Compounding for women's health: a compounder's perspective - need, regulations, and future.

Compounding medicine involves various health-care professionals working together to produce medications that treat patient conditions including menopause and other women's health-related illnesses. These medications are compounded under the standards and guidelines mandated by individual state pharmacy boards, the US Food and Drug Administration, and other professional organizations. Contrary to commercial medications, the personalized medicine aspect of compounding medications ensures that the patient's allergies, doses, and drug delivery preferences are addressed during formulation. In the foreseeable future, compounders will continue to formulate medications that are unavailable in the commercial sector, following strict safe-practice guidelines. More importantly, the application of pharmacogenomics and three-dimensional printing to compounding medications could revolutionize compounding formulations and generate new approaches for personalized medicine.

Custom-compounded bioidentical hormone therapy: why so popular despite potential harm? The case against routine use.

Wide rejection of conventional hormone therapy (HT) after the initial publication of the Women's Health Initiative (WHI) led to unjustified use of custom-compounded bioidentical hormones. In the USA, it became an unregulated drug manufacturer industry in disguise, without proper control and making false claims and misleading advertisements. Manufacturing quality is not ensured. Unspecific harm from compounding has occurred on a large scale, such as deaths from infected products and end-stage renal failure plus carcinoma due to confusion between different Chinese herbs. Oral estrogens increase venous thromboembolic and ischemic stroke events, even more when overdosed; these excess risks can be avoided by non-oral administration, readily accessible in custom-compounded HT by administering estradiol through diverse routes (of which transdermal is the best documented). Another risk specific to custom-compounded HT, resulting from estrogen/progestogen imbalance, might be excess endometrial carcinomas. HT can be optimized by continuously combining transdermal estradiol with progesterone (when required). Registered preparations do exist for such a more physiological treatment and therefore must be preferred. Custom compounding is only seldom legitimate, for example in case of allergy (such as to peanut oil) or to prescribe different combinations, doses or components (e.g. estriol, dehydroepiandrosterone or testosterone), even when not approved by local regulatory authorities despite being scientifically acceptable.

Bioidentical menopausal hormone therapy: registered hormones (non-oral estradiol ± progesterone) are optimal.

The many advantages of registered bioidentical sex hormones over registered, conventional, non-bioidentical menopausal hormone therapy (MHT) are considered. The transdermal route of estrogen administration avoids excess venous thromboembolic and ischemic stroke events. There is some indication that conjugated equine estrogens are more thrombogenic and most likely induce some hypertensive responses; estradiol might also be superior to conjugated equine estrogens (CEE) in terms of global cardiovascular health. The most valid evidence presently suggests that CEE-only treatment does not increase the risk of breast cancer and even may reduce it. But its combination with a synthetic progestogen (mainly medroxyprogesterone acetate) is a critical issue since it seems to be primarily associated with an increased incidence of breast cancer, however similar to or lower than that associated with some common lifestyle factors. Though not yet proven in a randomized, controlled trial, MHT continuously combining oral micronized progesterone with transdermal estradiol can presently be considered as the optimal MHT. It is not only safer than custom-compounded bioidentical hormones but also than oral conventional MHT and has the best breast profile; registered products for such optimal MHT are available around the world and must be preferred.

Why women choose compounded bioidentical hormone therapy: lessons from a qualitative study of menopausal decision-making.

BACKGROUND: In recent years, compounded bioidentical hormone therapy (CBHT) has emerged as a popular alternative to manufactured, FDA approved hormone therapy (HT)-despite concerns within the medical community and the availability of new FDA approved "bioidentical" products. This study aims to characterize the motivations for using CBHT in a U.S. sample of ordinary midlife women. METHODS: We analyze data collected from 21 current and former users of CBHT who participated in a larger qualitative study of menopausal decision-making among U.S. women. Interviews and focus groups were audio-recorded, transcribed verbatim, and analyzed thematically using an iterative inductive and deductive process. RESULTS: Although women's individual motivations varied, two overarching themes emerged: "push motivations" that drove women away from conventional HT and from alternative therapies, and "pull motivations" that attracted women to CBHT. Push motivations focused on (1) fear and uncertainty about the safety of conventional HT, (2) an aversion to conjugated estrogens in particular, and (3) and overarching distrust of a medical system perceived as dismissive of their concerns and overly reliant on pharmaceuticals. Participants also voiced dissatisfaction with the effectiveness of herbal and soy supplements. Participants were attracted to CBHT because they perceive it to be (1) effective in managing menopausal symptoms, (2) safer than conventional HT, (3) tailored to their individual bodies and needs, and (4) accompanied by enhanced clinical care and attention. CONCLUSIONS: This study finds that women draw upon a range of "push" and "pull" motivations in their decision to use CBHT. Importantly, we find that women are not only seeking alternatives to conventional pharmaceuticals, but alternatives to conventional care where their menopausal experience is solicited, their treatment goals are heard, and they are engaged as agents in managing their own menopause. The significance of this finding goes beyond understanding why women choose CBHT. Women making menopause treatment decisions of all kinds would benefit from greater shared decision-making in the clinical context in which they are explicitly invited to share their experiences, priorities, and preferences. This would also provide an opportunity for clinicians to discuss the pros and cons of conventional HT, CBHT, and other approaches to managing menopause.

Counseling in menopausal women: How to address the benefits and risks of menopause hormone therapy. A FIGO position paper.

Menopause marks the end of menstrual cyclicity and, depending on individual vulnerability, has several consequences related to gonadal steroid deprivation, especially if it is premature. Menopause may be more burdensome for some women than for others. Individual factors, such as personal history, socioeconomic status, ethnicity, and current health conditions, affect symptomatology and, thereby, the menopausal experience. In addition, some menopausal symptoms, such as severe hot flashes, sleep disorders, and depression, are markers of future health risks. Counseling is a fundamental part of health care in the peri- and postmenopause periods. It must include an assessment of the patient's symptoms, needs, desires, and risk profile to address the benefits and risks of menopausal hormone therapy (MHT) on an individual basis and promote a healthy lifestyle. Indeed, healthcare practitioners can and must protect the health and lives of mid-life women by increasing awareness of menopausal symptoms and ensuring healthcare options, especially MHT. The type and duration of MHT should be tailored based on the patient's history, menopausal age, physical characteristics, and current health status so that the benefits always outweigh the risks. This FIGO position paper focuses on the benefits and risks of MHT on health domains, target organs, and systems, and on systemic and vaginal MHT regimens, to provide indications that can be used in the clinical practice for menopausal counseling. Moreover, it offers insights into what FIGO considers the mainstay for the healthcare management of women in peri- and postmenopause, worldwide.

To clot, or not to clot: The dilemma of hormone treatment options for menopause.

Untreated menopause may have serious health implications, but treatments can have dangerous side effects. We evaluate menopausal symptoms as well as available treatments -the routes of administration and their effect on blood coagulation. Menopausal females may experience hot flushes, vulva- and vaginal atrophy and osteoporosis. Many treatments are available to relieve these symptoms such as Conjugated Equine Estrogen and bioidentical hormones. The routes of administration include oral and transdermal. Hormones that are administered orally undergo a hepatic first pass metabolism. The by-products have a lower efficacy and possibly enhanced side effects. Furthermore, hormone treatments influence the coagulation cascade through coagulation factors or their regulators. Increased coagulation poses a risk for venous thromboembolism. Currently a definite conclusion on whether the side effects from hormone treatments exceed the risk of untreated menopause cannot be made. However, a more individualised approach to hormone treatments may be the most feasible solution to this dilemma.

Human versus non-human sex steroid use in hormone replacement therapies part 1: Preclinical data.

Prior to 2002, hormone replacement therapy (HRT) was considered to be an important component of postmenopausal healthcare. This was based on a plethora of basic, epidemiological and clinical studies demonstrating the health benefits of supplementation with human sex steroids. However, adverse findings from the Women's Health Initiative (WHI) studies that examined the 2 major forms of HRT in use in the US at that time - Premarin (conjugated equine estrogens; CEE) and Prempro (CEE + medroxyprogesterone acetate; MPA), cast a shadow over the use of any form of HRT. Here we review the biochemical and physiological differences between the non-human WHI study hormones - CEE and MPA, and their respective human counterparts 17ß-estradiol (E2) and progesterone (P4). Preclinical data from the last 30 years demonstrate clear differences between human and non-human sex steroids on numerous molecular, physiological and functional parameters in brain, heart and reproductive tissue. In contrast to CEE supplementation, which is not always detrimental although certainly not as optimal as E2 supplementation, MPA is clearly not equivalent to P4, having detrimental effects on cognitive, cardiac and reproductive function. Moreover, unlike P4, MPA is clearly antagonistic of the positive effects of E2 and CEE on tissue function. These data indicate that minor chemical changes to human sex steroids result in physiologically distinct actions that are not optimal for tissue health and functioning.

A comparative characterization of estrogens used in hormone therapy via estrogen receptor (ER)-α and -ß.

Conventional hormone therapy (HT) containing estrogens such as ethinylestradiol (EE) have been associated with an increased risk of breast cancer and cardiovascular disease resulting in women seeking safer alternatives that are claimed to have fewer health risks. One such alternative gaining popularity, is custom-compounded bioidentical (b)HT formulations containing bioidentical estradiol (bE2) and estriol (bE3). However, the preparation of these custom-compounded estrogens is not regulated, and depending on the route of synthesis, steroid mixtures with differing activities may be produced. Thus, an investigation into the activities of estrogens prepared by custom-compounded pharmacies is warranted. The aim of this study was therefore to directly compare the pharmacological properties of bE2 and bE3 of unknown purity relative to commercially available, pure E2, E3 and estrone (E1) standards as well as synthetic EE used in conventional HT via the human estrogen receptor (ER)-α and -ß. We determined precise equilibrium dissociation constants (Kd or Ki values) and showed that bE2 and bE3 display similar binding affinities to the E2 and E3 standards, while EE had a higher affinity for ERα, and E1 a lower affinity for ERß. Furthermore, all the estrogens display similar agonist efficacies, but not potencies, for transactivation on a minimal ERE-containing promoter via the individual ER subtypes. Although E2 and E3 were equally efficacious and potent on the endogenous ERE-containing pS2 promoter in the MCF-7 BUS breast cancer cell line co-expressing ERα and ERß, E1 was less efficacious and potent than E2. This study is the first to demonstrate that the bioidentical estrogens, commercially available estrogen standards and synthetic EE are full agonists for transrepression on both minimal and endogenous NFκB-containing promoters. Moreover, we showed that these estrogens all increase proliferation and anchorage-independent growth of MCF-7 BUS cells to a similar extent, suggesting that custom-compounded bHT may in fact not be a safer alternative to conventional HT. Furthermore, our results showing that E3 and E1 are not weak estrogens, and that E3 does not antagonize the activity of E2, suggest that the rationale behind the use of E3 and E1 in custom-compounded bHT formulations should be readdressed. Taken together, the results indicating that there is mostly no difference between the custom-compounded bioidentical estrogens, commercially available estrogen standards and synthetic EE, at concentrations reflecting serum levels in women using estrogen-containing HT, suggest that there is no clear advantage in choosing bHT above conventional HT.

Women's Health: Polycystic Ovarian Syndrome, Menopause, and Osteoporosis.

Surveys consistently show that a significantly higher percentage of women with chronic medical conditions report use of complementary and integrative medicine (CIM) approaches compared with men. A total of 54.5% of women report use of at least one CIM approach specifically for obstetric or gynecologic problems. However, primary care providers remain an underutilized resource by patients for guidance in the safe and appropriate use of integrative therapies. This article provides a practical overview of the most appropriate integrative therapies to consider in the management of commonly seen women's health conditions: polycystic ovarian syndrome, menopause, and osteoporosis.

17ß-Estradiol and natural progesterone for menopausal hormone therapy: REPLENISH phase 3 study design of a combination capsule and evidence review.

Several formulations combining estrogens and progestins for hormone therapy (HT) have been approved worldwide for the treatment of menopausal symptoms, yet recent data indicate a decline in their use and an increase in compounded bioidentical HT. Up to now, no single product combining natural 17ß-estradiol and progesterone has been approved by the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA). A phase 3 trial (REPLENISH) is underway to study a novel oral formulation of solubilized 17ß-estradiol and natural progesterone combined in a single gelatin capsule (TX-001HR; TherapeuticsMD, Inc, Boca Raton, FL) for treating vasomotor symptoms (VMS) in postmenopausal women. The REPLENISH trial evaluates the efficacy and safety of TX-001HR (4 doses) versus placebo for the reduction of moderate to severe VMS frequency and severity at 4 and 12 weeks and evaluates the endometrial safety of the combinations at 1 year. TX-001HR contains hormones that are molecularly identical to endogenous estradiol and progesterone and is intended as an option for women who prefer bioidentical hormones; further, it does not contain peanut oil, a common allergen. The constituents of TX-001HR, in a pharmacokinetic report, showed similar bioavailability and safety compared with reference estradiol tablets and micronized progesterone capsules administered together. Published data suggest a safer profile of estradiol and natural progesterone compared with HT containing conjugated equine estrogens and progestins. This report summarizes the methodology of the REPLENISH trial and reviews the evidence suggesting clinical differences between HT containing progesterone or progestins, and estradiol or conjugated equine estrogens.

Bioidentical hormones, menopausal women, and the lure of the "natural" in U.S. anti-aging medicine.

In 2002, the Women's Health Initiative, a large-scale study of the safety of hormone replacement therapy (HRT) for women conducted in the United States, released results suggesting that use of postmenopausal HRT increased women's risks of stroke and breast cancer. In the years that followed, as rates of HRT prescription fell, another hormonal therapy rose in its wake: bioidentical hormone replacement therapy (BHRT). Anti-aging clinicians, the primary prescribers of BHRT, tout it as a safe and effective alternative to treat menopausal symptoms and, moreover, as a preventative therapy for age-related diseases and ailments. Through in-depth interviews with 31 U.S.-based anti-aging clinicians and 25 female anti-aging patients, we analyze attitudes towards BHRT. We illustrate how these attitudes reveal broader contemporary values, discourses, and discomforts with menopause, aging, and biomedicine. The attraction to and promise of BHRT is rooted in the idea that it is a "natural" therapy. BHRT is given both biomedical and embodied legitimacy by clinicians and patients because of its purported ability to become part of the body's "natural" processes. The normative assumption that "natural" is inherently "good" not only places BHRT beyond reproach, but transforms its use into a health benefit. The clinical approach of anti-aging providers also plays a role by validating patients' embodied experiences and offering a "holistic" solution to their symptoms, which anti-aging patients see as a striking contrast to their experiences with conventional biomedical health care. The perceived virtues of BHRT shed light on the rhetoric of anti-aging medicine and a deeply complicated relationship between conventional biomedicine, hormonal technologies, and women's bodies.

Use of compounded bioidentical hormone therapy in menopausal women: an opinion statement of the Women's Health Practice and Research Network of the American College of Clinical Pharmacy.

Menopausal symptoms affect a significant portion of women. Traditional treatment with manufactured hormone therapy can alleviate these symptoms, but many women and their health care providers are concerned about the risks, such as venous thromboembolism and certain types of cancer, demonstrated with manufactured hormone therapy. Compounded bioidentical hormone therapy has been proposed and is often used as a solution for these concerns. Despite this use, no data are currently available to support the claims that compounded bioidentical hormone therapy is a safer or more efficacious option compared with manufactured hormone therapy. A common misperception is that all manufactured products consist of synthetic hormones and all compounded medications consist of natural hormones; however, in fact, significant overlap exists. Several key stakeholder organizations have issued statements expressing concern about the lack of evidence regarding the efficacy and safety of compounded bioidentical hormone therapy, in addition to concerns regarding prescribing patterns. The Women's Health Practice and Research Network of the American College of Clinical Pharmacy recommends against the consistent use of compounded bioidentical hormones as a safer option compared with manufactured therapy and supports the statements of other key organizations, acknowledging the need for more robust clinical studies to evaluate the potential advantages and disadvantages of compounded bioidentical products compared with manufactured products.