must be evaluated promptly with endometrial biopsy, ultrasonography, or both

Premenstrual-like symptoms (breast tenderness, bloating, mood swings, headache) can occur when HRT is initiated. Many resolve spontaneously within a few months. Lowering the progesterone dose or switching from cyclical to continuous HRT can help

Dosing Standards for Estrogen | Endocrine Society

The hormonal induction of puberty as early as 11 to 12 years of age with low-dose estrogen in hypogonadal girls with Turner Syndrome (TS) is safe and effective and does not interfere with linear growth.(1,2)

The psychological benefit to undergo age-appropriate pubertal maturation is supported by reports of increased quality of life and psychological well-being in adults with TS who did not experience delayed induction of puberty and late menarche.(3,4)

Exogenous hormone therapy is aimed to most closely mimic physiologic puberty and is preferably coordinated with the final phase of growth hormone therapy. Evidence is increasing that transdermal micronized estradiol is the most physiological form and route of estrogen therapy commercially available. In a recent study, transdermal estradiol therapy resulted in levels of estradiol, estrone, and bioestrogen metabolites closer to normal and with a greater suppression of LH and FSH levels than following oral estradiol replacement. (5,6) For patients who are unable to tolerate estradiol patch therapy or prefer to use pills, the use of low dose oral micronized estradiol provides a reasonable therapeutic alternative, with an initial dose of 0.25 mg daily.

The overall approach is to increase the estrogen dose gradually over 3 to 3.5 years and to use growth, bone maturation, hormone levels, degree of feminization, patient satisfaction, bleeding pattern, and side effects as a guide. To ensure a healthy endometrium, a progestin should be introduced approximately 2.5 years after starting estrogen or earlier if breakthrough bleeding occurs. For the physician caring for young adult women with TS, from both the physiological and safety perspectives, the continued use of transdermal estradiol with a cyclical progestin once puberty is complete makes sense.

This daily regimen is relatively complex and may be expensive, if the estradiol patches are not covered by insurance. Compliance may not be sufficient to preserve bone health. Oral estradiol at a dose of 1-2 mg a day cycled with a progestin is less costly and some patients find it easier to take a daily pill than change patches once to twice weekly. The oral contraceptive pill is more than adequate for bone health, is less expensive, convenient to use and rarely is associated with intra-cycle bleeding.(7) The adverse publicity to chronic estrogen use stemming from the WHI study can be addressed by providing a simple explanation of how the findings do not apply to younger women going through menopause and younger hypogonadal women.

The specifics of low dose regimens to induce puberty in adolescents with TS continue to be explored and evaluated.(8) One approach adopted by many, has been the use of fractionated or partial estradiol patches to achieve a very low dose at the start of pubertal induction. An alternative best practice soon to be assessed in a multicenter Quality Initiative being sponsored by the Pediatric Endocrine Society and open to all its members for participation, enables the initiation of puberty with the application of an entire 25 mcg
estradiol patch for one week, monthly and then titrating the dose gradually by initially increasing the duration of patch usage and subsqequently the patch dose.

References

Rosenfield R.L., Devine N., Hunold J.J., Mauras N., Moshang T., Jr., Root A.W., 2005 Salutary effects of combining early very low-dose
systemic estradiol with growth hormone therapy in girls with Turner syndrome. J Clin Endocrinol Metab 90:6424-6430
Ross J.L., Quigley C.A., Cao D., Feuillan P., Kowal K., Chipman J.J., Cutler G.B., Jr., 2011 Growth hormone plus childhood low-dose
estrogen in Turner’s syndrome. N Engl J Med 364:1230-1242
Carel J.C., Ecosse E., Bastie-Sigeac ., et al. Quality of life determinants in young women with Turner’s syndrome after growth
hormone treatment: results of stature population-based cohort study. J Clin Endocrinol Metab 2005; 90:1992-1997
Boman U.W., Bryman I., Moller A., Psychological well-being in women with Turner syndrome: somatic and social correlates. J Psychosom Obstet Gynaecol 2004; 25(3-4):211-219
Torres-Santiago L., Mericq V., Taboada M., Unanue N., Klein K., Singh R., Hossain J. , Santen R., Ross J., Mauras N., 2013 Metabolic effects of oral vs. transdermal 17beta estradiol (E2): a randomized clinical trial in girls with Turner Syndrome. J Clin Endocrinol Metab 98:2716-2724
Taboada M., Santen R., Lima J., Hossain J., Singh R., Klein K.O., Mauras N., 2011 Pharmacokinetics and pharmacodynamics of oral and transdermal 17beta estradiol in girls with Turner syndrome. J Clin Endocrinol Metab 96:3502-3510
van Pareren Y.K., de Muinck Keizer-Schrama S.M., Stijnen T., Sas T.C., Jansen M., Otten B.J., Hoorweg-Nijman J.J., Vulsma
T., Stokvis-Brantsma W.H., Rouwe C.W., Reeser H.M., Gerver W.J., Gosen J.J., Rongen-Westerlaken C., Drop S.L., 2003 Final height in girls with turner syndrome after long-term growth hormone treatment in three dosages and low dose estrogens. J Clin Endocrinol Metab 88:1119-1125
Bondy C.A., for the Turner Syndrome Consensus Study Group 2007 Care of girls and women with Turner syndrome: a guideline of the
Turner syndrome study group. J Clin Endocrinol Metab 92:10-25

Serum estradiol level according to dose and formulation of oral estrogens in postmenopausal women

In the present study evaluating serum estradiol level in postmenopausal women using MHT with different doses and formulations of estrogens, serum estradiol level with MHT using EH or EV was similar to previous studies reporting estrogen circulating levels of 30–50 pg/mL for estradiol 1 mg and 60–110 pg/mL for estradiol 2 mg^12,13. However, although serum estradiol level increased with dose of estrogen, amount of increase was not directly proportional to dose of estrogen; in particular, for oral estradiol, doubling the estrogen dose from 1 to 2 mg presented an increase of approximately 60% instead of doubling the serum estradiol level. This finding suggests that ‘low-dose’ estrogen might be adequate as an initial MHT. Then, clinicians can do upward titration based on clinical response^3,14.

For a long time, CE 0. 625 mg has been the most widely used MHT and is considered the ‘standard dose’ of MHT. Generally, CE 0.625 mg is thought to be equivalent to 1–2 mg of estradiol, which is in accordance with our study showing that the serum estradiol level of CE 0.625 mg (76.8 pg/mL) remains between that of 1 mg (65.8 pg/mL) and 2 mg (107.6 pg/mL) of estradiol.

Although the optimal range for serum estradiol level to achieve therapeutic efficacy has not been established, a serum estradiol level of 60 pg/mL is needed to prevent osteoporosis¹⁵ and reduce 50% of hot flashes¹⁶. However, 0.45 mg of CE (serum estradiol level of 60.1 pg/mL in the current study) was similarly effective for treating VMS compared to 0.625 mg of CE in a randomized controlled trial¹⁷, which suggests that CE 0.45 mg is not inferior to CE 0.625 mg in terms of the effects on VMS. In addition, in a recent study, worsening of VMS when MHT was changed from 1 mg of estradiol to tissue-selective estrogen complex (TSEC) occurred in 16. 7% of users, which was significantly lower than the rate of worsening of VMS when MHT changed from 2 mg of estradiol to TSEC (41.7%)¹⁸. When putting these findings together and considering that the lowest effective dose of MHT should be used to treat VMS and prevent bone loss¹, TSEC containing 0.45 mg of CE and 20 mg of bazedoxifene could be the best initial MHT option for healthy postmenopausal women with an intact uterus.

In addition to serum estradiol level, serum FSH level also has been used to address the relative potencies of estrogens. In the present study, however, serum FSH level did not differ significantly between 1 and 2 mg doses of estradiol (20.9 vs. 25.0 IU/L), in contrast to serum estradiol level. Of interest, whereas the serum estradiol level was similar, serum FSH level was significantly higher in CE 0.45 mg (43.8 IU/L) than estradiol 1 mg (20.9 IU/L). Since CE is a mixture of estrogens, effects of CE on serum FSH level might be different compared with estradiol, even in the similar serum estradiol level. Considering that associations between serum FSH levels and surrogate markers or clinical outcomes of several diseases have been demonstrated recently, further investigation might be needed to explain the difference in responses to MHT for serum FSH level and serum estradiol level.

Although EV 1 mg is equivalent to estradiol 0.76 mg and EH and estradiol are identical, serum levels of estradiol were not significantly different between EV and EH in the present study. It might result from a small number of subjects, and a further large-scale study is warranted to draw a clear conclusion.

The present study has several strengths. First, this study was performed in a single center, and serum estradiol level was measured using the same kit. This allowed for direct comparisons of serum estradiol levels with different doses and formulations of estrogens. Second, the present study included only young healthy postmenopausal women who are the main candidates for MHT. Pharmacokinetics of oral estrogens may differ between younger and older postmenopausal women due to decrease in liver and kidney function, cardiac output, pulmonary function, muscle mass, and body composition associated with aging^19,20. Finally, we considered many variables that could affect serum estradiol level. Age and body mass index were addressed, and women with a history of bilateral oophorectomy, premature ovarian insufficiency, known liver or kidney disease, or malignancy were excluded. Current smokers, heavy alcohol drinkers, and users of any medication that could affect serum estradiol level were also excluded from analyses.

However, our findings should be interpreted with caution. First, mass spectrometry, which can determine serum estradiol level more accurately, was not used in our study. However, the aim of this study was to compare relative potencies of various regimens based on the same method for measurement, not to determine estradiol concentration exactly. Second, differences in serum estradiol level do not directly reflect differences in the effects of MHT. Although serum estradiol concentration is closely correlated with the effects of estrogen on various tissues^21,22, actions of each estrogen can differ according to target tissue, and a single measurement of serum estradiol level for general comparisons of ‘estrogenicity’ might be questionable. Indeed, potency of hormones is determined by interactions with receptors and response elements on the DNA and by intracellular concentration²³, not solely by serum estradiol level. Third, effects of CE might not absolutely depend on serum estradiol level, because CE is a mixture of estrogens and major components of CE are estrone sulfate and equilin sulfate. It also might be difficult to measure serum estradiol concentrations in CE users. Fourth, pharmacokinetics of MHTs such as maximal peak or 24-h change of serum estradiol concentrations are unknown, and serum estradiol level was measured at a single time point. In addition, only drugs available in our country were included, and our results could not be extrapolated to other doses, formulations, or administration routes of estrogens. Finally, we did not consider type or dose of progestogen. However, progestogens do not affect the serum estradiol level²⁴.

Physiological Estrogen Replacement Therapy for Puberty Induction in Girls: A Clinical Observational Study – FullText – Hormone Research in Paediatrics 2014, Vol.

81, No. 4

Abstract

Background/Aim: The goal of estrogen replacement therapy (ERT) in girls with hypogonadism is to achieve the endocrine milieu similar to natural puberty, where transdermal administration is the most physiological route. The aim of the study was to evaluate guidelines for the induction of puberty with transdermal estradiol (E₂) patches in a large outpatient setting. Methods: In a retrospective study, serum E₂ levels from 18 clinics were analyzed at the Göteborg Pediatric Growth Research Center laboratory, as part of the initiation of ERT in girls with hypogonadism. Exclusion criteria were pubertas tarda and pubertal arrest. Eighty-eight observations (50 with Turner syndrome, TS) were included. Serum E₂ levels were determined by extraction + radioimmunoassay (detection limit 4 pmol/l) and analyzed in relation to the dose of Evorel® (25 µg/24 h, containing 1. 60 mg estradiol hemihydrate; Janssen-Cilag Pharmaceutica N.V., Beerse, Belgium). Results: There was a linear relationship between serum E₂ and the weight-based dose, with r = 0.56, p Conclusions: For the initiation of ERT with nocturnally administered E₂ patches, we recommend reduced starting doses of 0.05-0.07 µg/kg, with the goal of mimicking E₂ levels during gonadarche. In older girls, when breast development is of high priority, the starting dose can still be 0.08-0.12 µg/kg.

Introduction

The overall goal of estrogen replacement therapy (ERT) in girls with hypogonadism is to establish an age-appropriate endocrine milieu resulting in normal growth, bone mass accrual, uterine growth and maturation, development of secondary sexual characteristics and cognitive functions, at a tempo consistent with the peer group [1,2]. The very early part of the pubertal growth spurt and the development of secondary sexual characteristics are regulated by increasing serum levels of nocturnal estrogens, where low serum estrogen levels are growth promoting and higher levels are needed for complete breast and body development [3,4].

Thereby, pubertal ERT consists of two major parts: first, low estrogen doses to promote onset of pubertal growth; second, increased estrogen doses to finalize the pubertal development. In a girl with hypogonadism, the optimal estrogen treatment route, drug, dose and dosing tempo have to be determined for the individual patient. Many of these decisions are based on tradition, rather than on evidence.

Current dosing guidelines are based on the investigation of nocturnal application of transdermal patches in a limited number of hospitalized patients [5]. The aim of the present retrospective study was to use a large set of empirical data to evaluate the current dosing guidelines for initiation of ERT to achieve morning estradiol (E₂) levels similar to those seen during the very first signs of spontaneous puberty.

Subjects and Methods

Study Group

The study group consisted of girls with hypogonadism. Girls treated with nocturnal application of Evorel® patches (25 µg/24 h, containing 1. 60 mg estradiol hemihydrate) during the years 2001-2011 were included in the potential study group. Inclusion criteria were those treated with doses of 0.05-0.15 µg/kg body weight. Exclusion criteria were girls with pubertas tarda or pubertal arrest. Lack of information on E₂ patch dose, body weight or time of blood sampling also resulted in exclusion. We did not have sufficiently reliable data on breast development in relation to dose in the study group, and pretreatment E₂ samples were not always available; for some girls, we were obliged to rely on the referral information on hypogonadism and the absence of pubertal development.

In total, 142 fulfilled the inclusion criteria derived from 54 girls. Repeated E₂ determinations on subjects during treatment with the same E₂ dose per kilogram body weight (rounded to two decimals) were identified in 28 subjects with 2-5 samplings per girl and dose. For these observations, the median values were calculated and used in the study, which reduced the observations to 88.

In all, 88 observations from 54 individuals were included. The diagnoses given on the referrals were Turner syndrome (TS) in 31, other reasons for primary ovarian failure in 7, hypopituitarism in 7, androgen resistance (gonadectomized) in 3 and ovarian failure due to chemotherapy in 6. The age range was 10.5-16.9 years (n = 29, median 14.1 years) for doses of 0.05-0.07 µg/kg, 9.9-18.0 years (n = 42, median 14.0 years) for doses of 0.08-0.12 µg/kg and 11.7-17.0 years (n = 17, median 14.7 years) for doses of 0.13-0.15 µg/kg.

Design

We recommended cutting the matrix patches (Evorel = Systen®; 25 µg/24 h, containing 1.55 mg E₂ as 1.60 estradiol hemihydrate; Janssen-Cilag Pharmaceutica N.V., Beerse, Belgium) to obtain a dose of 0.08-0.12 µg/kg as the puberty induction starting dose [5]; see figure 1 for cutting instructions. However, during the 10-year period of this study, pediatricians have started to use lower doses than the recommended guideline. It is recommended to place the patch on the superior lateral glutea in the evening at bedtime and remove it the following morning [5], resulting in approximately 10 h of treatment. Within 1-2 weeks of the start of treatment, physicians were recommended to monitor the morning serum E₂ with the patch still in situ, in order to adjust the dose if the target E₂ range was not reached.

Fig. 1

Cutting instructions for 1/14 to 2/7 Evorel patches (Systen; Janssen-Cilag Pharmaceutica; 25 µg/24 h).

Study Material

The retrospective study consisted of registered serum E₂ levels from samples sent for analysis to the Göteborg Pediatric Growth Research Center laboratory, at the Queen Silvia Children’s Hospital, Göteborg, Sweden. All clinical information on the referrals was recorded, together with the assay result. The samples were submitted from 18 clinics in Sweden. Included were those girls who broadly followed the guidelines by Ankarberg-Lindgren et al. [5] for puberty induction with ERT. With this retrospective design, the study lacks confirmatory clinical and laboratory data on the diagnosis. The analysis has to rely on the diagnosis recorded. Furthermore, no information of compliance was found.

E

₂ Determination

Serum E₂ concentrations were determined in duplicate by an assay which involves a diethyl ether extraction step prior to radioimmunoassay (Spectria® Estradiol RIA; Orion Diagnostica, Espoo, Finland) [1,6]. The extraction E₂ radioimmunoassay has been validated especially for pediatric use [6] and is accredited by the SWEDAC quality control agency in Sweden, SS-EN ISO 15189 (No. 1899). The lower limit of detection was 4 pmol/l. The cross-reactivity of the E₂ antiserum was below 1% for 30 E₂-related steroids. The intra-assay coefficient of variation was 8-17% for concentrations in the 4-100 pmol/l range, while the interassay coefficient of variation was 19% at 6 pmol/l, below 12% for 10-40 pmol/l, and below 10% for 70 pmol/l and above.

Statistical Analyses

Relationships between E₂ dose and obtained serum E₂ were estimated with Pearson’s correlation analyses. Linear regression analysis and correlation analysis were performed with Origin 9.0, OriginLab Corp., Northampton, Mass., USA. For girls in whom more than one observation was made for a given dose, the median was used in the statistical analyses.

Ethics Statement

Informed consent was obtained, in accordance with the Swedish Biobank Act (Biobankslagen SFS 2002:297), in the form of parental agreement to the inclusion of their child’s samples and referrals in a biobank.

Results

All Kinds of Hypogonadism

For the 29 girls who started ERT at 0.05-0.07 µg/kg, all had serum E₂ levels above the reference interval for prepuberty (B1) [7]. Sixteen of them had levels in the peripubertal range (7-24 pmol/l), Tanner breast stage 1-2 (B1-2), while 12 were within the reference interval for Tanner breast stage 2 (B2; 24-47 pmol/l), and 1 was just above the B2 range (fig. 2a).

Fig. 2

Serum E₂ concentrations in relation to E₂ dose per kilogram body weight from a matrix patch (Evorel; 25 µg/24 h, containing 1. 60 mg E₂ hemihydrate; Janssen-Cilag Pharmaceutica) in girls with hypogonadism. The morning serum samples were drawn with the patch still in situ. The gray area depicts the reference interval for girls in early puberty divided into three areas: peripubertal levels, i.e. levels seen during assumed gonadarche in girls with Tanner breast stage 1-2 (B1-2), breast stage 2 (B2) and the transition stage between breast stages 2 and 3 (B2-3), respectively. a Eighty-eight samples from 54 girls with any kind of hypogonadism. Linear regression analysis showed that serum E₂ (pmol/l) = 307.2 × E₂ dose (µg/kg) + 1.7 (r = 0.56, p < 0.0001). b Fifty E₂ samples from a subgroup of 31 girls with TS. Linear regression analysis showed that serum E₂ (pmol/l) = 314.3 × E₂ dose (µg/kg) + 1.6 (r = 0.59, p < 0.0001).

Of the 42 girls receiving the dose 0.08-0.12 µg/kg, 20 still had low levels corresponding to B1-2; 18 had serum E₂ within the reference interval for B2, while 4 had levels above the B2 interval (fig. 2a).

Among the 17 girls who were treated with 0.13-0.15 µg/kg, only 9 had E₂ levels within the B2 interval, while 5 had E₂ levels in the B2-3 interval (46-77 pmol/l) and 3 in the Tanner breast stage 3 (B3) interval. The relationship between E₂ dose per kilogram body weight and the E₂ serum concentration for the total group is shown in figure 2a. Linear regression analysis for doses of 0.05-0.07 µg/kg resulted in serum levels of 17-23 pmol/l and doses of 0.08-0.12 µg/kg resulted in 26-39 pmol/l.

Turner Syndrome

A subgroup analysis was performed on 50 blood samples from the 31 girls with TS. A linear relationship was found between E₂ dose and obtained serum levels (fig. 2b). Linear regression analysis for doses of 0.05-0.07 µg/kg resulted in serum levels of 17-24 pmol/l and doses of 0.08-0.12 µg/kg resulted in 27-39 pmol/l. When the two functions (TS vs. all kinds of hypogonadism) were compared, there was no significant difference.

For the 21 TS girls who started E₂ treatment on 0.05-0.07 µg/kg, 12 had serum E₂ levels within the B1-2 interval, while 8 observations were within the B2 interval and 1 was just above the B2 range. Furthermore, in 18 girls receiving the dose 0.08-0.12 µg/kg, 12 had E₂ levels in the B1-2 interval, 4 were within the B2 interval, and 2 were in the interval seen both in breast stages 2 and 3 (B2-3). However, in the 11 girls who were treated with a higher dose (0.13-0.15 µg/kg), 5 had E₂ levels within the B2 interval while 4 had E₂ levels in the B2-3 interval and 2 in the B3 interval (fig. 2).

In table 1, the obtained doses of E₂ (µg/kg) are converted to the corresponding individual patch doses. This study was made with 25-µg patches; however, if the 25-µg patches are not available, the surface of a 50-µg patch is double the size of a 25-µg patch, and our results may be converted accordingly.

Table 1

Doses of pubertal ERT converted to the corresponding individual patch doses

Discussion

We have previously published a recommendation that transdermal E₂ matrix patches should be cut to administer low doses; with nocturnal application, the serum E₂ levels and diurnal rhythm in normal girls undergoing puberty can be closely mimicked [5]. Our regimen has become a worldwide guideline [8,9,10]. However, the published guidelines were based on a limited group of hospitalized patients [5]; in the present study, we evaluated how this regimen works in an outpatient setting, using an even lower starting dose, testing a larger group of hypogonadal girls and assessing the reported dose in relation to the achieved morning level of serum E₂.

The results from this study suggest that the ERT starting dose should be 0.05-0.07 µg/kg, which is lower than in our previous study [5]. With this reduced regimen, the risk of too high a serum E₂ concentration, compared to the reference interval for Tanner stage B2, will be reduced. This is also supported by recent results from girls in spontaneous puberty, demonstrating an association of serum E₂ levels of 13-31 pmol/l with increased height velocity or onset of the pubertal growth spurt [3].

For clinics with access to ultrasensitive methods for determination of childhood E₂, we recommend starting with a dose of 0. 05-0.07 µg/kg and following the morning serum E₂ level within 1-2 weeks, when the patient is comfortable with the regime. This makes it possible to rapidly adjust the dose if the individual target serum level is not reached.

For clinics without access to an ultrasensitive E₂ assay, we recommend starting with the same dose of 0.05-0.07 µg/kg and following the clinical signs of breast development or increment in uterine size by ultrasound. If no effect is found on breast development after 9-15 months, the dose can be increased. If breast development starts within 3 months, consider reducing the dose if the aim is low E₂ levels in the beginning of puberty, or refraining from dose increment for at least 12 months. This consideration could be applied to other effects of E₂, such as development of the uterus and advancement of bone age, but we have limited data on how E₂ levels relate to uterine development, and we cannot give any recommendations on these measures.

For those clinical situations in which breast development is a higher priority than a continued favorable growth – for example in older girls or in girls with TS and pubertal arrest – we would recommend starting with higher doses, such as 0.08-0.12 µg/kg; these girls may already have been exposed to pubertal levels of E₂.

Our recommendation to give 4 µg (1/7 to 1/6 of a 25-µg patch, or 1/14 to 1/12 of a 50-µg patch) for puberty induction in girls weighing approximately 63 kg is in line with obtained serum E₂ concentrations in postmenopausal women using the 50-µg Evorel patch. The average serum E₂ concentration of 184 pmol/l in an average 63-kg woman using the 50-µg patch [11] is about 12 times higher than our target level for serum E₂ for puberty induction; thus, our recommended dose of 4 µg is 1/12 of the adult dose.

Physiological age is preferable as a guide to deciding when to start the treatment, as it supports normal bone mineral accrual [12], and there is also the psychological advantage for the girl to reach puberty at the same age as her peers [13]. Earlier ERT may also improve cognitive function, as demonstrated in girls with TS [14]. For these reasons, there is international consensus to induce puberty in girls with TS around the age of 12 years [8], which is approximately 1 year later than the average pubertal onset in normal girls.

In the present study, some of the girls started ERT earlier (girls aged 9-11 years) than the recommendation from guidelines [8]. The reason for an earlier start of pubertal ERT was to mimic the peripubertal levels (gonadarche) of E₂ seen 1-2 years before the start of breast development [15]. And indeed, the present study shows that it is possible. Whether it is possible to mimic the prepubertal levels by cutting the patch to even smaller pieces needs to be studied in the future.

In our previous study, we found that low doses of ≤0.08 µg/kg may not necessarily induce breast development [5]. However, after the first administration of patches in doses of 0.08-0.12 µg/kg, breast development occurred within 3-6 months for the majority. It was also found that girls with E₂ levels above the B2 reference interval on the initial dose developed to stage B3 within 10 months of the start of ERT [5]. Nevertheless, some girls need higher doses, possibly due to individual breast sensitivity to E₂, all drawing attention to the need for close monitoring of serum E₂ levels in relation to clinical development.

There are both benefits and risks associated with pubertal ERT. The most serious risk is that no product is authorized for this indication; thus, treatment is performed off label with formulas intended for adults, which may result in adult E₂ levels and too fast a pubertal development [16,17,18], or in attempts to manipulate adult doses to mimic E₂ levels seen during spontaneous puberty [5,19].

Nonetheless, transdermally administered ERT can achieve serum E₂ levels, as well as a diurnal rhythm, similar to spontaneous puberty and the associated risks are low. Transdermal ERT has minimal, if any, effect on hepatic clotting factor production and other protein changes associated with the liver first-pass effect. Whereas oral ERT in postmenopausal women is associated with an increased risk of deep vein thrombosis and pulmonary thromboembolism [20,21,22], breast cancer [23], reduced insulin-like growth factor-I levels, increased fat mass and reduced lean body mass [24], none of these effects are evident with transdermal ERT. Furthermore, studies on physiological sex steroid replacement therapy (transdermal E₂ and progesterone) in postmenopausal women and women with premature ovarian failure resulted in lower blood pressure and improved renal function compared to oral regimens [22,25]. Transdermal ERT in girls with TS has shown a faster bone accrual in the spine, increased uterine growth, improved overall body composition and lower luteinizing hormone/follicle-stimulating hormone concentrations compared to oral ERT [17,26,27]. Moreover, ethinyl E₂ – a potent synthetic estrogen used in oral contraception – has different binding properties compared to natural estrogen (17β-E₂ in transdermal preparations), in that ethinyl E₂ has a fourfold selectivity for estrogen receptor α compared to 17β-E₂, which has similar selectivity for both α- and β-forms [28].

This is not a randomized, placebo-controlled clinical trial and has all the weaknesses that an observational study has. In addition, hospitalized patients are more closely controlled regarding the dose, compared to patients in outpatient settings. Nevertheless, even if there was a relatively high interindividual variance in the present study, we found a linear relationship between ERT dose and serum E₂ levels, in the TS group as well as in the group with hypogonadism of various etiologies. Although E₂ levels of 24-30 pmol/l were seen over the dose range from 0.05 to 0.15 µg/kg, a doubling of the dose resulted in an approximate doubling of the serum E₂ level. This indicates that the results may be applied to any kind of hypogonadism.

We conclude that for the initiation of ERT in order to induce pubertal development with the nocturnally administered patch, the recommended starting dose is 0.05-0.07 µg/kg, equivalent to 2-6 µg from an E₂ patch. In older girls, when breast development is a high priority, the starting dose can be 0.08-0.12 µg/kg, corresponding to 3-7 µg from an E₂ patch.

Acknowledgments

This work was supported by grants from the Sahlgrenska Academy at the University of Gothenburg, the Swedish Medical Research Council, the Petter Silfverskiöld Foundation and the Northern County Councils Cooperation Committee (Visare Norr). We wish to thank the staff at the Göteborg Pediatric Growth Research Center laboratory at the Queen Silvia Children’s Hospital in Göteborg, especially Ann-Marie Månqvist and Irène Leonardsson. We are also grateful to all the pediatricians who submitted samples to the laboratory, enabling us to establish the ERT target dose.

Disclosure Statement

C.A.-L., B.K. and E.N. declare no conflicts of interest.

References

Norjavaara E, Ankarberg C, Albertsson-Wikland K: Diurnal rhythm of 17 beta-estradiol secretion throughout pubertal development in healthy girls: evaluation by a sensitive radioimmunoassay. J Clin Endocrinol Metab 1996;81:4095-4102.

Ankarberg-Lindgren C, Norjavaara E: Estradiol in pediatric endocrinology. Am J Clin Pathol 2009;132:978-980.

Albin AK, Niklasson A, Westgren U, Norjavaara E: Estradiol and pubertal growth in girls. Horm Res Paediatr 2012;78:218-225.

Janner M, Fluck CE, Mullis PE: Impact of estrogen replacement throughout childhood on growth, pituitary-gonadal axis and bone in a 46,XX patient with CYP19A1 deficiency. Horm Res Paediatr 2012;78:261-268.

Ankarberg-Lindgren C, Elfving M, Wikland KA, Norjavaara E: Nocturnal application of transdermal estradiol patches produces levels of estradiol that mimic those seen at the onset of spontaneous puberty in girls. J Clin Endocrinol Metab 2001;86:3039-3044.

Ankarberg-Lindgren C, Norjavaara E: A purification step prior to commercial sensitive immunoassay is necessary to achieve clinical usefulness when quantifying serum 17beta-estradiol in prepubertal children. Eur J Endocrinol 2008;158:117-124.

Ankarberg-Lindgren C, Mahler TB, Norjavaara E: Biological reference intervals for serum estradiol and testosterone in children. Horm Res Paediatr 2013;80(suppl 1):179.

Bondy CA, Turner Syndrome Study G: care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab 2007;92:10-25.

Davenport ML: Approach to the patient with Turner syndrome. J Clin Endocrinol Metab 2010;95:1487-1495.

Palmert MR, Dunkel L: Clinical practice. Delayed puberty. N Engl J Med 2012;366:443-453.

Reginster JY, Albert A, Deroisy R, Colette J, Vrijens B, Blacker C, Brion N, Caulin F, Mayolle C, Regnard A, Scholler R, Franchimont P: Plasma estradiol concentrations and pharmacokinetics following transdermal application of Menorest 50 or Systen (Evorel) 50. Maturitas 1997;27:179-186, erratum in Maturitas 1997;28:193-195.

Mora S, Weber G, Guarneri MP, Nizzoli G, Pasolini D, Chiumello G: Effect of estrogen replacement therapy on bone mineral content in girls with Turner syndrome. Obstet Gynecol 1992;79:747-751.

Carel JC, Elie C, Ecosse E, Tauber M, Leger J, Cabrol S, Nicolino M, Brauner R, Chaussain JL, Coste J: Self-esteem and social adjustment in young women with Turner syndrome – influence of pubertal management and sexuality: population-based cohort study. J Clin Endocrinol Metab 2006;91:2972-2979.

Ross JL, Roeltgen D, Feuillan P, Kushner H, Cutler GB Jr: Effects of estrogen on nonverbal processing speed and motor function in girls with Turner’s syndrome. J Clin Endocrinol Metab 1998;83:3198-3204.

Norjavaara E, Albertsson Wikland K, Ankarberg-Lindgren C: A sensitive estradiol assay can predict the onset of puberty before thelarche. Horm Res 2005;64(suppl 1):23.

Mauras N, Shulman D, Hsiang HY, Balagopal P, Welch S: Metabolic effects of oral versus transdermal estrogen in growth hormone-treated girls with Turner syndrome. J Clin Endocrinol Metab 2007;92:4154-4160.

Nabhan ZM, Dimeglio LA, Qi R, Perkins SM, Eugster EA: Conjugated oral versus transdermal estrogen replacement in girls with Turner syndrome: a pilot comparative study. J Clin Endocrinol Metab 2009;94:2009-2014.

Bannink EM, van Sassen C, van Buuren S, de Jong FH, Lequin M, Mulder PG, de Muinck Keizer-Schrama SM: Puberty induction in Turner syndrome: results of oestrogen treatment on development of secondary sexual characteristics, uterine dimensions and serum hormone levels. Clin Endocrinol (Oxf) 2009;70:265-273.

Piippo S, Lenko H, Kainulainen P, Sipila I: Use of percutaneous estrogen gel for induction of puberty in girls with Turner syndrome. J Clin Endocrinol Metab 2004;89:3241-3247.

Scarabin PY, Oger E, Plu-Bureau G: Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 2003;362:428-432.

Canonico M, Oger E, Plu-Bureau G, Conard J, Meyer G, Levesque H, Trillot N, Barrellier MT, Wahl D, Emmerich J, Scarabin PY, Estrogen Thromboembolism Risk Study G: Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the Esther Study. Circulation 2007;115:840-845.

L’Hermite M, Simoncini T, Fuller S, Genazzani AR: Could transdermal estradiol + progesterone be a safer postmenopausal HRT? A review. Maturitas 2008;60:185-201.

Opatrny L, Dell’Aniello S, Assouline S, Suissa S: Hormone replacement therapy use and variations in the risk of breast cancer. Br J Obstet Gynaecol 2008;115:169-175; discussion 175.

O’Sullivan AJ, Ho KK: Route-dependent endocrine and metabolic effects of estrogen replacement therapy. J Pediatr Endocrinol Metab 2000;13(suppl 6):1457-1466.

Langrish JP, Mills NL, Bath LE, Warner P, Webb DJ, Kelnar CJ, Critchley HO, Newby DE, Wallace WH: Cardiovascular effects of physiological and standard sex steroid replacement regimens in premature ovarian failure. Hypertension 2009;53:805-811.

Alves ST, Gallichio CT, Guimaraes MM: Insulin resistance and body composition in Turner syndrome: effect of sequential change in the route of estrogen administration. Gynecol Endocrinol 2006;22:590-594.

Taboada M, Santen R, Lima J, Hossain J, Singh R, Klein KO, Mauras N: Pharmacokinetics and pharmacodynamics of oral and transdermal 17beta estradiol in girls with Turner syndrome. J Clin Endocrinol Metab 2011;96:3502-3510.

Harris HA, Bapat AR, Gonder DS, Frail DE: The ligand binding profiles of estrogen receptors alpha and beta are species dependent. Steroids 2002;67:379-384.

Author Contacts

Ensio Norjavaara, MD, PhD

Göteborg Pediatric Growth Research Center, Department of Pediatrics

Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg

SE-416 85 Göteborg (Sweden)

E-Mail [email protected]

Article / Publication Details

First-Page Preview

Received: July 23, 2013
Accepted: October 16, 2013
Published online: February 04, 2014

Issue release date: May 2014

Number of Print Pages: 6

Number of Figures: 2

Number of Tables: 1

ISSN: 1663-2818 (Print)
eISSN: 1663-2826 (Online)

For additional information: https://www.karger.com/HRP

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Researcher promotes low dose estrogen

If researchers like Donna Shoupe, professor of obstetrics/gynecology, get their way, postmenopausal women will be going a lot farther on much lower doses of estrogen than they are taking today

Shoupe, director of the USC Women’s Health Center, is conducting research on low dose estrogens. Today, about 20 to 40 percent of all postmenopausal women are on estrogen replacement therapy, and .625 milligrams of Premarin, the most popular dose of the most prescribed estrogen, is about half the dose prescribed to women a decade ago, said Shoupe.

“We’re going to get even lower,” she predicted.

Actually, what Shoupe is most interested in finding is the optimum dose for a selected patient with certain characteristics. For example, she said, women who still have their ovaries continue to produce hormones even after menopause, so they may be eligible for lower doses than women who have had their ovaries removed.

“I’m interested in trying to fine tune the dose so you don’t overtreat them,” said Shoupe. “Especially because, the more estrogen you give them, the more bleeding they have and the less likely they are to continue taking the medication. So to improve compliance, you need to fine tune it.”

Lower doses may also help mitigate the risk of cancers often associated with estrogen replacement therapies, such as increased risk of breast, uterine and ovarian cancer. “I do think there’s a relationship between high dose estrogen and breast cancer, ” Shoupe acknowledged.

“However, most of the data that would link estrogen to breast cancer is high doses used for long periods of time. And I think one of the big advantages of getting the dose lower, down to what we need, is so we can optimize the benefits and really get rid of the risks-or at least minimize the risks,” she said.

Those risks, she said, have been keeping women from taking estrogen post-menopause.

Those who do take it, she says, “probably take it to relieve symptoms, and they don’t realize that the reason they should be taking it is for the long term health benefits.”

Among the benefits being shown by research, she said, are:

o Cardiovascular. Estrogen has been shown to cut risk of heart attack and stroke.

o Osteoporosis. Estrogen minimizes the associated back pain, loss of height, immobility, curvature of the spine, fracture of the hips, necessity for surgery

o Alzheimer’s. There’s a 70 percent reduction in Alzheimer’s after five years of estrogen replacement therapy.

o Better teeth. Those on estrogen replacement therapies keep their teeth longer.

In the future, said Shoupe, lower doses combined with greater public awareness of the health benefits will mean even more women will opt for estrogen replacement therapies.

In addition, “We’re getting a lot more estrogens, we’re getting a lot more delivery systems. There’s a ring that delivers estrogen, new patches that deliver estrogen. Researchers are working on patches to deliver the progestins.”

Indeed, Shoupe is currently working on a plastic device that would deliver progesterone inside the uterus. “Because that’s the only place you really need it in a menopause patient. There’s no need to take it orally,” she said.

Some low doses are currently available, such as a .5 milligram of Estrace (one milligram of Estrace is considered comparable to .625 of Premarin).

But women haven’t been asking for the lower doses, and, said Shoupe, “It is an area that has not been well studied. Most women have been thrown into ‘menopause’ or ‘nonmenopause’ categories, which is fine if you’re trying to get a dose that can fit everybody. But we need to refine it so that you can take all the characteristics of your patient into account and give just enough estrogen to get the benefits and substantially reduce the risks and side effects.”

Prescribing hormone replacement therapy | GPonline

1 CPD Credit Take a test on this article and claim your certificate on MIMS Learning

Prescribing HRT is not difficult. The evaluation, discussion, agreement and arriving at a decision to prescribe may be seen as time consuming, but look at it as an investment.

For most women who are sufficiently troubled by their menopausal symptoms to seek help, benefit from HRT will exceed risk (see 10 top tips on menopause). If you get it right they will feel better, not come back until scheduled for review and then thank you for giving them their life back. It is a rewarding aspect of medicine.

The best management option for the individual will vary with what is bothering her most. You will need to consider her symptom profile, her risk profile and her preferences and concerns. You will need to understand where she is in the menopause transition.

When you get to prescribing, ask yourself some simple questions, as follows.

Are her symptoms general or exclusively urogenital? True menopausal symptoms derive from estrogen deficiency. If the flushes are tolerable but urogenital symptoms are significant, then low dose vaginal estrogens should not only be sufficient but will often be more effective as an initial strategy.

Has she got a uterus? More strictly, is there possibly any endometrium remaining? If so, then as well as estrogen she will need progestogen to provide opposition and prevent hypertrophy and malignant change, as otherwise risk doubles over 5 years. If she has a levonorgestrel intrauterine system (LNG IUS) which has been in place over five years but is deemed adequate for contraception at her age, she will still need additional progestogen.

Has she had a period in the last year? If so, she should be offered a cyclical regimen unless she already has an in-date Mirena ® LNG IUS. If so, only estrogen is needed. If she has not had a period in the last year she will need either continuous progestogen and estrogen, or tibolone.

Does she have any significant cardiovascular risk factors, gallstones, thyroid replacement therapy or other metabolic issues, which indicate a non-oral estrogen is preferable?

What does she want to use?

Does she need contraception?

Figure 1 shows a menopause clinical pathway highlighting history, examination, and management including hormonal treatment.

Hormonal therapy

Oral estrogen is available in three formats:

conjugated equine estrogen which is a complex mixture derived from the urine of pregnant mares,

estradiol valerate and

micronised 17β estradiol.

The latter is my oral format of choice, with conjugated equine estrogen as the alternative. Women happy with any one do not need to change. 17β estradiol is the most important systemically active estrogen in vivo, and is the type of estrogen used in non-oral preparations such as patches or gel.

Patches should be changed once or twice a week dependent on brand, while gel has to be applied daily. There are pros and cons to both and the option should ultimately be the choice of the woman. Bioavailability will differ between women but as a rough approximation, 1.5mg estradiol delivered as gel = 50mcg/day from a patch = 2mg oral estradiol 17β.

Progestogens fall into different classes, and the two to familiarise yourself with are the testosterone derivatives (C19 progestogens such as levonorgestrel and norethisterone) and the progesterone derivatives (C21 – progesterone, dydrogesterone and medroxyprogesterone acetate). The activity at the testosterone receptor is one of the factors that result in different responses to different progestogens and if your patient appears intolerant, change class.

It is helpful to work out which types of estrogen and progestogen are available in the marketed products. This enables you to develop a simple formulary to allow low start and standard cyclical combinations, to move to continuous within the same family, and then progressively to drop the dose as women generally can be managed with lower doses over time.

Figure 2 shows the basis of a simple limited oral HRT formulary, although other options are available.

If your patient has previously has had no issues with a first line 30mcg ethinylestradiol/150mcg levonorgestrel combined oral contraceptive, and her cardiovascular risk profile is satisfactory, then a 17β estradiol + norethisterone oral combination is likely to suit. If she has had progestogen-related side effects in the past, a C21 combination could be chosen initially.

Some patch brands offer sequential and continuous regimens with C19 progestogens. Cutaneous absorption of C21 progestogens is limited but there is the option of developing a bespoke regimen using estrogen only with either:

micronised oral progesterone (200mg cyclically for 12-14 days a month or 100mg daily for continuous use). This has a sedative profile so it can be helpful to take at night

medroxyprogesterone acetate (10mg cyclically or 5mg continuously).

The general rule is to start with a low estrogen dose (such as 1mg oral) and then increase if needed unless your patient is under 45. Such women often have a higher replacement requirement and should be started at standard doses.

Warn her that if she is given a cyclical preparation, two prescription charges will be levied, and provide three months’ supply. Review before she runs out considering her symptoms, her reaction to the product, bleeding pattern and risk profile. Modify if necessary considering estrogen dose and route and then the progestogen.

Once stable, review annually but aim to move women to a continuous regimen by about five years, as this has been shown to give best protection. With time, dose requirement to manage symptoms does reduce and women can be reassured that the dose needed to maintain bone density is quite low so they will not lose protection.

There is no limit as to how long HRT can be prescribed. It is an individual decision, reviewed annually, with the risks and benefits discussed such that the decision to continue is informed. In women below the typical age of menopause (51-52) replacement can be seen as protective. HRT is not delaying the inevitable, if symptoms return they would have been present anyway and the lowest effective dose is always sought.

Menopause often comes when there are other significant challenges in women’s lives. Helping your patient to cope may not just give her life back but have a cascading effect on those around her. The risks are few, the rewards can be great – do not be afraid to prescribe what she is missing.

Case study 1

Anne is 48 and has not had a period for three months. This is the first time she has missed two in a row but her periods have become less predictable in the last few years. She took Microgynon 30® for contraception but stopped when she was 40 after her husband had a vasectomy.

She has come to see you as she has dreadful hot flushes and night sweats, cannot sleep and is moody and tearful which is quite out of character. She is a police officer and she is not sure if she can continue to do her job like this. Her two teenage daughters have told her “to get a grip” and none of the products in the health food shop have helped.

What is her best option?

Microgynon 30®

Fluoxetine 20mg/day

Estradiol 50mcg/day + norethisterone continuous twice weekly patch

Clonidine 50mg bd

Estradiol 1mg + cyclical norethisterone daily oral regimen

Discussion

An estradiol 1mg + cyclical norethisterone daily oral regimen would be a very reasonable starting option as the 1mg dose may be sufficient, and if not can be increased at the 3 month review.

Estradiol 50mcg/day + norethisterone continuous twice weekly patch could help symptoms considerably but might result in erratic bleeding that is difficult to assess, and is not recommended within 12 months of the last period.

If Anne has no significant risk factors, Microgynon 30® could be considered and could help but symptoms may return in the pill free week and it is not the best option. Neither SSRIs (such as fluoxetine) or SNRIs are recommended by NICE unless there is overt depression – which is not the case for Anne.

Clonidine may affect flushing, but no other symptoms, and is not recommended by NICE.

Case study 2

Bettina is 51. She has a BMI of 38, diet-controlled type II diabetes and stopped smoking last year. She had a Mirena® coil inserted 8 years ago to manage both her contraception and heavy periods and it was replaced after 5 years. She is suffering greatly from both day time flushes and sweats at night. She sweats profusely and finds this very embarrassing as she has to deal with the public in her job. She bleeds occasionally without warning but it is very light, her blood pressure is 128/76 and she takes no other medication.

What are her best options?

Estradiol 50mcg/day + norethisterone continuous twice weekly patch

Estradiol 0.06% gel – two measures = 1.5mg daily

Estradiol 50mcg/day twice weekly patch

Estradiol 1mg + 5mg dydrogesterone continuous daily tablet

Isoflavone phytoestrogens from the health food shop

Discussion

Her best options are estradiol gel or estradiol patch. As Bettina has cardiovascular risks a non-oral delivery route is recommended, and either estradiol 0.06% gel 1.5mg daily or estradiol 50mcg/day twice weekly patch would be an appropriate dose. Additional progestogen is not needed with an in date Mirena®.. She therefore does not need a norethisterone continuous twice weekly patch.

The option of estradiol 1mg + 5mg dydrogesterone continuous daily tablet would involve an appropriate estrogen dose for initiation, but the oral route is not recommended for a woman at higher cardiovascular risk, and she does not need the progestogen.

Isoflavone phytoestrogens from the health food shop are not recommended as the evidence of efficacy and safety is sparse. Consensus clinical experience is that they are unlikely to help very severe symptoms.

Case study 3

Carol is 55. She has come to see you for her annual review. She has been taking estradiol 2mg with cyclical dydrogesterone 10mg tablets for the last three and a half years. When she started, her periods had become haphazard and up to four months apart. She had started on the lower dose 1mg + 10mg combination but it did not settle her flushes enough.

She has been very well since, is about to become a grandmother and is stepping down to working just three days a week. She would like not to bleed now, although her existing bleeding is not heavy or painful. It now takes 3-4 days into the new pack before it starts and she needs only light protection for 2-3 days. She is slim, active, has never smoked and her blood pressure is 118/74.

What is her best option?

Estradiol 2mg oral with a LNG IUS

Estradiol 50mcg/day, twice weekly patch, with a LNG IUS

Estradiol 1mg with continuous dydrogesterone 5mg oral

Estradiol 1mg with cyclical dydrogesterone 10mg oral

Estradiol 0.5mg with continuous dydrogesterone 2.5mg oral

Discussion

Estradiol 1mg with continuous dydrogesterone 5mg oral is Carol’s best option. This uses the components that she already tolerates well, in a lower dose continuous regimen, and would be appropriate in this scenario.

Estradiol 0.5mg with continuous dydrogesterone 2.5mg oral would use the same well tolerated components in a very low dose continuous regimen. It represents a substantial reduction in dose and the interim 1mg combination would be a more appropriate first step. It may prove possible to step down to this dose after three months.

Estradiol 2mg oral with a LNG IUS would use the same estrogen route and dose, but her bleeding is not so much of a problem as to warrant intrauterine progestogen as the first line suggestion (though it would be an option).

Estradiol 50mcg/day twice weekly patch, with a LNG IUS, would have a similar effect and might be considered if there were cardiovascular risk factors, but Carol has done very well with the oral route and at present there is no overriding reason to change. Her bleeding is not so much of a problem as to lead to intrauterine progestogen as the first line suggestion (though it would be an option).

Estradiol 1mg with cyclical dydrogesterone 10mg oral: Carol may manage with this lower dose combination, but she does not want to bleed and a continuous regimen would offer best protection.

Dr Sarah Gray is a GP specialist in women’s health in Cornwall

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Hormone replacement therapy – reliable help when you have menopause symptoms

2019.12.09

Physiology of menopause

Menopausal transition is the period of a woman’s life when her ovarian activity stops with menstruation. This is a transition from a noticeable decrease in a woman’s reproductive function to complete infertility due to the gradual depletion of ovarian follicles and a noticeable violation of hormone synthesis. Advanced female estrogen deficiency causes symptoms of menopausal syndrome.Menopause is linked to hereditary genes and lifestyle. Essential nutrition, physical activity, bad habits, environmental factors, medical conditions, surgery, radiation and chemotherapy. Early symptoms (hot flashes, sweating, palpitations, headaches and dizziness, fainting, changes in blood pressure, chills, depression, irritability, drowsiness, insomnia, memory impairment, lack of concentration, lack of energy, decreased libido, panic attacks) percent.women and lasts about 7 years. Late symptoms develop even later, when the unpleasant first symptoms of menopause seem to be over. New problems are emerging: osteoporosis, cardiovascular disease and senile dementia. All these changes are directly related to the absence of endogenous estradiol in the blood, since estrogens have a protective effect on the cardiovascular system. They are antioxidants, calcium channel blockers and have a positive effect on fat metabolism, reducing the risk of atherosclerosis.Estradiol reduces vascular tone and relieves spasms.

Hormone therapy for menopause (also known as hormone replacement therapy) is one way to reduce symptoms. Sex hormones are most effective in correcting postmenopausal symptoms. Based on common sense, elementary logic and the basic pharmacological principle, it is best to treat with estradiol, since only its deficiency causes all of the above symptoms of menopausal syndrome.

However, the vast majority of patients refuse HRT.They say they would prefer to go “the natural way” to endure an unpleasant life, “do not want to interfere with nature” or more often say that “HRT causes breast cancer or cardiovascular disease.” Myths and scientifically unfounded interpretations that still exist in press publications prevent women from making timely medical recommendations.

So what are the benefits of HRT?

Women are afraid of menopause because their lives are changing.Is it so difficult for their soul and body to survive? – Definitely so. But everyone experiences this period in completely different ways: one says that there is something, but I do not feel anything, and the other comes immediately asking for help, because they do not know how to deal with it, and especially those who who works in community service. For example, when you suddenly feel a wave of heat, you “breathe out red,” cold sweat, and this happens at an unpredictable rate. Most often it causes irritation and irritation, distraction and fatigue from insomnia, so how much can a person stretch? Then a woman cannot work, live a normal life.Otherwise, the woman may say that her period is over, and with so much knowledge, I have not felt anything. It all depends on the level of these symptoms. A woman can decide for herself whether she goes through menopause without the help of doctors, expecting a natural physiological outcome of the condition or without suffering, because she is really poor and wants to improve her quality of life and avoid the long-term consequences of this condition). It can be stated unequivocally that help is possible and has the right to exist, only to know how much and when it is needed, what are the contraindications.Modern HRT has developed, specifying both the drug itself and its indications and contraindications. When properly prescribed and used, it is a safe, effective and reliable treatment for women during menopause. Numerous studies and recommendations support this statement. For most women, all menopausal symptoms improve within a few months of taking HRT.They notice improvements in sleep, mood, and concentration. They notice an increase in energy than before starting HRT.HRT usually stops hot flashes and night sweats within a few weeks, with a series of vaginal and vulvar discomfort that subside within 1-3 months. In some cases, treatment can take up to a year to achieve the desired improvement. During HRT treatment. relieves symptoms of vaginal dryness, reduces sexual discomfort, recurrent urinary tract infections, vaginal discharge, reduces joint pain and improves hair and skin structure. So what prevents women from having such effective treatment?

And what are the risks of HRT? Is it generally safe?

Many women are afraid to take HRT because of the potential risks.The media released a lot of negative information about the risks of using HRT ten years ago. This stopped using PHT. Although the results were later revealed to have been misinterpreted and there is now ample evidence to support the benefits of HRT, the negative portrayal of HRT remains. Recent studies have shown that a woman’s real risk of developing breast cancer is more dependent on many other factors (such as age, family history, genetics, lifestyle, and overall health) regardless of whether HRT is used independently.This is why it is very important for the physician to discuss the individual risks and benefits with each of their patients.
Smoking, regular exercise, and a healthy diet can significantly reduce the risk of heart disease, stroke, and many types of cancer that women mistakenly attribute to hormone replacement therapy.

MYTH: You have to wait until your symptoms get really bad or even unbearable before your doctor can give you HRT

Many women postpone seeking medical attention because they seem to be wasting their time unnecessarily and are anxious to wait until symptoms become really bad.This is not the case, because HRT will help even with mild symptoms. In addition, there is growing evidence that the sooner HRT is started, the better your protection against osteoporosis and heart disease will be.

MYTH: HRT only delays menopause

Many women avoid taking HRT because they think that menopause will only start later after it stops. All the symptoms you may experience after stopping HRT are the same menopausal symptoms that you would experience even if you have never taken HRT.e. Symptoms of estrogen withdrawal may occur without consulting a doctor (therefore, it is best to reduce the dose and exit slowly to stop HRT). These will be temporary symptoms and should only last a few weeks if they appear. In addition to HRT, many women have experienced menopausal symptoms for more than ten years, and some women still have hot flashes after age 75.

MYTH: You must stop HRT after 5 years

Many doctors try to convince women to stop taking HRT after five years.But in reality, there is no good scientific reason. Each woman should be assessed separately for how long she should take HRT. The duration of HRT use is an individual choice and depends on your personal risks and benefits. If you are younger than 51, you should take HRT until you are 51, regardless of the age at which you start. There is no specific age at which you should stop taking HRT.

MYTH: HRT causes clot formation (deep vein thrombosis in the legs).

Continuous use of certain HRT medications increases the risk of small clots forming in the veins of your legs. The increased risk is very low and only higher if you have other risk factors for clot formation, such as obesity or thrombosis. However, if you use HRT separately from an estrogenic component such as a gel or patch, it is absorbed directly into your body, which means clotting factors are not activated in your liver (like swallowing a pill), and this is not associated with an increased risk of blood clot formation. …

MYTH: HRT will cause heart attack and stroke

If you are on HRT before the age of 60, your risk of heart attack does not actually increase. Women who take estrogen alone (without a progestogen) actually have a lower risk of heart disease compared to women who do not take HRT. The risk of stroke in women under the age of 60 is also very low, whether you are taking HRT or not. HRT lowers cholesterol, which is good for your heart and body.

MYTH: You cannot take HRT if you have migraines

Many women find their migraines get worse as they go through menopause. Since they were not given oral contraceptives for migraines at a young age, many women (and doctors) are mistaken in believing HRT should not be used. If you have migraines, you should take estrogen in the form of gels or patches, not pills.

MYTH: Taking topical (suppository) estrogen for vaginal dryness carries the same risks as taking HRT pills

Vaginal dryness is very common and using estrogen as a vaginal pill, cream, or ring can be really effective.Using topical estrogen in this way is not the same as taking HRT, so the risks are not the same. This is because these drugs help restore estrogen to the vagina and surrounding tissues without providing estrogen to the entire body. These products can be safely taken by most women, both regularly and for long periods (usually indefinitely), as failure to take this treatment usually leads to a relapse of symptoms.

MYTH: Natural treatments for menopause are always safer than HRT

Many of the HRT hormones given today are “body-identical,” which means that they have the same molecular structure as our body’s hormones.They are also natural in that they are derived from a plant chemical.

Studies have shown that homeopathic remedies are comparable to placebos (although placebos are often beneficial), and multivitamins do not address menopause problems in practice. Then maybe just promoting healthy lifestyles is not enough to prevent menopause?

Unfortunately, a healthy lifestyle does not have a greater impact on the correction of symptoms of menopausal syndrome, although it is recommended for postmenopausal women.On the other hand, good nutrition, adequate physical activity, and the right working and resting conditions contribute to good health.

Femininity and contraception “Pharmvestnik

Dienogest + estradiol valerate

The basis of COCs are analogs of two hormones – gestagen and estrogen. The first component is designed to suppress ovulation and prevent pregnancy, the second is to ensure cycle control. As you know, it is estrogens that are responsible for the formation of the female reproductive system, secondary sexual characteristics, as well as the timeliness of endometrial rejection and the regularity of menstruation.It is no coincidence that they are called “hormones of femininity.” For a long time, manufacturers have sought to obtain a contraceptive based on a natural analogue of estrogen, which would be identical to the hormone produced in the female body.

Estradiol valerate is a substance that is isolated from plants. It is chemically identical to a woman’s endogenous estrogen and is therefore more gentle than synthetic hormones1.

Dienogest, which is used as a gestagenic component, has a minimal systemic effect on the body, due to which it is well tolerated.An important task of the gestagenic component is the protective effect on the endometrium. Dienogest has a pronounced antiproliferative activity, due to which reliable protection of the uterus and a high contraceptive effect are achieved2.

By combining estradiol valerate with dienogest, as well as using a unique dynamic dosing regimen, it was possible to create a modern contraceptive based on a natural component. It not only fulfills its main function and is well tolerated, but also supplies estrogen to a woman’s body, identical to her own.And this in the best way affects the appearance, well-being and sexuality.

This drug is of particular importance for women 35+, who begin to develop signs of so-called age-related changes, manifested in symptoms of estrogen deficiency. Women who receive the so-called “natural estrogen” in optimal doses manage to maintain their youth and beauty longer. Also, with age, some diseases may develop that become obstacles to the use of hormonal contraceptives, therefore it is very important that the drug is highly tolerated and contains minimal doses of hormones.This problem was solved, among other things, due to the dynamic dosing regimen, which has already been mentioned. It repeats the natural female cycle as much as possible and allows you to deliver the right dose of hormones at the right time. The package contains 28 tablets of different colors. Of these, 26 contain active ingredients. The procedure for taking them is such that there is a gradual decrease in the dose of estrogen and an increase in gestagen. The two remaining pills are placebo. Each active tablet contains a minimum dose of hormones to provide protection against unwanted pregnancies.Also, for the convenience of patients, manufacturers are developing packaging where you can mark the day you start taking COCs, which allows you to avoid inaccuracies that can lead to unpleasant consequences in the future.

Unique female image

Everyone knows that hormones have a huge impact on the beauty and health of women. This is especially true of estrogen, which contributes to the acquisition of a special image and maintaining attractiveness. Therefore, it is so important that the analogue of estrogen included in the COC is as close as possible to that produced in the body.With a lack of the “hormone of femininity” worsens the condition of the skin, joints, hair, nails. Women who take COCs (especially with estrogen identical to natural) are less susceptible to these troubles. In addition, the antiandrogenic effect of dienogest also contributes to an improvement in appearance, as it reduces the oiliness of the skin, making it clearer.

Some women, taking COCs of previous generations, noted a decrease in libido. Such an effect could arise due to a lack of estrogen or an excessive influence of the progestogen entering the body.However, in modern drugs, such consequences are minimized. This is achieved due to the dynamic mode of COC intake, which allows you to accurately dose the required amount of hormones. Also, the use of estrogen, which is most suitable for the female body, and dienogest, which has metabolic neutrality, also helps to increase sexuality. Therefore, modern COCs do not have a negative effect on libido, and even on the contrary, they contribute to the improvement of sexuality, which was disturbed by the reception of the previous OC3.

It is very important for women to maintain a stable weight. This factor still scares many women when choosing a contraceptive. The optimal dosage of hormones in modern preparations based on estradiol valerate and dienogest allows you to keep all metabolic processes at a natural physiological level, so the weight remains stable even with prolonged use4.

Disruption of the balance of estrogen and gestagen in the body can lead to other undesirable consequences.Heavy menstruation may be accompanied by pain in the lower abdomen, nausea, dizziness, and weakness. COCs based on estradiol valerate and dienogest in most cases significantly reduce the amount of lost menstrual blood, reduce the duration and pain of bleeding. Thanks to this, the development of iron deficiency anemia is prevented.

1Zakhurdaeva L.D. Estrogens: Biological and Pharmacological Effects (2010)
2 Oettel M, Carol W, Elger W. A 19-norprogestin without 17β-ethinyl group II: dienogest from a pharmacodynamic point of view.Drugs Today 1995: 31: 517–36.
3Salvatore Caruso, Carmela Agnello, Mattea Romano, Stefano Cianci, ect. Preliminary Study on the Effect of Fourphasic Estradiol Valerate and Dienogest (E2V / DNG) Oral Contraceptive on the Quality of Sexual Life // J Sex Med. 2011. No. 8
4 Parke S., et al. Metabolic effects of a new four-phasic oral contraceptive containing estradiol valerate and dienogest [abstract] // Obstet Gynecol. 2008.

Doctor’s blog

What do birth control pills contain?

One of the most common and reliable methods of contraception is birth control pills, which do not pose a threat to the female body and solve many female problems.The harm of birth control pills is not as great as many women think.

The composition of modern birth control pills contains a small amount of hormones with an almost 100 percent guarantee of protection against pregnancy. Estrogen and progestogen are the two main ingredients in birth control pills. Their dosage and combinations in different chemical contraceptives are different. Therefore, it is necessary to correctly select the dose, as well as the time and frequency of administration, so that the harm of contraceptive pills is minimal.

How do birth control pills work?

Combined birth control pills, firstly, prevent ovulation, and secondly, they make it difficult for sperm to enter the uterus, and also prevent the fertilized egg from attaching to the walls of the uterus.

There are monophasic and three-phase birth control pills. Monophasic drugs have the same composition regardless of the day of the cycle, and three-phase drugs have different hormone levels.Of course, the harm of these two classes of contraceptive pills is different. A special type of contraceptive pill is mini-pills. They do not contain estrogen.

What harm can be caused by birth control pills?

Despite its positive effects, many women are wary of taking chemical contraceptives due to long-held myths about the harm that birth control pills can cause.

There are several common contraceptive pill myths that have no clear basis.

“Birth control pills lead to rapid weight gain”

This myth is the most popular. The estrogen in birth control pills leads to a buildup of fluids in the tissues, which increases body weight by 1–2 kg. However, these are not fatty deposits, but simply fluid in the tissues. As a result, cellulite may appear. This is the only possible harm to birth control pills in this situation.

“Using birth control pills leads to cancer.”

In fact, many birth control pills prevent ovulation, which reduces the risk of inflammation.

“Birth control pills will lead to acne”

Addiction to chemical contraceptives can lead to excess oiliness on the face. This is a small harm in this case. If this does not go away, then you need to consult with your doctor and change the drug.In addition, drospirenone is included in the composition of chemical contraceptives, which eliminates skin problems. Usually birth control pills have a positive effect on the skin, acne and acne will go away.

“Long-term use of birth control pills can lead to infertility.”

Contraception does not affect a woman’s ability to have children. Just after the end of taking the drug, the woman’s body undergoes adaptation for several months.

“With the constant use of the contraceptive pill, pauses are necessary.”

There is no need to pause. A break, on the other hand, can lead to an unwanted pregnancy, while the established cycle will be disrupted. The contraceptive pill can be taken for several years, even ten years without any interruption.

When taking chemical contraceptives, be sure to pay attention to the following:
The first three months of taking birth control pills may cause discharge between periods.
If you suddenly forgot to take the drug, then, as soon as you remember, take it. Even if it turns out that you took 2 birth control pills on day. If the pass was more than one day, then there is a risk of getting pregnant. You still need to finish the package to the end, even if your period has already begun.
Antibiotics may reduce the effectiveness of birth control pills.
If diarrhea begins within a few hours after taking the drug, then you need to take another birth control pill.
Birth control pills do not affect your child’s health and development.

Women over 35 years old, and at the same time smokers, are not recommended to take chemical contraceptives. There is a risk of blood clots, and in this case, the harm of contraceptives can be fully manifested.

90,000 Birth control pills, which is better?

overview

Often, girls develop a negative attitude towards sex after the onset of sexual activity. And this is not the fault of education, not moral principles, but an elementary fear of conception. In the age of the latest medical technologies, abortion is not painful, but what is the physical pain in comparison with emotional experiences.

Not many will dare to give birth to one child after another, and often they have to terminate a pregnancy against their will.Afraid of getting pregnant, the girl is looking for excuses to avoid the embrace of her husband, and the harmony of family life begins to crumble right before our eyes.

All of this can be avoided if birth control pills are used correctly. The issues of contraception are successfully covered by the gynecologists of the “CM-Clinic”. They will find an individual approach to the patient and offer the best solution in the current situation, providing a list of products to choose from.

Types of contraceptive drugs

Drugs, the use of which helps to avoid conception, are:

hormonal direction;
non-hormonal.

Hormone pills, in turn, are distributed to:

oral;
mini – drank.

Oral remedies are taken orally daily for maximum effect. These contraceptives contain different amounts of hormones. If some women can take pills with a large amount of hormonal substances without consequences, then for others certain contraindications are revealed.They are divided into:

Monophasic;
Two-phase;
Three-phase.

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Our operator will contact you from 8:00 to 22:00
Applications received after 22:00 will be processed the next day.

Combined oral tablets

The body produces two types of female hormones: estrogen and progesterone. Combined oral preparations contain similar hormones, but are of artificial origin.

Ethinyl estradiol is used instead of estrogen, and progesterone is replaced by levonorgestrel. The clinic works with patients with different hormonal levels. Doctors-gynecologists will make a competent selection of the optimal drug.

Monophasic contraceptives

One package contains tablets, which are enough to be taken daily for one or even several months. Progestogen and estrogen are contained in proportions, the value of which is constant.Allocates: Diana-35, Mersilon, Regulon, Novinet, Rigevidon, etc. Which of them to choose, the doctor gynecologist-endocrinologist “CM-Clinic” will tell you based on the test results and prescribe a special treatment.

Two-phase remedies

In tablets, the amount of gestagen fluctuates depending on the period of the menstrual cycle. In the first half of it, pills of one color are taken, in the second another. These means include Antevion.

Three-phase drugs

This group has fewer negative indications, since the doses of estrogen and gestagen are strictly regulated depending on the phase of the monthly cycle.In each of the three periods, the girl takes contraceptives, painted in three colors.

Thus, an optimally balanced ratio of hormonal substances is achieved, and there is a minimal harmful effect on the girl’s body. They are prescribed after 35 years.

Overweight girls who smoke can safely take drugs of this group. These include Tri-regol, Tri-merci, Triziston, Trimersi. It is worth noting that all tablets begin with the prefix “Three”.

Side effects from taking such drugs containing only a gestagen or progestin are minimal, therefore it is often prescribed to nursing mothers, patients with cardiovascular diseases, diabetes mellitus, and congenital heart disease.

After taking them, the mucus in the vagina thickens and becomes viscous, the mucous membrane of the uterine cavity changes, as a result of which the egg cell traveling through the ovary cannot be implanted. Progestin contains: Exluton, Charosetta, etc.

Non-hormonal contraceptives

Their second name is spermicides. When not having a regular sex life, then non-hormonal contraceptive drugs will be of great service to her. Their action is of a local nature, the effectiveness is not inferior to hormonal pills, therefore, it is better to choose them from all the available options. Ten minutes before intercourse, 1 tablet should be inserted as deep as possible into the vagina.

There are some downsides:

it is undesirable to use constantly, so as not to disturb the genital microflora.It is worth comparing your condition before using the pill and after;
It is not allowed to take a bath or shower immediately after intercourse and a couple of hours before it.

But these tablets also have a lot of advantages:

Non-hormonal drugs do not cause hormone imbalances;
they are convenient to use;
they have almost no contraindications, except for individual sensitivity to certain components that cause allergic pathologies;
pill price is available for most women.New birth control pills can also be purchased without a prescription.

Postcoital tablets

Contraceptives are used in the first three days after sexual intercourse. You can not use more than one tablet at a time, because a loading dose of hormones can cause irreparable harm to health. An example of a drug is Postinor.

The doctor – gynecologist of the “CM-Clinic” center will provide qualified assistance to select the most suitable for you from a whole list of modern drugs, and will explain in detail how to use them.

Lecture “Hormones of Female Attractiveness” | News TsPS Medica

Hormones of female attractiveness.

How to stay beautiful and healthy always? This question worries, perhaps, every woman.

Genetics in this matter is only 30% of success, the remaining 70% are in the hands of a woman and depend only on her.

How to use this 70% to the maximum?

Many people count calories, visit the gym, beautician.is that enough?

We are accustomed to thinking that we make decisions ourselves, we manage our own lives. This is partly true. But sometimes something makes women feel unexplained emotions and even do strange things (what PMS is, perhaps, there is no need to explain to anyone). Suddenly there are unreasonable mood swings, suddenly there are problems with appearance or health …
What is the reason? And the fact that a woman is primarily a hormonal creature.

It is hormones that control our well-being and mood, shape our appearance, control metabolic processes, affect the immune system and ensure the well-coordinated work of all organs.Flawlessly clear skin, shiny hair and health are the result of stable hormonal levels.

Let’s figure out which hormones primarily affect female attractiveness.

Estrogens are under No. 1.

This is a whole group of female sex hormones, which include estrone, estriol and estradiol. All of them are produced in the ovaries, are responsible for the formation of a female figure, the development of the genitals and regulate the menstrual cycle.

Estrogens are involved in the process of cell renewal throughout the body, including the skin.Estrogen has a positive effect on the beauty of hair: it gives them shine, preserves youth and health. Estrogens cheer up, dispose to flirting and coquetry, prevent the deposition of cholesterol in the walls of blood vessels, make eyes shine, smooth wrinkles, make the skin elastic and elastic, thereby making a woman beautiful. In addition, estrogens cheer up and dispose to flirting and coquetry – they contribute to the development of attraction in women to males. Against the background of an increase in the production of estrogen, coordination of movements improves and thereby gait, the quality of speech changes.

Estrogen is rightfully considered the main female beauty hormone. Its deficiency affects not only health, but also appearance.

Under No. 2 progesterone.

The main task of progesterone is the development of the egg and its placement in the uterus, which is why it is often called the pregnancy hormone. In non-pregnant women, progesterone is also present and increases in the second phase of the menstrual cycle, which, alas, has a negative effect on appearance.

“Progesterone promotes fluid retention in the body, increases the permeability of the vascular wall, the skin becomes elastic, sebum production increases and acne breakouts appear.Puffiness of the face may appear due to fluid retention.

Progesterone also actively promotes fat storage, preparing us for pregnancy, even if we are not planning it. Therefore, in the second phase of the cycle, many are gaining one or two extra pounds. In addition, progesterone reduces the body’s resistance to infections, which has a beneficial effect on the pathogenic microflora of the skin due to weakening of the immune system and often leads to the formation of acne. ⠀

However, its lack leads to many female diseases that can lead to cancer.

We have analyzed only 2 important hormones for the female body.

But there are no less important DHEA, melatonin, cortisol, testosterone, etc.

This topic is extremely broad and complex. A modern woman needs not only to have a general idea of the most important hormones affecting her body, but also to be able to control them.

And to learn this, the MEDIKA Reproduction Center invites you to a lecture “Hormones of female attractiveness” on August 27 at 19.00.

In the lecture, you will learn which hormones primarily affect female attractiveness and how hormones control our health and well-being.

For whom this lecture is:

for those who want to better understand themselves and their body
for those who want to understand the cause of their negative emotions
for those who want to prolong their youth and preserve their beauty
for those who want to return colors to their intimate life.

What will you learn in the lecture?

9 main hormones affecting women’s health and beauty. How do you manage them?
PMS myth or truth?
How to increase libido and elasticity of intimate muscles?
How to cope with cellulite, loss of skin turgor?
What is the effect of vitamins and minerals on women’s health?
How to continue living a fulfilling life during menopause? Is it worth preparing for it in advance?

When and where will the lecture take place?

August 27 (Thursday) at 19:00

Ave.Toreza, 72, conference hall of the hospital of the Russian Academy of Sciences.

Registration by phone: 8 (812) 565-1840

give me youth ”In Russia, they figured out how to overcome female old age. Doctors already have a plan: Society: Russia: Lenta.ru

According to the chief geriatrician of the Ministry of Health Olga Tkacheva, the aging process has slowed down. In the last century, a 50-year-old man was considered a very old man – now this is almost the peak of his career. Doctors say that youth can be prolonged further, and practically free of charge.The Russian community of gynecologists has developed recommendations for maintaining women’s health, including for older women. Is it true that Russian women, in comparison with European peers, age early, are there pills for youth and why a doctor cannot be fat – “Lente.ru” was told by an obstetrician-gynecologist, candidate of medical sciences, associate professor of the Department of Obstetrics, Gynecology and Reproductive Medicine of the faculty of advanced training of medical workers of the Medical Institute of the RUDN University Irina Shestakova.

“Tape. ru “: The Ministry of Health has recently announced the advisability of revising age limits. Russians under 30 were asked to be considered children. WHO classifies people under 44 years of age as youth. Physiologically, are the standards for the onset of old age, that is, menopause, also shifting?

Irina Shestakova : The average age of menopause in white women has been stable for many years – 51 years. This has been clearly proven in international epidemiological studies.

But it is wrong to say that menopause is synonymous with old age.This does not mean either the loss of external attractiveness, or the approach of physical decrepitude, or the decline in working capacity. Many women during this period even live more actively than before.

Nowadays they write a lot about the fact that Russian women do not know how to age beautifully. I was just young, and tomorrow is a grandmother. While no one will dare to call their peers in Europe old women. Is genetics to blame?

My professional practice is 23 years. And I can compare what a woman was in menopause in the 90s and what she is now.This is heaven and earth. As a rule, women born in 1960-68 who are now entering menopause were no longer afraid, but, on the contrary, actively used hormonal contraception. They no longer have a history of six or seven abortions. They drove the birth of children, they are committed to a healthy lifestyle. Today, some older women look even better than their younger girlfriends. It’s all about the attitude to yourself. Indeed, the role of genetics in maintaining health is no more than 30 percent.

Shot: the film “Love and Doves”

Menopause is primarily a hormone deficiency.Is it true that if they are restored, old age will slow down?

Indeed, there is menopausal hormone therapy (MHT). But keep in mind that MGT is only part of an overall strategy for maintaining the health of older women. That is, it is not a “pill of youth”, but exactly the same medicine as an antibiotic or anti-inflammatory drug with its indications and contraindications.

It is prescribed for the manifestations of menopause: hot flashes, increased sweating, sleep disturbances, and sometimes a decrease in general tone.After all, female hormones are involved in almost all processes in the body. Women usually say during this period: I don’t recognize myself, everything has changed for me, I can’t concentrate, I get tired, I don’t get enough sleep. And my memory became short, I forget where I put the water, put the keys, etc. For this, the hormones estrogens, which are produced by the ovaries, are also responsible. That is, the task of MHT is to partially make up for the estrogen deficiency. After all, we prescribe small doses of hormones, which are several times less than the levels of estrogen in the blood of women in their youth.And the woman literally becomes the same in a few weeks.

Some doctors advise women 20-30 years old to measure their hormone levels in order to then maintain this rate and be forever young.

It borders on quackery. This is not practiced anywhere in the world in medicine. The fact is that the level of ovarian hormones in the blood is variable. If we put a special measuring sensor to a person, which will register these indicators, then we will see that the amount of hormones, even during the day, will regularly jump.What “gold standard” can we talk about here?

Related materials

00:02 – August 7, 2018

We do not match hormones to something. Exceptions: diabetes mellitus and thyroid disease. They really select the dose of drugs, focusing on the level of hormones in the body. But in gynecological endocrinology, it does not happen that a patient has taken a blood test and the doctor has prescribed drugs solely on its basis. The gynecologist is guided by clinical indications.That is, I first of all analyze the complaints and examine the patient, ask her questions. Analyzes are just an auxiliary tool, they are not the main thing. We do not treat analyzes, but the patient.

Earlier, many gynecologists spoke directly about the dangers of hormones. Has the attitude changed now?

Over the past twenty years, there have been strong advances. Here the greatest contribution was made by the professor, gynecologist-endocrinologist Smetnik Vera Petrovna, who left us last year. Back in 1992, she created the Russian Menopause Association, thanks to which our gynecologists began to receive up-to-date information.Professor Smetnik and colleagues conducted a study to study the prevalence of the use of hormonal contraceptives and hormone replacement therapy among female gynecologists. It turned out that even in the Central District they are used by no more than 50 percent of gynecologists. That is, this suggests that many doctors are still afraid of hormonal drugs.

Fears did not form out of nowhere, were they?

There was a period in the history of medicine in the 1960s when hormone replacement therapy was called almost a means of youth.But then the results of the Women’s Health Initiative study were obtained in the United States. More than 15 thousand patients took part in it. All were divided into groups of 50-60; 60-70 and 70+ years old. And all of them were prescribed hormone replacement therapy for the first time.

In groups over 60 years of age, heart attacks, strokes, and cancer began to increase. Unfortunately, journalists began to discuss the extremely negative results of this study. Part of the information has reached Russia that hormone replacement therapy is dangerous without adjusting for age.It was 2001. But then the researchers put everything on the shelves, analyzed and came to new conclusions.

After comparing all the data, it was confirmed that taking hormone replacement therapy increased the risk of cancer and cardiovascular diseases in groups of women who were over 60 years old at the time of its appointment. For the rest, this therapy turned out to be effective and safe.

What other contraindications are there?

If the patient has a history of thrombosis, heart attack, breast cancer, then MHT is contraindicated.There is also the concept of a “window of opportunity”. Hormone therapy is effective and safe if it is started either within ten years after menopause or under the age of 60.

For example, a 70-year-old lady comes to me and says: give me youth. And she already often has urinary disorders, osteoporosis. hormone replacement therapy will be useless and dangerous for her, the window of opportunity has already closed.

If a woman started taking medications on time, how long can she continue to do so?

The Russian clinical guidelines say that if therapy is started in a window of opportunity, then there is no reason to stop it, focusing solely on age.Nowadays the concept of titration applies to hormones. That is, at one age we give one dose of the drug, at another – another. The older the patient, the lower the dose.

Photo: Alexander Utkin / RIA Novosti

You said that hormone replacement is a small part of general therapy for older women. What else does it include?

We look at how the lady eats, how physically active she is, whether she smokes, whether she has a sexual partner, whether she has friends, whether she walks regularly.MGT occupies twenty percent of this list. Everything else is a way of life.

Patients can say: continuous healthy lifestyle is on the verge of moralizing.

Quitting smoking and obesity is not moralizing at all, but a scientifically proven fact. We tell the patient directly: if you want, continue smoking. But at the same time, a positive effect from such and such drugs may not be obtained. For example, smoking is a contraindication for hormonal contraceptives. Because smoking increases blood clotting.Obesity is also a reason to be very selective in the appointment of hormonal drugs.

We are now working under the slogan: “a gynecologist is a female therapist.” That is, it is not as often happened before: the doctor took a smear from a woman – and that’s it. No. The gynecologist should become a conductor of the preventive direction in medicine in relation to the health of women.

How’s that?

The gynecologist, in addition to his “classical” tasks, corrects problems with weight, heals unclean skin, and sometimes a depressed mood.Let’s say a patient comes to him with the intention of only passing tests for infections. But if the doctor sees other problems, he must say. Including about bad breath, remind the woman of the need to diagnose cervical and breast cancer, to lose weight.

Are bad breath, weight loss and women’s health interrelated?

Smell can be a sign of the onset of osteoporosis of the jaws. When does a woman start to lose her teeth? When menopause comes and estrogen deficiency occurs.Estrogen deficiency accelerates the development of dental problems.
And obesity is the main factor in the development of many diseases: heart attack, stroke, cancer, diabetes mellitus, arthritis, thrombosis and others. Only by losing weight, we remove a huge number of health problems.

How to understand if a lady is obese, or is she just moderately well-fed?

In women, obesity is diagnosed when the abdominal circumference at the navel is more than 80 centimeters.

How to deal with this?

Basically, you just need to explain to a person that he eats more than he spends.Many do not really understand why they are gaining weight. After all, therapeutic lifestyle modification is the initial treatment for obesity.
Our women love fairly simple food: cakes, sweets, etc. You ask – how many vegetables did you eat today? I don’t like it, it’s not tasty. To lose weight, you just need to remove high-calorie foods from the diet and move more. The most powerful absolutely free calorie burner is our walking, swimming, cycling muscles.

For many, this is almost a feat.

I have an example of a 46-year-old woman who came to me from a small town near Moscow. Very well-groomed face with makeup. Weight – more than 100 kilograms with a short stature. She took over 11 different medications every day. This is a lot. She says she was thin 20 years ago. And now – an accountant, serves several companies. And all clients regularly thank her with cakes.

Shot: clip of the Little Big group “Faradenza”

I did not appoint anything to her, except for losing weight.And she honestly said that I simply could not help with her weight. The second time this woman came to me a year later, she lost 40 kilograms. She said that she was very offended then at me, even cried: what kind of doctor is this, how can she push the patient away? And then she went to the village for a month, where every day she mowed the grass, brought water from a pump station, simple food, no sweets. Most of her health problems returned to normal on their own.
No feats are needed. Everything can be replaced. Love the cakes – have them once a week as a reward.You can’t live without sweets – there are seasonal sweet fruits.

On patient forums, you can often find a “fotozhaba”: a lady is sitting at a doctor’s appointment, he strongly recommends her to lose weight. But at the same time, the doctor himself weighs no less than the patient. In general, the usual situation in clinics. This is fine?

My leader, Corresponding Member of the Russian Academy of Medical Sciences, Viktor Evseevich Radzinsky, often tells stories from his practice. One of the most indicative, when in a hospital not a single obese patient has this diagnosis in the history of the disease.And the complexion of the doctors working in the department is similar to that of the patients.

Before recommending something, you have to start with yourself. My position here is tough. A doctor who prescribes treatment for obesity has no right to be overweight. Patients simply won’t believe him. How can a person with speech therapy problems work as an announcer who does not pronounce words? It’s the same here.

Fullness is not only from overeating, but also due to some kind of illness. And here already smacks of discrimination against disabled people?

There are very few such diseases.For example, there is a rare congenital pathology – the absence of a gene that is responsible for saturation – leptin. The person eats and cannot stop. The most common example of obesity due to illness is diabetes mellitus. But even for diabetics, there is now a wonderful new drug that can correct weight.

You say that a gynecologist can often replace several doctors at once. And to the patient – how can you understand whether a comprehensive approach has been applied to her or not, whether she has a good doctor?

If there is already some diagnosed disease, a woman can go to the “Clinical guidelines” section on the Ministry of Health’s website and see what is said about this disease in the section of the clinical guidelines “Information for patients”, which is written in an accessible language.It happens that the doctor did not say something – do not be offended. But if his words are at odds with what is written in this document – look for a second opinion.

It is more difficult when the reception was primary or prophylactic. But it is important that each visit is documented, and the doctor’s opinion with the diagnosis and recommendations is issued to the patient. Even after the first consultation, there should be a preliminary diagnosis. Let it change later, but this entry should still appear.

Provisional diagnosis can also be “checked” in clinical guidelines.That is, to see what kind of research it is proposed to conduct in such a situation. During the appointment, the doctor must give the patient a clear algorithm: what to do next, what research to conduct, whether it is necessary to come for a second appointment and when.

We mainly talked about the prolongation of youth in women with the help of hormones. Do men have such problems?

Men may also experience a lack of androgen hormones with age. But everything is more complicated there. Menopause refers to the loss of ovarian function.It is assessed simply: menstruation stops. In men it is not so unambiguous. Some of them may never experience hormone deficiency, while others have a pronounced lack of androgens. This is called andropause. And it is also corrected by urologists and endocrinologists. But the most important recommendation for men is exactly the same as for women – first of all, pay attention to your lifestyle, bad habits and weight.

types, advantages and disadvantages || Medical center “Centromed”

Family planning is based on protecting the couple from unwanted pregnancies.For this, various methods of contraception are used. The most popular oral contraceptives. This is due to the convenience of their use, the absence of discomfort during sex, both for women and men. They are hormonal drugs that contain the female sex hormones estrogen, progesterone. An increase in the concentration of blood hormones after taking an oral contraceptive causes a blockage of the ovulation process (the release of an egg from the ovary), which, accordingly, prevents its fertilization by sperm.In the absence of the opportunity to take hormonal drugs, there are contraceptive suppositories that have a spermicidal (kill sperm) effect, they are used immediately before intercourse.

Types of oral contraceptives

Contraceptives for women The modern pharmacological market contains several types of drugs, which include:

Monophasic – dosage, the ratio of hormones in all tablets is the same.
Biphasic – the dosage of estrogen remains the same in all tablets, and the dose of progesterone changes, respectively, 1 and 2 periods of the menstrual cycle.
Three-phase – the dosage of estrogen, progestogen changes three times throughout the entire menstrual cycle.

Depending on the concentration of hormones, the following types of oral contraceptives are isolated:

Microdosing – products with a minimum dosage of hormones, optimally suited for young women under the age of 25.
Low Dose – These preparations contain slightly higher hormone doses and are suitable for middle-aged women who have given birth.
High-dose – their use is recommended for persons with hormonal disorders in the body, since such drugs contain estrogen, progesterone in high doses.

Separately included are medicines that contain only a gestagen without estrogen, Mini-pili, they practically do not cause changes in the hormonal background of the body, but their reliability for contraception is somewhat lower.

The advantage of all oral contraceptives is the absence of discomfort during sex, high reliability. The disadvantages include – daily intake of hormonal contraceptives . For convenience, so that the woman does not have to constantly take pills, the implantation of a product containing estrogen is used. To date, our clinic uses the drug Implanon, which is injected under the skin, provides protection against pregnancy lasting up to 3 years.If necessary, if you want to become pregnant, the medicine can be removed from under the skin.

Which contraceptive suppositories to choose?

Contraceptive suppositories contain spermicides – substances that kill sperm. Before choosing a medicine, it is necessary to be guided by the reliability and the absence of an irritating effect on the mucous membrane of the vagina and cervix.

How to choose contraception?

The choice is influenced by several factors, which include:

Age of the woman.