THE PCCA BLOG

The FDA Removes the Black Box Warning on Estrogen: What Pharmacists Need to Know (2025 Update)

Fri, 13 Feb 2026 16:24:46 GMT

On November 10, 2025, the U.S. Food and Drug Administration (FDA) announced a major update to menopausal hormone therapy labeling: the agency is removing the broad black box warning from estrogen-containing products used for menopause, with one important exception—systemic estrogen-alone products will retain the boxed warning for endometrial cancer risk in women with an intact uterus.¹

For pharmacists, this isn’t just a labeling change. It’s a clinical counseling opportunity to help patients understand who hormone replacement therapy (HRT) is appropriate for, when it is most beneficial, and which risks still require screening and monitoring.

How We Got Here: The Women’s Health Initiative (WHI) and the “HRT Fear” Era

The Women’s Health Initiative (WHI), launched in the 1990s and sponsored by the National Heart, Lung, and Blood Institute (NHLBI), enrolled more than 161,000 postmenopausal participants.² One key goal was to evaluate whether hormone therapy could prevent cardiovascular disease, fractures, and cancer.

Key WHI findings (as widely interpreted at the time):

Estrogen + progestin was associated with increased risk of coronary heart disease, stroke, venous thromboembolism (VTE), breast cancer, and dementia.
Estrogen alone (in women with prior hysterectomy) showed more favorable outcomes in younger subgroups and was associated with reduced coronary heart disease and all-cause mortality in some analyses. It also showed a statistically significant reduction in invasive breast cancer incidence overall.

The practical takeaway became blunt: HRT was seen as broadly dangerous, HRT prescribing dropped sharply, and many women stopped therapy or avoided it altogether.

What was often lost in translation: the average age in the WHI hormone trial was around 63—well beyond the typical menopause transition—and the regimen studied (oral conjugated equine estrogen plus medroxyprogesterone) does not represent the full range of current hormone therapy options. Risk estimates were frequently generalized to younger, newly menopausal patients, even though their benefit–risk profile can differ meaningfully.

What Exactly Is the FDA Changing in 2025?

In the November 2025 announcement, the FDA and HHS began removing broad boxed warnings that had linked systemic menopausal hormone therapy to cardiovascular disease, breast cancer, and probable dementia. The agencies explicitly described prior warnings as “misleading” when interpreted without clinical context and current evidence.¹

What remains: the FDA will retain the boxed warning for endometrial cancer on systemic estrogen-alone products, reinforcing the importance of appropriate progestogen use (or other uterine protection strategies) for patients with a uterus.

A centerpiece of the updated position is the FDA’s endorsement of the timing hypothesis: the benefit–risk balance of systemic HRT depends heavily on when therapy starts. The FDA cited randomized data suggesting that women who initiate systemic hormone therapy within 10 years of menopause onset or before age 60 may experience benefits such as fewer fractures and reduced all-cause mortality, along with favorable relative risk changes for certain cardiovascular outcomes.¹

What This Means for Pharmacists: Counseling That’s Accurate, Individualized, and Confidence-Building

For years, counseling often defaulted to: “Use the lowest dose for the shortest time—only if absolutely necessary.” The updated labeling supports a more nuanced approach.

As boxed warnings are removed, pharmacists play an even bigger role in helping patients understand why “estrogen” is not one uniform exposure.

And the “uterus rule” remains critical: unopposed systemic estrogen in a patient with an intact uterus increases risk of endometrial hyperplasia and endometrial cancer, and the boxed warning for this risk remains.¹

Age and timing now matter more in patient conversations
A healthy 52-year-old within a few years of her final menstrual period does not share the same baseline risk profile as a 68-year-old initiating hormone therapy for the first time. Pharmacists can help frame this distinction clearly and consistently.
Route, formulation, and regimen matter—and WHI isn’t the full story The WHI primarily studied a specific oral regimen. Today’s practice commonly involves:
- estradiol,
- micronized progesterone,
- lower doses, and
- individualized schedules.
Removing a black box warning is not the same as removing risk Pharmacists should still screen for contraindications and red flags—especially in patients with:
- history of estrogen-dependent cancer (including many breast cancers),
- active or high-risk VTE, known thrombophilia, or prior stroke,
- unexplained vaginal bleeding,
- severe liver disease,
- uncontrolled or significant cardiovascular disease (depending on route/regimen).
Expect fear, confusion, and skepticism—and be ready for it Many patients have internalized the message that “hormones cause cancer and heart attacks.” A helpful counseling approach:
- acknowledge why patients were warned for decades,
- explain what we’ve learned since WHI (especially the role of age, timing, and regimen),
- emphasize shared decision-making with the prescriber.

Bottom Line for Pharmacy Practice

The FDA’s removal of the broad black box warning on estrogen therapy for menopause is a course correction, not a claim that estrogen is risk-free.

For pharmacists, this moment means:

Updating how we explain HRT risk and benefit in plain language.
Shifting from “avoid at all costs” to patient-specific risk–benefit counseling.
Helping patients understand why labeling changed and how that supports informed decision-making.

Many women will spend a large portion of life in the postmenopausal phase, and symptom relief plus long-term health considerations are real quality-of-life issues. Pharmacists are uniquely positioned to translate this regulatory update into balanced, evidence-informed guidance.

References

U.S. Food and Drug Administration. HHS advances women’s health, removes misleading FDA warnings on hormone replacement therapy. FDA Newsroom. November 10, 2025. Accessed December 29, 2025. FDA Newsroom
National Heart, Lung, and Blood Institute. Women’s Health Initiative (WHI). NHLBI, National Institutes of Health. Accessed December 29, 2025. NHLBI WHI

Optimizing the Patient Experience with the Right HRT Base: Insights from the Webinar

Wed, 28 May 2025 13:00:00 GMT

As compounders, we know that hormones get a lot of attention — but the base plays a critical role in the potential success of the therapy. During PCCA’s recent webinar, “Choosing the Right HRT Base for Patient Success,” Sara Hover, RPh, FAARM, along with seasoned compounders Jim Hrncir, RPh, and Madison Peach-Keen, PharmD, shared hard-earned insights on how base selection can elevate your HRT practice.

If you missed it, here’s a breakdown of the key takeaways — with the compounding pharmacist in mind.

Don’t Underestimate the Base

We all know APIs matter — but the delivery system can greatly contribute to clinical outcomes, adherence and patient satisfaction. The base you choose isn’t just a carrier; it influences absorption, stability, patient experience and the beyond-use date (BUD) that can be assigned to the preparation.

As Sara explained: “It’s not just that a base is anhydrous or hydrous — it’s about how it delivers the medication for the patient, how it supports the pharmacist’s workflow and how it meets the prescriber’s goals for the patient.”

From the Trenches: Jim Hrncir on What Works

A longtime HRT educator and compounder, Jim highlighted a success story with a complex vulvodynia case that responded only after he compounded estradiol, testosterone and naltrexone in PCCA’s Ellage® Anhydrous Vaginal. The patient was already on vaginal BHRT with little relief — but within one week of switching bases and formulation strategy, her pain dramatically improved.

His go-to favorite bases?

Atrevis Hydrogel®: A game-changer for male transdermal testosterone, especially for patients losing efficacy on standard creams.
VersaBase® Cream and Lipoderm®: Reliable options with predictable results.
Ellage Anhydrous Vaginal: For patients with sensitivities.
MucoLox™: Mucosal delivery for patients requiring better retention.

Jim’s advice: “Don’t push your belief system. Work within the practitioner’s [existing framework]. If they trust serum testing, meet them there — but equip them with the right tools and science.”

For the Newer Pharmacies: Lessons from Madison Peach-Keen

Six months into launching her own compounding pharmacy, Madison emphasized differentiation through education and uncompromising quality. Her BHRT strategy centers on:

Sourcing all hormones and bases from PCCA
Regularly educating providers with concise, clinically relevant updates
Leading with Anhydrous VersaBase® HRT for BUDs, texture and patient preference

Madison also swears by MucoLox + VersaBase® Gel as a combo for vaginal applications when enhanced mucosal contact time is needed, and favors Ellage Anhydrous Vaginal for its potential to minimize leakage.

Pro tip: “Education is critical. If you’re new to HRT, start with mastering the science, then teach your providers. That’s how you build credibility and grow volume.”

Anhydrous vs. Hydrous: Know When to Use What

Anhydrous bases provide greater BUD limits for nonsterile compounded preparations in USP 795. Longer BUDs for both hydrous and anhydrous nonsterile preparations are also available through PCCA’s FormulaPlus™ program. The decision about what base is most appropriate for each patient relies on the triad of patient care and communication between the prescriber, the pharmacist and the patient.

Key anhydrous points:

Anhydrous VersaBase HRT: Excellent glide, non-greasy feel and strong patient acceptance
Ellage Anhydrous Vaginal: Designed with mucoadhesive and self-emulsifying properties — engineered for high retention and hormone release
BUD advantage: Studies support 180-day dating for bracketed ranges. Anhydrous preparations have greater BUD limits in USP 795 and PCCA studies support 180-day dating for bracketed ranges of several formulations.

Backed by Data: What the Studies Show

Sara shared multiple in-house studies comparing hormone release and absorption using PCCA bases vs. alternatives. The verdict? Up to 4x greater absorption with PCCA’s VersaBase Cream for progesterone, and 2.7x more testosterone delivery with Atrevis compared to a competitor base.

These studies aren’t just internal wins — they’re talking points to show why you choose the bases that you use for your patients.

Bottom Line: It’s About Options and Outcomes

Your base can be the differentiator in your market. Offer patients and providers more than one texture or form, and you open doors for possibly improved adherence and outcomes.

Here’s what to keep in mind:

Build protocols around your best-performing bases.
Stay on top of base-specific absorption data.
Leverage BUD testing to streamline workflow and reduce waste.
Teach providers how and why base selection matters.
And when in doubt, let patients try the feel of the base — texture and feel can be critical.

Want to explore more? PCCA’s HRT Virtual Symposium is coming up July 24-25 — all online, jam-packed and worth your time.

Balance Hormones and Grow Your Practice

Thu, 19 Dec 2024 23:31:00 GMT

The numbers are in — forecasters predict 1.1 billion women worldwide will experience menopause in 2025.¹ In the U.S., more than 1 million women reach menopause each year, and more than 75 percent of these women work during menopause transition years. Research conducted by the National Institute on Aging indicates menopausal hormone therapy (MHT) reduced the severity of menopause symptoms while elevating mood, sexual function, cardiovascular and brain health.²

With all of these studies and reports, it’s no wonder that hormone replacement therapy (HRT) currently leads all compounding therapeutic areas in the U.S. — or that the U.S. HRT market value is forecasted to reach $12.6 billion within the next five years.³Maintaining up-to-date HRT knowledge is now a top priority for compounding pharmacists who support patients that experience the many side effects of perimenopause or menopause.

Introducing PCCA Master Courses: HRT

PCCA Master Courses: Hormone Replacement Therapy (HRT), a new education tool, will prepare compounding pharmacists to meet the needs of this expanding female patient segment. The dynamic platform delivers specialty education using:

Online, self-paced HRT education available on demand
Engaging, multimedia formats for interactive learning
Continuing education (CE) courses with 25 hours of CE applied for

“We understand the many nuances of compounding and recognize the varied responsibilities of compounding pharmacy owners and pharmacists,” said PCCA Director of Online Education Jerra Banwarth, RPh, FAPC. “This is why we wanted to develop a flexible program that accommodates their busy schedules. We also wanted to make it a dynamic experience to captivate and retain their interest — regardless of time or day. And we recognize the importance of specialty education — it’s an advantage that a compounding pharmacist can use to distinguish their practice from competitors.”

PCCA Master Courses: HRT was developed to be easy to follow and provides a true multimedia experience. Education is delivered through impactful audio, visual and animations, which helps learners better understand the physiological concepts of perimenopause through post-menopause.

Master Courses: HRT is composed of five courses:

Introduction to Hormones
Reviews foundational anatomy and physiology; explores the goals of HRT.
Testing and Therapy Options
Takes an in-depth look at different testing options and applications for utilization.
Clinical Evidence for HRT Patient-Centered Care
Provides insights into patient specific therapies, including dosing, routes of administration and formulations.
Bases for HRT Application
Explores appropriate bases, devices and compounding considerations for HRT formulations.
Building a Thriving HRT Compounding Practice
Provides a foundation for marketing your expertise and knowledge; offers professional recommendations on how to implement a hormone consultation practice.

Earn Your Certified Master Designation in HRT

Upon successfully completing the Master Course, learners can take their expertise further with the PCCA Certified Master* designation. The designation is achieved in two steps:

Successfully complete all courses in PCCA Master Courses: HRT by February 7, 2025.
Attend a PCCA HRT Symposium within 12 months: in-person or virtually at the Las Vegas HRT Symposium, February 20-22, or at the virtual HRT Symposium on July 24-25, 2025.

The HRT Symposium and Master Courses: HRT are complimentary educational achievements designed to help shorten the learning curve and create a powerful experience for pharmacists. In addition to increasing their knowledge, those who achieve the PCCA Certified Master designation can use it to market their practice to prescribers and patients.

“We work to ensure our education programs and symposiums benefit all attendees — from pharmacists to pharmacy technicians and medical practitioners,” said PCCA Senior Director of Education Renee Prescott. “We hire industry-expert speakers who share cutting-edge clinical research, provide ample time for participants to network and we apply for CEs, yet another benefit. More than 98 percent of participants give us an ‘A’ grade.”

Participants who achieve their initial Certified Master designation have the option to recertify by attending the PCCA HRT Symposium every two years.

“There’s always something new to learn,” said Jerra. “Serving this population not only helps women, it also benefits their families, friends, workplace and communities.”

Prepare to meet the needs of a growing market. Register today for PCCA Master Courses: HRT.

PCCA members with clinical service access may contact our Clinical Services team for additional information on compounding for HRT and other compounding concerns.

PCCA is recognized as the leader of quality products, education and advocacy in the compounding industry. Find out how a PCCA membership can benefit your compounding practice.

*The Certified Master award is an internal designation provided by PCCA. It does not denote a board certification or certification by a licensed health care body. Pharmacists and practitioners are eligible for the Certified Master designation.

References

Zhang L, Ruan X, Cui Y, Gu M, Mueck AO. Menopausal Symptoms and Associated Social and Environmental Factors in Midlife Chinese Women. Clin Interv Aging. 2020;15:2195-2208. Published 2020 Nov 16. doi:10.2147/CIA.S278976
National Institute on Aging. News. Research explores the impact of menopause on women’s health and aging. Research Highlights. 2022. Accessed December 2024 at https://www.nia.nih.gov/news/research-explores-impact-menopause-womens-health-and-aging#hormone
Grand View Research. Hormone Replacement Therapy Market Size, Share & Trend Analysis By Product (Estrogen & Progesterone Replacement Therapy), By Route of Administration, By Disease Type, By Region, And Segment Forecasts, 2023 – 2030. Accessed October 2024 at https://www.grandviewresearch.com/industry-analysis/hormone-replacement-therapy-market

These statements are provided for educational purposes only. They have not been evaluated by the Food and Drug Administration, and are not to be interpreted as a promise, guarantee or claim of therapeutic efficacy or safety. The information contained herein is not intended to replace or substitute for conventional medical care or encourage its abandonment.

What’s in Store at the LDN Virtual Conference

Fri, 15 Nov 2024 03:53:03 GMT

Individuals who suffer from symptoms of gastrointestinal, autoimmune, dermatological and pain conditions make up 80% of the patient population. But here’s the good news: multiple studies indicate that low-dose naltrexone (LDN) may potentially help many of these conditions. Take a sneak peek at topics our Clinical Services team will discuss during the Low-Dose Naltrexone One-Day Virtual Conference on Thursday, November 21, 2024.

The Immune System — Autoimmune Conditions and the Benefits of LDN

by Catherine Henderson, PharmD, PCCA Clinical Compounding Pharmacist

LDN has long been touted for its effects in autoimmune disorders. Understanding the mechanisms of LDN action involves diving deeper into immune system function and the irregularities that occur in autoimmune disorders. We’ll explore the data related to LDN’s various mechanisms for improving disease symptomatology and quality of life, as well as review real world published studies and cases of LDN use in various autoimmune disorders.

Dermatological Inflammatory Diseases and LDN

by Nat Jones, RPh, FAPC, PCCA Clinical Compounding Pharmacist

LDN is growing in popularity in the dermatology world. It has proven to be beneficial for pruritus and inflammation due to its ability to attenuate toll-like receptors found in the skin. We’ll discuss two cases: one of a tattoo allergic reaction and one of hidradenitis suppurativa (HS). Tattoo reactions to the coloring agents can be intense and difficult to treat. HS is a chronic inflammatory, potentially scarring, skin disease primarily affecting apocrine gland-rich areas of the body (axillary, groin, perianal, perineal regions and abdominal folds), often mediating pain and considerable morbidity, both physical and psychological.

The Use of LDN in Veterinary Patients

by Katy Hecker, PharmD, PCCA Clinical Compounding Pharmacist

As pet owners, we lovingly share many things with our pets including treats, affection and half of the bed. Research suggests we also share similarities in physiological function, disease state manifestation and treatment modalities utilized. Join in the discussion and learn more about the science behind LDN for veterinary clinical indications including behavioral disorders, atopic dermatitis, osteoarthritis, cancer, inflammatory bowel disease (IBD) and more!

Perimenopause and Menopause Are Inflammatory Conditions: The Use of LDN for Hormones and Weight Loss

by Sara Hover, RPh, FAARM, PCCA Director of Clinical Services

Understanding the inflammatory processes that characterize perimenopause and menopause will shed light on how the hormonal changes contribute to weight gain and obesity. Central to this discussion is the shift in estrogen profiles — from estradiol, which possesses anti-inflammatory properties, to estrone, a pro-inflammatory estrogen that becomes predominant during menopause. This hormonal transition fosters an inflammatory state that can disrupt metabolism and promote adiposity. Additionally, the presentation will explore various options aimed at reducing inflammation and managing weight effectively. Key strategies include optimizing sleep quality, utilizing probiotics to support gut health and implementing LDN as an innovative therapeutic approach. Attendees will gain a comprehensive understanding of the biological mechanisms linking menopause to inflammation and weight gain, along with practical interventions to enhance health and well-being during this pivotal life stage.

Using LDN for Chronic Pain Conditions

by Tricia Heitman, PharmD, PCCA Clinical Compounding Pharmacist

LDN is gaining attention for its anti-inflammatory properties and its ability to manage pain and opioid addiction. By acting on the opioid receptors at lower doses, LDN enhances endorphin production, which can help reduce inflammation and alleviate pain associated with various conditions such as arthritis, fibromyalgia and autoimmune disorders. Many patients report significant relief from chronic pain and inflammation while taking LDN. We will discuss the appropriate doses and review the literature associated with LDN and pain.

LDN for Gut Inflammatory Disorders

by Ranel A. Larsen, PharmD, PCCA Clinical Compounding Pharmacist

LDN is emerging as a promising therapeutic option for enhancing gut health, particularly in the context of IBD and irritable bowel syndrome (IBS). LDN helps to regulate immune responses, improve epithelial barrier function and reduce inflammation within the gut, all of which are critical for maintaining intestinal homeostasis. In IBD, LDN may lower disease activity and enhance quality of life, while in IBS, it can alleviate symptoms such as pain and bloating. Overall, LDN's role in improving gut health underscores its therapeutic potential to support management of complex gastrointestinal disorders.

How to Market LDN Studies

by Mark Gonzalez, PharmD, PCCA Clinical Compounding Pharmacist

Today’s compounding pharmacist wanting to effectively market LDN to practitioners and patients has access to tools that were not as available 20 years ago when LDN started to become popular. Clinical studies, therapeutic reviews and case series are now readily available to substantiate what were once only theories on the effectiveness of naltrexone in autoimmune disorders. These studies span a wide array of specialties and medical conditions. Research groups such as the LDN Research Trust, publications such as the series of three LDN books and many of the clinical presentations given on the subject of LDN all reference these studies. The pharmacist and marketer must leverage the power of this data as part of their communication to both the practitioner and the patient they are marketing to. With the additional aid of social media, positive patient stories can accompany the data from these clinical studies to make for attractive and effective marketing.

Register for the Low-Dose Naltrexone One-Day Virtual Conference today and get more details — plus more information — on the potentials of LDN. We look forward to additional discussions and answering your questions!

A Personalized Approach to HRT for Perimenopausal Women

Thu, 14 Nov 2024 04:23:17 GMT

by Sara Hover, RPh, FAARM, PCCA Director of Clinical Services

Perimenopause is a unique phase in a woman’s life, marked by fluctuating hormones and a wide range of symptoms. Hormone replacement therapy (HRT) can offer relief, but a one-size-fits-all approach may not yield the best results. A personalized approach, tailored to each woman’s unique hormonal profile, lifestyle and symptoms, can make all the difference in managing this transition effectively. Let’s explore the factors that contribute to low estrogen, the role of cortisol and progesterone, and why a customized approach to HRT is essential for perimenopausal women.¹

Understanding Estrogen Levels in Perimenopause

Estrogen is a key hormone for various bodily functions, from reproductive health to mood regulation. During perimenopause, estrogen levels fluctuate and eventually decline when menopause is reached. Several factors can contribute to low estrogen levels during perimenopause.

First, the natural abatement of ovarian function plays a major role; as women approach menopause, ovarian follicles reduce in number and function, resulting in decreased estrogen production. Genetic predisposition can also influence estrogen levels, as some women have genetic factors that may lead to an earlier or more abrupt drop. Additionally, lifestyle factors, including diet, stress and physical activity levels, significantly impact estrogen. For instance, poor nutrition or extreme physical training can suppress estrogen production.² Another crucial factor is high cortisol levels. Chronic stress increases cortisol, which may inhibit the body’s ability to produce adequate estrogen.³

By identifying these factors, healthcare providers can develop a more precise treatment plan, addressing not only hormonal imbalances but also lifestyle factors that might be exacerbating symptoms. During perimenopause, women are still making estrogen — maybe in an erratic fashion — but identifying the cause of low estrogen is most important. We should not give estrogen until there is certainty that the patient has entered menopause. Keep in mind that the testing results are a one-time snapshot of that moment and results may vary over time.¹

The Role of Cortisol in Perimenopausal Health

Cortisol, often referred to as the “stress hormone,” is produced by the adrenal glands and plays a significant role in managing stress and regulating metabolism. For perimenopausal women, high cortisol levels can have several consequences. Elevated cortisol can lead to increased fatigue and mood swings, as it causes feelings of exhaustion, irritability and mood fluctuations. It also disrupts other hormones; high cortisol can hinder estrogen production, exacerbating symptoms like hot flashes, insomnia and night sweats.

Furthermore, cortisol impacts progesterone levels due to a phenomenon known as “pregnenolone steal.” Since cortisol production draws on the same hormonal precursor (pregnenolone) that produces progesterone, the body under stress prioritizes cortisol production over progesterone, potentially leading to imbalances.⁴ By managing cortisol levels through stress reduction techniques, exercise and lifestyle modifications, women can help balance their hormones and reduce the intensity of perimenopausal symptoms.

Progesterone: The Balancing Hormone

Progesterone plays a vital role in regulating estrogen, stabilizing mood, promoting restful sleep and reducing anxiety. During perimenopause, progesterone levels begin to decline as ovulation becomes irregular, leading to several potential challenges.

One significant issue is estrogen dominance; when progesterone is low, estrogen may dominate, resulting in symptoms such as weight gain, bloating, breast tenderness and mood swings. Progesterone also affects sleep and anxiety levels, as it has a calming effect on the brain. Low levels of progesterone may lead to sleep disturbances and heightened anxiety, making this transitional phase more challenging.⁵ In addition, progesterone supports bone health, so declining levels can impact bone density over time.⁶ Replenishing progesterone through bioidentical hormones or other supplements, as determined by a healthcare provider, can help mitigate these symptoms and maintain hormonal balance.

Benefits of a Personalized HRT Approach

A personalized HRT approach considers each woman’s unique hormonal profile, lifestyle factors and symptom severity. This approach offers several distinct advantages. First, targeted hormone support is possible by measuring hormone levels and monitoring symptoms, allowing health care providers to recommend specific combinations and dosages of estrogen, progesterone and other hormones based on individual needs.

Personalized HRT plans address underlying causes; beyond hormone therapy, they may include lifestyle and nutritional adjustments to address root causes such as high cortisol or low progesterone. Ultimately, a personalized approach enhances a woman’s quality of life by addressing a broad range of factors — from hormonal imbalances to lifestyle changes — so she can experience a smoother perimenopausal transition with improved energy, mood and sleep quality.

Perimenopause doesn’t have to be a time of discomfort and uncertainty. A personalized approach to HRT empowers women to navigate this transition with a clear, effective and safe plan. With proper guidance, perimenopausal women can regain control over their bodies, ensuring that their unique needs are met. Whether through bioidentical hormone therapy, lifestyle changes or stress management, each woman deserves an individualized strategy that supports her well-being through this important life stage.

PCCA members with clinical services access may contact our Clinical Services team to answer any questions about HRT and other compounding concerns.

References

Smith, P., What You Must Know About Women’s Hormones. 2nd. Ed. Garden City Park, NY: Square One Publishing, 2022.
Delamater L, Santoro N. Management of the Perimenopause. Clin Obstet Gynecol. 2018 Sep;61(3):419-432. doi: 10.1097/GRF.0000000000000389. Accessed 2024 at https://pubmed.ncbi.nlm.nih.gov/29952797/
Woods NF, Mitchell ES, Smith-Dijulio K. Cortisol levels during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women's Health Study. Menopause. 2009 Jul-Aug;16(4):708-18. Accessed 2024 at https://pubmed.ncbi.nlm.nih.gov/19322116/
Solano ME, Arck PC. Steroids, Pregnancy and Fetal Development. Front Immunol. 2020;10:3017. Published 2020 Jan 22. Accessed 2024 at https://pmc.ncbi.nlm.nih.gov/articles/PMC6987319/
Stefaniak M, Dmoch-Gajzlerska E, Jankowska K, et al. Progesterone and Its Metabolites Play a Beneficial Role in Affect Regulation in the Female Brain. Pharmaceuticals. 2023; 16(4):520. Accessed 2024 at https://pubmed.ncbi.nlm.nih.gov/37111278/
Mills EG, Yang L, Nielsen MF, et al. The Relationship Between Bone and Reproductive Hormones Beyond Estrogens and Androgens [published correction appears in Endocr Rev. 2021 Nov 16;42(6):872. doi: 10.1210/endrev/bnab024]. Endocr Rev. 2021;42(6):691-719. Accessed 2024 at https://pubmed.ncbi.nlm.nih.gov/33901271/

Backed by Science: Anhydrous VersaBase® HRT

Tue, 12 Nov 2024 14:48:13 GMT

At PCCA Science, we continuously build and grow scientific support for compounding and the technologies our members use in their practices. We test our bases using various methods before, during and after the release of a new product. We regularly submit results of these studies for publication in peer-reviewed journals and make them available to our members, who in turn can share them with prescribers, physicians and patients.

In Vitro Evaluation of the Percutaneous Absorption of Progesterone in Anhydrous Permeation-Enhancing Base Using the Franz Skin Finite Dose Model and Mass Spectrometry

What does the study say?

This study, published in the Archives of Dermatological Research, compares how well progesterone penetrates the skin in two topical formulations: one using Anhydrous VersaBase HRT and the second using a non-ionic cream. Results of the study showed that Anhydrous VersaBase HRT had a 3.2-fold increase in skin penetration over the non-ionic cream base, indicating it may be a good base to use in topical progesterone formulations.

Figure 1: The Anhydrous VersaBase HRT formulation offered a 3.2-fold increase in optical density (p = 0.029) for progesterone penetrating layers of skin compared to the non-ionic cream formulation.

What do the results of the study mean to prescribers and physicians?

Progesterone in a topical preparation using Anhydrous VersaBase HRT shows exceptional delivery of the hormone through the skin compared to the standard non-ionic cream base. It also indicates that the stability and potency of progesterone in the Anhydrous VersaBase HRT formulation was consistent for more than 180 days. Consistent hormone delivery is commonly recognized as achieving optimal prescriptive therapeutic outcomes for patients.

What do the results mean to patients?

The 180 beyond-use date (BUD) means patients will make fewer trips to the pharmacy for refills. Consistent hormone delivery may potentially help patients achieve a better therapeutic outcome.

What does anhydrous mean and why is that important?

Literally, anhydrous indicates a substance that contains no water. For compounded preparations, it means the water activity (Aw) — or the amount of available water in a substance — is less than 0.6 (<0.6). This is important because compounded preparations with Aw <0.6 do not support the growth of bacteria, yeast or molds.

Get a summary of study methods, images, graphs and more here.

*USP 795 establishes BUD limits by type of preparation in the absence of a USP−NF Compounded Preparation Monograph or CNSP-specific stability information.

Progesterone: Size Matters

PCCA offers USP-grade Special Micronized Progesterone with an unparalleled particle size to promote better bioavailability:

100% <9 microns
99% <5 microns
90% <2 microns

Additional Benefits

Consistently sourced from FDA-registered and GMP-compliant facilities
Tested in PCCA formulations in a range of concentrations
Above and beyond USP standards

Managing Menopausal Weight Gain: The role estrogen plays with GLP-1 agonists

Wed, 11 Sep 2024 13:27:35 GMT

by Katy Hecker, PharmD, PCCA Clinical Services

In a woman’s life, the absence of menstruation for 12 months marks the official beginning of menopause. Waning ovarian function coupled with declining circulating hormone levels spark natural menopause, but menopause may also occur as result of surgical procedures such as following a hysterectomy and/or oophorectomy. Commonly reported symptoms of menopause include hot flashes, night sweats, vaginal dryness, sleep disturbances, mood swings and weight gain,¹ with an estimated 70% of menopausal women experiencing weight gain.²

Menopause and Body Composition

Menopause triggers body composition changes such as increased abdominal adipose tissue and decreased lean muscle mass. This change in body composition intensifies the risk of diabetes, cardiovascular disease, dyslipidemia (abnormal levels of lipids in the blood) and metabolic dysfunction-associated steatotic (fatty) liver disease. Heart disease is the leading cause of death in women; therefore, it is critical to address menopausal weight gain and the cardiometabolic changes that occur. Hormone replacement therapy, lifestyle modification and in some instances medication therapy may be beneficial to help combat menopausal weight gain.^2,3

GLP-1 and Weight Loss

GLP-1 is a hormone naturally produced in the central nervous system, intestine and pancreas. It is released in response to the consumption of fats and carbohydrates.^2,4GLP-1 increases insulin secretion, decreases glucagon release, slows gastric emptying and reduces food intake. Research also suggests it may reduce food reward behavior. The appetite suppressing effect of GLP-1 is due to its action in the hypothalamus and brainstem. Interestingly, this is the same region of the brain responsible for the food intake reduction effects of estrogen. Glucagon-like peptide-1 (GLP-1) receptor agonist and dual agonist therapies are FDA-approved for the treatment of obesity, weight management, type 2 diabetes mellitus and cardiovascular mortality reduction.⁴

Semaglutide and Hormone Replacement Therapy

Combining hormone replacement therapy with semaglutide, a GLP-1 receptor agonist, may lead to better outcomes for total body weight loss and subsequent improvements in cardiometabolic health. A recent retrospective review compared weight loss response and cardiometabolic changes in post-menopausal women using semaglutide in combination with and without hormone therapy. At three, six, nine and 12 months following semaglutide initiation, women using hormone therapy experienced approximately 30% greater total body weight loss than the non-hormone therapy users. Both groups showed improvements in cardiometabolic health marked by lower fasting blood glucose, blood pressure, LDL, total cholesterol and triglycerides.²

Reward Eating, GLP-1 and Estrogen

Reward eating is comprised of two categories, “wanting” and “liking.”⁵ Liking is associated with the palatability of the food and wanting is food craving triggered by a cue or stimuli which then leads to motivation to obtain a specific type of food.⁴ Research suggests women may exert a greater response to a centrally administered long acting GLP-1 agonist on food reward due to the activation of central estrogen receptor alpha. This reduction was noted with the “wanting” subtype of reward eating in women greater so than men. A reduction in the “liking” subtype of reward eating was displayed in both men and women. Administration of an estrogen receptor antagonist was sufficient to blunt the effects of the central GLP-1 agonist on food reward behavior in both men and women. This evidence suggests the activation of central estrogen receptor alpha may be critical for central GLP-1 agonist’s effect on reward eating.^4,5

Compounded Medications

There are many treatment strategies that may help menopausal women with the natural challenges and health risks associated with this phase of life. Combining therapies has yielded compelling results, and compounded medications can be personalized to meet the needs of each patient, offering a unique solution for various medication related concerns. For example, SubMagnaTM SL HMW can be used to deliver semaglutide in a sublingual dosage form. This may improve adherence in patients who have trouble swallowing or who are fearful of needles.

Members with clinical services access may contact our Clinical Services Team for help with PCCA formulas and other compounding questions.

References

World Health Organization. Menopause [Internet]. Oct 2022. Accessed August 2024 at https://www.who.int/news-room/fact-sheets/detail/menopause
Hurtado MD, Tama E, Fansa S, et al. Weight loss response to semaglutide in postmenopausal women with and without hormone therapy use. Menopause. 2024;31(4):266-274. doi:10.1097/GME.0000000000002310
Centers for Disease Control. About Women and Heart Disease [Internet]. May 15, 2024. Accessed August 2024 at https://www.cdc.gov/heart-disease/about/women-and-heart-disease.html#:~:text=Heart%20disease%20is%20the%20leading,affect%20women%20at%20any%20age
Elsevier Clinical Pharmacology. Glucagon-like Peptide-1 (GLP-1) Receptor Agonists and Dual Agonists [Internet]. Apr 9, 2024. Accessed August 2024 at https://elsevier.health/en-US/preview/glucagon-like-peptide-1-glp-1-receptor-agonists
Richard JE, Anderberg RH, Lopez-Ferreras L, et al. Sex and estrogens alter the action of glucagon-like peptide-1 on reward. Biol Sex Differ. 2016;7:6. doi:10.1186/s13293-016-0059-9

Antiaging: Estrogen and a Woman’s Skin

Wed, 31 Jul 2024 16:09:00 GMT

Studies show how estrogen deficiency in women decreases skin firmness, impairs wound healing, increases the number and depth of wrinkles, and contributes to skin thinning and dryness.

by Chelsea Turner, PharmD Candidate, Clinical Services Intern, and Beau Harger, PharmD, PCCA Clinical Compounding Pharmacist/Training Instructor

Skin aging can simply be defined as changes to the skin that occur due to growing older.¹ Oftentimes, many think skin aging correlates with chronological age; however, skin aging actually correlates to the period of estrogen deficiency, especially in menopausal women.² Studies indicate both collagen atrophy and estrogen deficiency have implications on the skin’s elasticity and firmness, as well as wrinkles.³ Estrogen replacement therapy might be an answer for aging skin, as it can increase collagen content, dermal thickness and elasticity; stimulate connective-tissue turnover; and decrease the likelihood of dry skin.⁴

Estrogen’s Role

Estrogen has more than 400 functions in a woman’s body and manifestations of estrogen deficiency may appear in various ways. In menopausal and postmenopausal women, estrogen deficiency is evidenced by decreased skin firmness, impaired wound healing, increased number and depth of wrinkles, skin thinning and skin dryness.

An extremely important role of estrogen is its relationship with structural components — collagen and elastin fibers — that naturally occur in human skin.

The reduction of collagen is traditionally considered the principal factor in the progressive degeneration of skin elasticity; retaining estrogen levels, however, inhibits collagen degradation by helping to maintain collagen balance. Elastin fibers are another structurally important component of skin that help prevent accelerated degenerative changes in the dermis. Studies indicate topical estrogen increases the number and thickness of elastic fibers in the skin.

One of the most common complaints from older women regarding their skin is dryness. Healthy skin requires a substantial amount of water content, which is significantly impacted by a woman’s menstrual cycle and age. Clinical studies indicate topical estrogen therapy can lead to increased water capacity by increasing naturally occurring moisturizing factors such as hyaluronic acid.² The activity of sebaceous secretions is also very important, as their activity is regulated by levels of circulating hormones. Estrogen replacement alone has a sebum-suppressive effect, which can decrease the size and number of sebaceous glands; the addition of progesterone, however, results in increased skin surface lipids.⁵

Topical Estrogen Replacement

The number of estrogen receptors is much greater in facial skin than in breast or thigh skin.⁶ Topical estrogens, such as estriol, have improved both elasticity and firmness, as well as decreased wrinkle depth and pore size by 61–100 percent, when applied to the face and neck.⁷

Compounded preparations offer individualized treatment options for patients and can include a wide variety of active pharmaceutical ingredients. For example, a formula of a topical estrogen, such as estriol, could be prescribed by a practitioner and compounded with VersaBase Cream by a pharmacist to potentially prevent signs of aging in the skin and possibly minimize systemic effects. VersaBase Cream is a great option for application to the face and neck, as it stimulates the natural moisturizing barrier through its emulsion system, leaving a soft and silky feel. VersaBase Cream is noncomedogenic, hypoallergenic, nonirritating and odor-free.

PCCA members with clinical services access may contact our Clinical Services team for help with antiaging formulas and other compounding concerns.

References

Wong, Q. Y. A., & Chew, F. T. (2021). Defining skin aging and its risk factors: a systematic review and meta-analysis. Scientific reports, 11(1), 22075. Accessed July 2024 at https://pubmed.ncbi.nlm.nih.gov/34764376/
Brincat, M. P., Baron, Y. M., & Galea, R. (2005). Estrogens and the skin. Climacteric : the journal of the International Menopause Society, 8(2), 110–123. Accessed July 2024 at https://pubmed.ncbi.nlm.nih.gov/16096167/
Calleja-Agius, J., Muscat-Baron, Y., & Brincat, M. P. (2007). Skin ageing. Menopause international, 13(2), 60–64. Accessed July 2024 at https://pubmed.ncbi.nlm.nih.gov/17540135/
Calleja-Agius, J., & Brincat, M. P. (2009). Effects of hormone replacement therapy on connective tissue: why is this important?. Best practice & research. Clinical obstetrics & gynaecology, 23(1), 121–127. Accessed July 2024 at https://pubmed.ncbi.nlm.nih.gov/19095501/
Sator, P. G., Schmidt, J. B., Sator, M. O., Huber, J. C., & Hönigsmann, H. (2001). The influence of hormone replacement therapy on skin ageing: a pilot study. Maturitas, 39(1), 43–55. Accessed July 2024 at https://pubmed.ncbi.nlm.nih.gov/11451620/
Punnonen, R., Lövgren, T., & Kouvonen, I. (1980). Demonstration of estrogen receptors in the skin. Journal of endocrinological investigation, 3(3), 217–221. Accessed July 2024 at https://pubmed.ncbi.nlm.nih.gov/7430556/
Schmidt, J. B., Binder, M., Demschik, G., Bieglmayer, C., & Reiner, A. (1996). Treatment of skin aging with topical estrogens. International journal of dermatology, 35(9), 669–674. Int J Pharm Compd. 1998;2(4):270-274. Accessed July 2024 at https://pubmed.ncbi.nlm.nih.gov/8876303/

The Vaginal Microbiome, Menopause & HRT

Thu, 09 May 2024 03:38:07 GMT

Menopause causes more than hot flashes, mood swing and changes in libido; it also impacts diseases caused by shifting changes in the vaginal microbiome. Bridget Briggs, MD, sheds light on the vaginal microbiome, its influences on a woman’s health throughout various life stages, as well as how HRT helps mediate changes — and associated diseases — in the vaginal microbiome during menopause.

by Dr. Bridget Briggs, PCCA HRT Symposium Keynote Speaker

The vaginal microbiome (VM) is a complex ecological system that includes commensal, symbiotic and pathogenic organisms that inhabit the vaginal surfaces and its cavity. These organisms include bacteria, viruses and fungi.

The composition of organisms within the VM changes throughout the various stages of a woman’s life:

Childhood: Corynebacterium spp., Escherichia coli (E. coli), and Mycoplasma spp. form the vaginal microbiome.
Puberty: At puberty, the vaginal microbial niche shifts toward other predominant colonies, including Lactobacillus spp., Atopobium and Streptococcus spp.
Reproductive Ages: During reproductive age, the vaginal microbiome houses a range of bacterial communities, including lactobacilli (L. crispatus, L. gasseri, L. jensenii and L. iners) along with anaerobic bacteria.
Menopause: Further changes in the composition of the VM include Gardnerella vaginalis, Ureaplasma urealyticum, Candida albicans and Prevotella spp., with a progressive decrease in species of lactobacillus.

VM and Lactobacillus

The composition of the vaginal microbiome can vary widely between individuals. It influences a woman’s reproductive health, immune responses and overall wellbeing. Imbalance in the microbiome is linked to bacterial vaginosis (BV), thrush (a common yeast infection), urinary tract infections (UTIs) and influences fertility.

Lactobacillus species dominate in a healthy vagina and are associated with cervicovaginal health. Disruption of the microbial status quo — notably during menopause — is associated with disease. Hormone replacement therapy (HRT), however, has shown to improve the vaginal microbiome:

Vaginal estradiol (E2) tablets resulted in substantial changes in the VM and metabolome with a lowering in pH, particularly in women with high-diversity bacterial communities at baseline.
Low pH moisturizer or placebo did not significantly impact the vaginal microbiota or metabolome despite lowering the vaginal pH.
Estradiol use may offer additional genitourinary health benefits to postmenopausal women.
A small randomized clinical trial of a vaginal probiotic in postmenopausal women found short-term decreases in proinflammatory gene pathways with increased vaginal lactobacilli.
A 2020 study conducted on 228 premenopausal women suggested that daily administration of a vaginal dose of Lactobacillus crispatus, after treatment with vaginal metronidazole, can reduce recurrence of bacterial vaginosis after 12 weeks.¹

Menopause, VM and Urinary Health

Decrease in lactobacillus results in an elevated vaginal pH and higher microbial diversity. Decreased levels may also cause vaginal epithelium atrophy (thinning of the vaginal epithelium), dyspareunia (painful intercourse), dysuria (pain when urinating) and other genitourinary symptoms of menopause (GSM), due in part from the changes in the local microenvironment.

GSM affects approximately 50% of postmenopausal women. A 2013 cross-sectional study (n = 87) showed that women with signs of mild or moderate vulvovaginal atrophy (VVA) had greater odds of having highly diverse microbiota depleted of lactobacilli than microbiota dominated by L. crispatus when compared to women with no VVA.
Use of HRT in menopause indicates the reversion of lactic acid bacteria (LAB) microbial diversity to premenopausal levels; use of HRT has also shown not to increase the prevalence of bacterial vaginosis in postmenopausal women.
Postmenopausal women have been found to display significantly lower levels of free glycogen than premenopausal women.²

Benefits of Estriol

A study on the effect of ultra-low dose estriol vaginal tablets (0.03 mg) and Lactobacillus acidophilus compared to placebo was investigated in 87 postmenopausal women. The instillation of lactobacilli and ultra-low dose estriol was found to significantly improve the vulvovaginal symptoms in these women.

A second study was conducted on 60 postmenopausal women, who were randomly assigned to receive oral isoflavone alone, isoflavone plus probiotic or hormonal replacement therapy (1 mg estradiol and 0.5 mg norethisterone acetate). After 16 weeks, the hormonal therapy group showed an increased number of lactobacilli in the vagina, similar to that seen in premenopausal state, and a decrease in vaginal pH. Conversely, no change in pH value was found in the isoflavone group and isoflavone plus probiotic group.¹

Impact of Progesterone on the VM

DMPA injection reduced total bacterial load and abundance of Gardnerella vaginalis.
Localized progesterone contraceptive also reduced lactobacillus abundance.
Progesterone inhibits vaginal epithelium proliferation. Lack of epithelial-derived glycogen in a progesterone-enriched environment may reduce lactobacillus and other bacterial abundance.
Due to increased levels of endogenous estrogen and progesterone during pregnancy, the contributions of exogenous progesterone may be obscured in pregnant women.¹

Additional Influences

The intestinal microbiota have a role in shaping the vaginal microbiota. Both are formed throughout the stages of development and are influenced by lifestyle, use of antibiotics and hormones; both produce metabolites that help guide the immune system to be tolerogenic (producing immunological tolerance) or pro-inflammatory. The use of antibiotics can have long lasting negative impacts on a person’s microbiome and promote chronic disease development. Various forms of oral, vaginal or fecal transplanted probiotics can help to influence disease states.

Interested in learning more?

Attend the July 18-19 HRT Virtual Conference, Winning with Weight Loss, Detox and the Microbiome. This highly engaging symposium features a lineup of experts shaping the field of HRT — including: Dr. Briggs; Carrie Jones, ND; Pamela Smith, MD, MPH, MS; Daniel Banov, RPh, MS; Sara Hover, RPh, FAARM; and Ranel Larson, PharmD.

References

Auriemma, R.S., Scairati, R., del Vecchio, G., et al. (2021). The Vaginal Microbiome: A Long Urogenital Colonization Throughout Woman Life. Front. Cell. Infect. Microbiol. 11. Sec. Microbiome in Health and Disease. Accessed July 2021 at https://www.frontiersin.org/articles/10.3389/fcimb.2021.686167/full
Meštrović, T., Matijašić, M., Perić, M., et al. (2020). The Role of Gut, Vaginal, and Urinary Microbiome in Urinary Tract Infections: From Bench to Bedside. Diagnostics (Basel, Switzerland), 11(1), 7. Accessed December 2020 at https://pubmed.ncbi.nlm.nih.gov/33375202/

Decoding the Intricacies of Infertility

Wed, 24 Apr 2024 15:48:11 GMT

In recognition of National Infertility Awareness Week, April 21-27, PCCA Director of Clinical Services Sara Hover, RPh, FAARM, discusses how fertility is increasingly viewed as an indicator of overall health; how the intertwine of metabolic balance, hormone production and mitochondria impact fertility; as well as a way compounders can help those whose individual needs exceed commercially available medicines.

by Sara Hover, RPh, FAARM, PCCA Director of Clinical Services

In the complicated web of human biology, fertility stands as a vital sign, signaling the well-being of our reproductive health, as well as our overall health. Yet, behind the veil of conception lies a labyrinth of factors — from genetics to lifestyle — and even the most minute cellular processes. Infertility, a silent struggle for many, sheds light on the multifaceted nature of reproduction, intertwining with metabolic health, regulation of hormones — including estrogen and progesterone — mitochondrial function, as well as the important role that melatonin plays.

Fertility as a Vital Sign

Traditionally, vital signs such as heart rate, blood pressure and body temperature have served as indicators of overall health. However, fertility, often overlooked in routine medical assessments, is increasingly recognized as another crucial marker of well-being.¹ Heavy cramping is a red flag that there is a problem with nutrients, like magnesium, as well as a problem with the gut or hormonal imbalance.² While the ability to conceive may seem solely reproductive, it reflects broader physiological harmony within the body.

Reproduction and Metabolic Health

The interplay between reproductive health and metabolic well-being is profound. Research suggests that conditions such as obesity, insulin resistance and diabetes can significantly impact fertility. Metabolic imbalances disrupt hormonal equilibrium, impairing ovulation in women and sperm production in men.³Furthermore, excess adipose tissue can lead to the overproduction of estrogen, disrupting the delicate hormonal dance essential for conception.

Hormonal Balance

Estrogen and progesterone prepare the uterus for implantation. The changes that occur in the uterus have been termed endometrial receptivity. The window that is optimal for implantation of a fertilized egg is very narrow and for those patients with luteal phase defect — when the body prepares the uterus for pregnancy — the chances of being successful are greatly diminished.⁴Many women rely on progesterone to supplement the luteal phase of their cycle. Although there are many commercial product options, some may require a compounded prescription to meet their individual needs.

Adhering to the Vaginal Mucosa

Getting the hormone to adhere to the mucosal tissue is important, especially with progesterone and its need to maintain contact with the endometrium. One of our bases, MucoLox™ (PCCA #30-4782), is the perfect delivery vehicle because it adheres to the vaginal mucosal tissue, thereby increasing contact time with the mucosal surfaces. This makes it an ideal choice for use in vaginal compounded preparations.⁵

The Role of Mitochondria

Within the intricate machinery of cellular function, mitochondria emerge as powerhouse organelles crucial for energy production. Surprisingly, these tiny structures play a pivotal role in fertility. Mitochondria provide the energy needed for sperm motility, egg maturation and embryo development. Any compromise in mitochondrial function can undermine reproductive success, highlighting the intricate link between cellular health and fertility.^6,7

Mitochondria and Melatonin

Melatonin, often associated with sleep regulation, exerts profound effects on reproductive function. Emerging research suggests that melatonin receptors are present in the ovaries, testes and placenta, indicating involvement in reproductive processes. Moreover, melatonin's antioxidant properties safeguard reproductive cells from oxidative stress, essential for maintaining integrity and viability. Disruptions in melatonin signaling, whether due to sleep disturbances or environmental factors, can adversely affect fertility.^8-10

Putting It All Together

Infertility transcends mere reproductive challenges; it illuminates the intricate interplay between our bodies' myriad of systems. Understanding fertility as a vital sign underscores its significance in gauging overall health. From metabolic balance to mitochondrial function and the regulation of hormones like estradiol, progesterone and melatonin, every aspect of our physiology contributes to the delicate dance of conception. By unraveling the complexities of infertility, we pave the way for more holistic approaches to reproductive health, ensuring that every individual has the opportunity to embark on the journey of parenthood if desired.

References

Su, R.W., Fazleabas, A.T. (2015). Implantation and Establishment of Pregnancy in Human and Nonhuman Primates. Adv Anat Embryol Cell Biol.216:189-213. Accessed April 2024 at https://pubmed.ncbi.nlm.nih.gov/26450500/
Naraoka, Y., Hosokawa, M., Minato-Inokawa, S., et al. (2023). Severity of Menstrual Pain Is Associated with Nutritional Intake and Lifestyle Habits. Healthcare (Basel). 11(9):1289. Accessed April 2024 at https://pubmed.ncbi.nlm.nih.gov/37174831/
Marinelli, S., Napoletano, G., Straccamore, M., et al. (2022). Female obesity and infertility: outcomes and regulatory guidance. Acta Biomed. 93(4):e2022278. Accessed April 2024 at https://pubmed.ncbi.nlm.nih.gov/36043953/
Lessey, B.A., Young, S.L. (2019). What exactly is endometrial receptivity? Fertil Steril. 111(4):611-617. Accessed April 2024 at https://pubmed.ncbi.nlm.nih.gov/30929718/
PCCA Science. (2015). Evaluation of the Safety and Toxicological Profile of MucoLox: Human Oral Mucosa, Nasal Mucosa and Vaginal Mucosa (Part 3/3). PCCA Document #98929
Beikoghli, K.S., Kararigas G. (2022). Oestrogenic Regulation of Mitochondrial Dynamics. Int J Mol Sci. 23(3):1118. Accessed April 2024 at https://pubmed.ncbi.nlm.nih.gov/35163044/
May-Panloup, P., Chretien, M-F., Malthiery, Y., et al. (2007). Mitochondrial DNA in the Oocyte and the Developing Embryo. Curr Top Dev Biol. 77:51-83. Accessed April 2024 at https://www.sciencedirect.com/science/article/abs/pii/S007021530677003X?via%3Dihub
Reiter, R.J., Sharma, R., Romero, A,, et al. (2023). Aging-Related Ovarian Failure and Infertility: Melatonin to the Rescue. Antioxidants (Basel). 12(3):695. Accessed April 2024 at https://pubmed.ncbi.nlm.nih.gov/36978942/
Batıoğlu, A.S., Sahin, U., Gürlek, B., et al. (2012). The efficacy of melatonin administration on oocyte quality. Gynecol Endocrinol. 28(2):91-3. Accessed April 2024 at https://pubmed.ncbi.nlm.nih.gov/21770829/
Tamura ,H., Takasaki, A., Miwa, I., et al. (2008). Oxidative stress impairs oocyte quality and melatonin protects oocytes from free radical damage and improves fertilization rate. J Pineal Res. 44(3):280-7. Accessed April 2024 at https://pubmed.ncbi.nlm.nih.gov/18339123/

Advocate for Patients ACT Legislative Conference

Wed, 17 Apr 2024 22:49:16 GMT

by Amy Shank, PCCA Director of Government Affairs, and Claire Casey, PCCA Government and Public Affairs Specialist

Decision-makers who have met with compounding pharmacists in their districts and those who have toured a compounding pharmacy are more likely to understand the role of compounding in health care. To some, the compounding profession remains misunderstood. Compounders who tell their story — about their patients’ unique medical needs and their role and impact in the community — bridge this education gap.

The annual ACT Legislative Conference in Washington, D.C., is a key avenue for compounders to connect with their lawmaker and tell their story. Scheduled on May 14-15, 2024, registration remains open for PCCA member compounding pharmacists. Compounders will highlight two front-of-mind concerns.

Access to Compounded Hormones: Patients have relied on compounded hormones for decades when a manufactured product did not meet their medical need. This access is threatened due to recommendations by the National Academies of Sciences, Engineering and Medicine (NASEM)¹ that state commonly compounded hormones be considered for the FDA’s “difficult-to-compound” products list. If this proposal were fully implemented, patients from all backgrounds would face barriers in accessing therapies that include hormones such as progesterone, testosterone, estradiol and many more. Moreover, it would hinder prescribers and pharmacists from offering suitable treatment options to their patients when commercially available products don’t meet the patients’ needs.

A publication in Menopause² shows that there is more evidence available than what was identified and considered by the NASEM committee, and the evidence review process was not thorough — which casts doubt on these recommendations. Prescribers need all available treatment options for their patients.
Ensuring the Ability to Provide Informed Feedback to the FDA: Following enactment of the Drug Quality and Security Act (DQSA), the FDA has been utilizing guidance documents to enact regulatory framework. From prescription requirements for all human compounds to guidance on insanitary conditions at pharmacies, as well as guidance on medications compounded for animal patients — the FDA has used this guidance process to communicate regulatory directives, including guidelines used during the inspection process. Recently, the agency proposed to issue certain guidance documents “‘for immediate implementation’ without prior public participation.” This effectively eliminates the comment processes from guidance development — and may lead the FDA to implement policies that negatively impact patient safety, access to medical products and overall public health.

Pharmacists and pharmacy organizations want an avenue for meaningful dialogue and engagement with the agency, and maintaining an opportunity for a public comment period is critical to this effort. FDA should preserve and enhance its notice and comment process for guidance documents so they are appropriately informed by stakeholder insights and ultimately serve the best interests of public health. PCCA and compounders would like to be a continuing resource for all decision-makers. Our hope is for patient-centric policies that allow continued access to necessary and sometimes lifesaving compounded medications.

References

The National Academies of Sciences, Engineering and Medicine. (2020). The Clinical Utility of Compounded Bioidentical Hormone Therapy: A Review of Safety, Effectiveness, and Use. Accessed April 2024 at https://nap.nationalacademies.org/resource/25791/cBHT%20Recommendations%20Insert.pdf
Liu, Y., Yuan, Y., Day, A.J., Zhang, W., John, P., Ng, D.J., Banov, D. (2022). Safety and efficacy of compounded bioidentical hormone therapy (cBHT) in perimenopausal and postmenopausal women: a systematic review and meta-analysis of randomized controlled trials. Menopause 29(4); 465-482. Accessed April 2024 at https://journals.lww.com/menopausejournal/fulltext/2022/04000/safety_and_efficacy_of_compounded_bioidentical.13.aspx

Unraveling the Connection: VAT, Estradiol, Cognitive Health & Menopause

Wed, 17 Jan 2024 15:13:49 GMT

by Sara Hover, RPh, FAARM, PCCA Director of Clinical Services

In both men and women, the presence of VAT has been associated with an increased risk of compromised brain network structure and cognitive impairment. However, a fascinating discovery emerges when exploring the role of estradiol, a key female sex hormone, in mitigating the negative consequences of VAT, particularly in women during midlife.¹

Visceral Adipose Tissue and Cognitive Impairment

Visceral adipose tissue, the fat stored around internal organs, has long been implicated in various health conditions. Recent studies have uncovered its association with compromised brain network structure and cognitive decline. Both men and women with higher levels of VAT exhibit an increased risk of cognitive impairment, highlighting the importance of understanding the interplay between body composition and brain health.²

Women in Midlife: Accelerated Cognitive Aging and VAT

Notably, women during midlife face a unique set of challenges associated with changes in hormonal balance while transitioning into menopause. The presence of VAT during this phase has been linked to accelerated cognitive aging, possibly due to association with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. This suggests that the impact of VAT on cognitive function is particularly pronounced during the transition to menopause and the years that follow. Excess stress — and losing hormones is a stressor — can lead to metabolic changes resulting in weight gain. It has been noted that there is a significant relationship between the overactivity of the HPA axis and abdominal fat and/or metabolic syndrome. Chronic stress could lead to the development of obesity.³ VAT amplifies the negatives associated with age including cognitive health. It has been hypothesized that estradiol reduces the negative effects of VAT in women.

Estradiol's Protective Role Gets an A: Anti-Inflammatory, Anti-Apoptotic and Antioxidant

Amidst the concerning findings related to VAT and cognitive aging in women, the role of estradiol emerges as a potential protective factor. Estradiol, a form of estrogen, is known for its multifaceted functions in the female body. Research suggests that estradiol levels may play a crucial role in mitigating the negative consequences of VAT on brain structure and function.

First, it has been found that estradiol has anti-inflammatory properties. When women go through menopause, either naturally or surgically, many experience systemic inflammation. Neuroinflammation has negative effects on cognition.⁴ Estradiol is vasodilatory and thus promotes blood flow to the brain, therefore enhancing circulation. The delivery of oxygen and nutrients to the brain supports overall brain health. Another important function of estradiol is how it functions as an anti-apoptotic agent. Apoptosis, or programmed cell death, is a natural process in the body, but estradiol helps to prevent excessive cell death in the brain, preserving its integrity. Lastly, estradiol has antioxidant properties that help reduce oxidative damage to the brain. Oxidative stress is a common factor in age-related cognitive decline. Estradiol combats this to protect the brain.

Preserving Myelin Architecture: A Key Aspect of Cognitive Health

Myelin, the protective sheath around nerve fibers, is crucial for efficient neural communication. Research suggests that estradiol may play a vital role in preserving myelin architecture. This preservation is essential for maintaining the integrity of neural pathways and ensuring optimal cognitive function. Low-estrogen states, such as menopause, have long been recognized as a time where more women experience exacerbations of myelin-related diseases such as multiple sclerosis (MS).⁵ Therefore, estradiol’s role in protecting the myelin sheath has been the center of research in MS, but this research also has application for brain health and cognition.¹

Complex Interplay

The intersection of visceral adipose tissue, estradiol levels and cognitive health in women during midlife reveals a complex interplay with profound implications. VAT's association with compromised brain network structure and accelerated cognitive aging underscores the need for a holistic approach to health during this critical phase. The protective effects of estradiol, including vasodilation, anti-apoptosis and antioxidation, offer a ray of hope in understanding and potentially mitigating the cognitive consequences of VAT. As research continues to unfold, recognizing the importance of hormonal balance and lifestyle factors becomes paramount in promoting cognitive well-being, particularly for women navigating the intricate journey of midlife.

References

Zsido, R. G., Heinrich, M., Slavich, G. M., et al. (2019). Association of Estradiol and Visceral Fat With Structural Brain Networks and Memory Performance in Adults. JAMA network open, 2(6), e196126. Accessed January 2024 at https://doi.org/10.1001/jamanetworkopen.2019.6126
Anand S.S., Friedrich M.G., Lee D.S., et al. (2022) Evaluation of Adiposity and Cognitive Function in Adults. JAMA Netw Open. 5(2):e2146324. Accessed January 2024 at https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2788555
Vicennati, V., Pasqui, F., Cavazza, C., Pagotto, U., & Pasquali, R. (2009). Stress-related development of obesity and cortisol in women. Obesity (Silver Spring, Md.), 17(9), 1678–1683. Accessed January 2024 at https://doi.org/10.1038/oby.2009.76
Villa, A., Vegeto, E., Poletti, A., & Maggi, A. (2016). Estrogens, Neuroinflammation, and Neurodegeneration. Endocrine reviews, 37(4), 372–402. Accessed January 2024 at https://doi.org/10.1210/er.2016-1007
Christianson, M. S., Mensah, V. A., & Shen, W. (2015). Multiple sclerosis at menopause: Potential neuroprotective effects of estrogen. Maturitas, 80(2), 133–139. Accessed January 2024 https://doi.org/10.1016/j.maturitas.2014.11.013

GSM: A Common Symptom of Menopause

Wed, 10 May 2023 11:00:00 GMT

by Sara Hover, RPh, FAARM, PCCA Clinical Services Manager

Menopause, defined as the permanent cessation of menstruation (amenorrhea), is a natural part of aging. Perimenopause occurs prior to menopause and is caused by an erratic release of hormones. A woman is not considered menopausal until she experiences 12 consecutive months of amenorrhea.

One of the most common symptoms associated with menopause is genitourinary syndrome of menopause (GSM), more commonly known as vulvovaginal atrophy. GSM can vary from woman to woman and may include vaginal dryness, burning or itching, urinary issues, painful intercourse and decreased libido. These changes, which occur in the vaginal area, are most likely due to a lack of estrogen.¹

Estrogens and the Vaginal Microbiome

Estrogen — in particular estriol — plays an important role in maintaining the health of the vaginal microbiome, which contains microorganisms that normally inhabit the vaginal canal. These microorganisms, mainly lactobacilli, help maintain a healthy pH and protect against infection. The reduction in lactobacilli changes the vaginal environment to an alkaline pH of more than 5. The normal pH of vaginal tissue is 3.5-4.5.²

During menopause, the decrease in estrogen levels can lead to changes in the vaginal microbiome composition. The reduction of lactobacilli and the increase of other microorganisms may cause an imbalance, known as bacterial vaginosis (BV). BV is associated with an increased risk of urinary tract infections and sexually transmitted infections.³

Estrogens and the Vaginal Epithelium

Estrogens also play an important role in maintaining the health of the vaginal epithelium, which is the outer layer of cells that line the vaginal canal. The decrease in estrogen levels during menopause can lead to a thinning of the vaginal epithelium, making it more susceptible to infection and injury. Vaginal supportive tissues demonstrate a 75% decrease in collagen I, the major determinant of tissues’ tensile strength, in menopausal women compared with premenopausal women. Systemic estrogen therapy results in restoration of collagen I levels to the premenopausal state.⁴

Hormone therapy, which includes the use of estrogen in combination with progesterone, can help alleviate the symptoms of GSM. However, it is important to discuss the potential risks and benefits of hormone therapy with a healthcare provider.

The Base Matters

When choosing a compounding base for vaginal hormone therapy, make sure the base is nonirritating and has been tested for the delicate vaginal tissue. Also consider if the base has mucoadhesion properties, such as those in PCCA Ellage® Anhydrous Vaginal (PCCA #30-5110). Ellage offers longer contact times, which means hormones in the preparation adhere to the vaginal tissue longer. In addition, the properties of Ellage may help prevent leakage to a greater degree than bases without mucoadhesion.

Another factor to consider is ensuring hormones are released into the vaginal fluid without affecting the pH of the vagina. As previously mentioned, maintaining an appropriate pH helps support friendly microorganisms. PCCA Science conducted studies that show Ellage is nonirritating and incredibly gentle on mucosal tissue, providing a pleasant base for customized vaginal preparations.

GSM is a common condition that affects many women during menopause and some during perimenopause. The condition can cause discomfort, pain and may lead to an increased risk of infection. Estrogens play an important role in maintaining the health of the vaginal microbiome and epithelium, and hormone therapy can be an effective treatment option for women experiencing GSM symptoms. Consult with the prescribing physician and choose the right base to help women experiencing GSM.

Attention PCCA Members! Get additional information to help hormone therapy patients by signing up for the PCCA HRT Symposium, held in person and virtually, on July 13-15, 2023. Click to register.

References

Kim, H. K., Kang, S. Y., Chung, Y. J., et al. (2015). The Recent Review of the Genitourinary Syndrome of Menopause. J Menopausal Med. 21(2), 65–71. Accessed January 2023 at https://DOI.org/10.6118/jmm.2015.21.2.65
La Rosa, V. L., Ciebiera, M., Lin, L. T., Fan, S., et al. (2019). Treatment of genitourinary syndrome of menopause: the potential effects of intravaginal ultralow-concentration oestriol and intravaginal dehydroepiandrosterone on quality of life and sexual function. Prz Menopauzalny, 18(2), 116–122. Accessed January 2023 at https://DOI.org/10.5114/pm.2019.86836
Achondou, A. E., Fumoloh, F. F., Aseneck, A. C., et al. (2016). Prevalence of Bacterial Vaginosis Among Sexually Active Women Attending the CDC Central Clinic Tiko, South West Region, Cameroon. Afr J Infect Dis. 10(2), 96–101. Accessed January 2023 https://DOI.org/10.21010/ajid.v10i2.4
Alperin, M., Burnett, L., Lukacz, E., et al. (2019). The mysteries of menopause and urogynecologic health: clinical and scientific gaps. Menopause. 26(1), 103–111. Accessed January 2023 at https://DOI.org/10.1097/GME.0000000000001209

PCOS: More than Insulin Resistance

Wed, 09 Sep 2020 12:59:06 GMT

By Sara Hover, RPh, FAARM, PCCA Clinical Compounding Pharmacist

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age world-wide.¹ The diagnostic criteria have changed over the last several years and vary a bit for adolescents.² Therapeutic options for PCOS include medication, achieving hormone balance and lifestyle management. Treatment goals address the most prominent symptoms, including hirsutism, infertility and acne as well other issues related to insulin resistance.¹ Recently, links have been made between PCOS, hypothyroidism,³ periodontal disease⁴ and low vitamin D levels.⁵

I covered hirsutism in my blog post “ An Innovative Option for Hirsutism: Topical Meformin ,” so here I will discuss other comorbidities that can be addressed to help this patient population. The complicated pathophysiology of PCOS, which intertwines epigenetics and environmental factors, has yet to be completely illuminated. Current treatment revolves around managing symptoms.

Hormone Balance

Women with PCOS have many anovulatory cycles resulting in lower progesterone production. This lack of progesterone production creates an imbalance between estrogen and progesterone, resulting in endometrial hyperplasia, a condition where the endometrium becomes excessively thick. Women with PCOS-induced endometrial hyperplasia are more likely than women without PCOS to develop endometrial carcinoma.⁶ Therefore, it is prudent to monitor hormone levels and create proper balance between estradiol and progesterone. Life is about balance, after all. There are some studies showing that women with PCOS have an insensitivity to progesterone associated with elevated fasting insulin.⁷ Therefore, reducing insulin levels will promote progesterone functionality. This is just another example of the intertwining of the systems of the body.

Insulin Resistance

Insulin resistance is the most prominent metabolic consequence for PCOS patients, affecting nearly 70% of this population. When the insulin receptor is unresponsive to insulin, higher amounts of this hormone are required to send the same message. This results in increased production and release of insulin. Hyperinsulinemia (abnormally high blood insulin level) and insulin resistance are both also seen in lean PCOS patients, not just obese patients.⁸ Excess insulin can contribute to excess androgen production by direct stimulation of the ovarian theca cells. Hyperinsulinemia also leads to higher free testosterone by suppressing sex hormone binding globulin.⁹ Treating insulin resistance with medication and lifestyle changes can therefore have an incredible impact on PCOS.

Metformin has emerged as the prominent treatment choice in PCOS to reduce insulin resistance and lower insulin levels. The major drawback with metformin is the gastrointestinal side effects with the oral dosage form, including diarrhea, nausea, indigestion and abdominal pain.¹⁰ An alternative delivery method to avoid the stomach would be permeation-enhanced topical or vaginal administration. Pharmacy compounding may be a good choice in these instances where patients need customized medication options in various dosage forms.

Hypothyroidism

Subclinical hypothyroidism is frequently detected in PCOS patients. One of the cross functions of thyroid hormones is to act as an insulin agonist in muscle tissue and insulin antagonist in the liver. Therefore, if thyroid hormone is low, there would be an effect on glucose utilization and production. Thyroid hormone replacement in PCOS patients may also lead to a reduction in serum androgen level. In fact, some authors have considered insulin resistance to result from hypothyroidism.³ It could be hypothesized that the increased rate of infertility in PCOS could also be linked to decreased thyroid hormones. Finding the right balance of thyroid hormones can be tricky, though. Custom formulations of T4 (levothyroxine sodium) and T3 (liothyronine) or porcine thyroid hormone provide another tool in the prescriber’s toolbox to meet individual patient needs, and this is another particular area where pharmacy compounding may be able to help.

Periodontal disease

A recent review correlated a link between PCOS and periodontal disease, which is a chronic inflammatory condition that can cause destruction of the tissue that surrounds teeth.⁴ The risk of PCOS patients developing periodontal disease is inconclusive, but it is worth it for practitioners to be aware of the correlation. Dentists should be aware and monitor their patients for possible PCOS, and practitioners treating PCOS should question patients on their dental health. There are several dental preparations that can reduce gum inflammation and promote healing for gingival disease.

Vitamin D3

The relationship between vitamin D and PCOS is controversial but interesting. Current literature recognizes that Vitamin D is a hormone and is instrumental in immune system function while playing a role with certain disease states, such as Type 2 diabetes, cardiovascular disease and cancer. ^5,11 An underlying issue of all those disease states as well as PCOS is inflammation. Vitamin D has shown to inhibit the release of inflammatory cytokines, thereby reducing inflammation. Many observational studies have demonstrated that PCOS patients with a low vitamin D level had increases in body mass index, insulin resistance, testosterone and dehydroepiandrosterone.⁵ This information provides an opportunity for pharmacists to educate patients while providing a quality vitamin D3 supplement. Working with patients and providers to optimize vitamin D3 levels may therefore play a critical role in helping PCOS patients.

Many of the potential treatment options I’ve discussed in this article are specifically relevant to pharmacy compounding. Balancing hormones, compounding prescriptions in alternative dosage forms when commercial products do not meet patient needs, and helping them achieve optimal nutrition and lifestyle choices are all advantages of prescribers and patients working closely with compounding pharmacists. Pharmacies looking for supplements to offer their patients might consider Wellness Works, which carries professional-grade vitamin D3 softgels (5,000 IU). PCCA members with Clinical Services access can also find some examples of commonly requested compounding formulas in our database that may be relevant to discuss with practitioners concerning these patients. If they have questions about compounding for patients with PCOS, they can contact our clinical compounding pharmacists at 800.331.2498.

Sara Hover, RPh, FAARM, has been a compounding pharmacist for over 20 years and joined the PCCA Clinical Services team in June 2013. Before joining the PCCA staff, she was the owner and pharmacist of Creative Compounds in Prosper, Texas, an independent, compounding-only pharmacy that focused on women’s health and nutrition. In addition to her expertise in hormone replacement therapy, Sara possesses a vast knowledge of homeopathics as well as herbal and vitamin supplements. Sara obtained her Bachelor of Science degree from the University of Texas at Austin in 1994. She is a lifetime member of the University of Texas College of Pharmacy Alumni Association.

Photo by Clarisse Meyer on Unsplash.

References

1. Witchel, S. F., Oberfield, S. E., & Peña, A. S. (2019). Polycystic ovary syndrome: Pathophysiology, presentation, and treatment with emphasis on adolescent girls. Journal of the Endocrine Society, 3 (8), 1545–1573. https://doi.org/10.1210/js.2019-00078

2. Tehrani, F. R., & Amiri, M. (2019). Polycystic ovary syndrome in adolescents: Challenges in diagnosis and treatment.International Journal of Endocrinology & Metabolism, 17(3). https://dx.doi.org/10.5812%2Fijem.91554

3. Fatima, M., Amjad, S., Ali, H. S., Sr., Ahmed, T., Kahn, S., Raza, M., & Inam, M. (2020). Correlation of subclinical hypothyroidism with polycystic ovary syndrome (PCOS). Cureus, 12(5). https://dx.doi.org/10.7759%2Fcureus.8142

4. Machado, V., Escalda, C., Proença, L., Mendes, J. J., & Botelho, J. Is there a bidirectional association between polycystic ovarian syndrome and periodontitis? A systematic review and meta-analysis. Journal of Clinical Medicine, 9(6). https://dx.doi.org/10.3390%2Fjcm9061961

5. Wang, L., Lv, S., Li, F., Yu, X., Bai, E., & Yang, X. (2020). Vitamin D deficiency is associated with metabolic risk factors in women with polycystic ovary syndrome: A cross-sectional study in Shaanxi China. Frontiers in Endocrinology, 11. https://dx.doi.org/10.3389%2Ffendo.2020.00171

6. Li, X., Feng, Y., Lin, J.-F., Billig, H., & Shao, R. (2014). Endometrial progesterone resistance and PCOS. Journal of Biomedical Science, 21(1). https://dx.doi.org/10.1186%2F1423-0127-21-2

7. Blank, S. K., McCartney, C. R., Chhabra, S., Helm, K. D., Eagleson, C. A., Chang, R. J., & Marshall, J. C. (2009). Modulation of gonadotropin-releasing hormone pulse generator sensitivity to progesterone inhibition in hyperandrogenic adolescent girls — Implications for regulation of pubertal maturation.The Journal of Clinical Endocrinology & Metabolism, 94(7), 2360–2366. https://doi.org/10.1210/jc.2008-2606

8. Sanchez-Garrido, M. A., & Tena-Sempere, M. (2020). Metabolic dysfunction in polycystic ovary syndrome: Pathogenic role of androgen excess and potential therapeutic strategies. Molecular Metabolism, 35. https://doi.org/10.1016/j.molmet.2020.01.001

9. Marshall, J. C., & Dunaif, A. (2012). Should all women with PCOS be treated for insulin resistance? Fertility and Sterility, 97(1), 18–22. https://doi.org/10.1016/j.fertnstert.2011.11.036

10. Metformin. (2020). In Clinical Pharmacology. Retrieved from http://clinicalpharmacology-ip.com/Forms/drugoptions.aspx?cpnum=379&t=0

11. Norman, A. W. (2008). From vitamin D to hormone D: Fundamentals of the vitamin D endocrine system essential for good health. The American Journal of Clinical Nutrition, 88(2), 491S–499S. https://doi.org/10.1093/ajcn/88.2.491S

These statements are provided for educational purposes only. They have not been evaluated by the Food and Drug Administration, and are not to be interpreted as a promise, guarantee or claim of therapeutic efficacy or safety. The references cited did not necessarily evaluate PCCA products or formulas included in these statements. The information contained herein is not intended to replace or substitute for conventional medical care, or encourage its abandonment.

Oral vs. Topical Estrogen: What the Literature Is Showing about Health Risk (Part Two)

Wed, 13 Nov 2019 14:48:00 GMT

By Pamela W. Smith, MD, MPH, MS; Nat Jones, RPh, FIACP, PCCA Clinical Compounding Pharmacist; and Sara Hover, RPh, FAARM, PCCA Clinical Compounding Pharmacist

In the first part of this article, we introduced some new information that is important to consider for patients who need bioidentical hormone replacement therapy (BHRT). Recent medical literature is shedding more light on the risk of venous thromboembolism (VTE) associated with estrogen and how the route of administration can affect its likelihood. Specifically, we reviewed what the literature is showing and discussed compounded sublingual and buccal estrogen. Here, we will continue the discussion further with compounded topical estrogen.

Compounded Topical Estrogen
In addition to sublingual and buccal estrogen, another common route for compounded hormone replacement is topical. Many times, the terms “topical” and “transdermal” are used interchangeably. Strictly speaking, topical refers to the delivery of a drug into the skin to treat a dermal disorder, with the skin as the target tissue. In contrast, transdermal, or percutaneous, absorption refers to the delivery of a drug through the skin for systemic effect. However, we often refer to BHRT compounds as topical because they are topically applied. So when we talk about topical BHRT here, these compounds are intended for hormone delivery through the skin.

There are many factors to consider with absorption through the skin: physical and chemical properties of the drug, molecular weight, solubility, partition coefficient and dissociation constant, the nature of the carrier vehicle, and the condition of the skin. With hormones, the most important factors are the molecular weight and the vehicle or base.

The low molecular weight of hormones definitely lends them to topical delivery as an excellent option. However, we also have to consider the size of the drug particle. When a drug is reduced to a number of smaller particles, or micronized, the total surface area is greater, which results in an increased rate of dissolution. As Allen and Ansel point out, “Due to the different rates and degrees of absorption obtainable from drugs of various particle size, it is conceivable that products of the same drug substance prepared by two or more reliable pharmaceutical manufacturers may result in different degrees of therapeutic response in the same individual.”¹ In other words, the particle size of a hormone can make a clinical difference, so it’s an important consideration in compounding for BHRT.

The base of the compounded preparation is also critical. The type of base and permeation enhancers used can affect absorption of hormones, and the delivery system must be able to release the drug in a reproducible way. As we mentioned in part one, hormones are lipophilic, and a good base will enhance their diffusion through the stratum corneum.¹ In-depth discussion of the importance of a proper base is outside the scope of this article, but we mention this aspect of hormone absorption to stimulate thought.

The main advantage of topical administration is bypassing the first-pass effect.² Estrogen that is absorbed orally passes through the portal vein into the liver, where it is heavily conjugated before being released into the systemic circulation, which may account for the negative effects we listed in the first part of this article. Since this is only seen with oral administration, it is reasonable to hypothesize that this is related to first-pass hepatic metabolism.

One of the disadvantages of topical delivery is the potential for transference to family members and pets. Therefore, compounders should counsel their patients to be aware of contact with others and identify areas to apply creams that will minimize exposure to others. Another perceived disadvantage to topical hormone delivery relates to the limitations of different types of lab testing. The gold standard is serum testing, for example, but topical hormone application does not typically show up in blood serum results. It shows in the saliva. We could write an entire book explaining and debating the differences between serum testing and saliva testing. Each type of testing is looking at a specific compartment of the body and provides different information. We will leave this topic for a future article. Despite the disadvantages of transference or the debate over testing, topical delivery of estrogen is a practical, proven compounding option, and as we have seen in this article, it is safer than oral delivery for postmenopausal women.

The risk of VTE is a very important consideration for choosing the route of estradiol administration, and being cognizant of the possibility of oral absorption from other dosage forms, such as troches, is an important factor to be aware of as well. While a certain type of compound may be popular, the risk of potential harm must take precedence over convenience when making a dosage form recommendation. Consequently, after review of the medical literature, topically applied estrogen is the only form of estrogen replacement that we recommend for a postmenopausal woman.

Pamela W. Smith, MD, MPH, MS, spent 20 years as an emergency room physician with the Detroit Medical Center and then 24 years as an anti-aging/functional medicine specialist. She is a diplomat of the Board of the American Academy of Anti-Aging Physicians and is an internationally known speaker and author on the subject of metabolic, anti-aging and personalized medicine. She has been featured on CNN, PBS and many other television networks; has been interviewed in numerous consumer magazines; and has hosted two of her own radio shows. She is currently the Director of the Center for Personalized Medicine and the founder of The Fellowship in Anti-Aging, Regenerative, and Functional Medicine. Dr. Smith is also the co-director of the Master’s Program in Metabolic and Nutritional Medicine at the Morsani College of Medicine, University of South Florida. Additionally, she is the Director of Medical Education for the American Academy of Anti-Aging Medicine. She is the author of the best-selling books HRT: The Answers, What You Must Know about Women’s Hormones, and many others.

Nat Jones, RPh, FIACP, graduated from the Virginia Commonwealth University, Medical College of Virginia’s School of Pharmacy in 1979. In 2014, after 20 years of owning a compounding pharmacy, he joined PCCA’s staff. Nat has given continuing education lectures at medical professional seminars and webinars on numerous topics, including general compounding, wound care, pain management, nutrition, otolaryngology, women’s health, sexual dysfunction, insulin resistance, hormone replacement therapy, neurotransmitter imbalance and dermatology. He has published many articles and case studies in magazines and professional journals along with an open-access ebook titled Advances in Psoriasis with Avid Science. Since 2016, Nat has served on the Texas State Palliative Care Interdisciplinary Advisory Council.

A version of this article originally appeared in PCCA’s members-only magazine, the Apothagram.

References
1. Allen, L. V., Jr., & Ansel, H. C. (2013). Ansel's pharmaceutical dosage forms and drug delivery systems (10th ed.). Baltimore, MD: Lippincott Williams & Wilkins.
2. Goodman, M. P. (2012). Are all estrogens created equal? A review of oral vs. transdermal therapy. Journal of Women’s Health, 21(2), 161–169. https://doi.org/10.1089/jwh.2011.2839

Oral vs. Topical Estrogen: What the Literature Is Showing about Health Risk (Part One)

Mon, 11 Nov 2019 17:06:00 GMT

By Pamela W. Smith, MD, MPH, MS; Nat Jones, RPh, FIACP, PCCA Clinical Compounding Pharmacist; and Sara Hover, RPh, FAARM, PCCA Clinical Compounding Pharmacist

Compounded bioidentical hormone replacement therapy (BHRT) is an important treatment option for women around the world. Colleagues and patients alike come to us for guidance about this, and our recommendations should be based in part on knowledge about the available delivery options and their impact on safety. In the area of BHRT, some new information has come to light in medical literature that is important to consider for patients. Therefore, we would like to review the risk of venous thromboembolism (VTE) associated with estrogen and how the route of administration can affect its likelihood. In the first part of this article, we will review what the literature is showing and discuss compounded sublingual and buccal estrogen. In the second part of this article we will discuss compounded topical estrogen.

VTE is a general term for a blood clot that forms in a vein. This can manifest as a deep vein thrombosis, where the clot forms in a deep vein of the leg, pelvis or arm.¹ VTE also encompasses pulmonary embolism, which is when a blood clot reaches the lungs.² According to the Centers for Disease Control and Prevention, these “are often underdiagnosed and serious, but preventable medical conditions” that can result in “serious illness, disability, and in some cases, death.”¹ Symptoms of deep vein thrombosis include redness of the skin in the affected area as well as swelling, pain and tenderness to the touch. Pulmonary embolism symptoms include low blood pressure, lightheadedness, fainting, difficulty breathing, fast or irregular heartbeat, chest pain, or even coughing blood. Both conditions are treatable through immediate medical care.¹ There are many risk factors for VTE, including recent surgery, long periods of immobilization and family history, among others.²

What the Literature Says
In recent years, there has been an enormous amount of discussion in the medical literature about estrogen and its route of administration for hormone replacement therapy. The overwhelming evidence has shown that oral estrogen replacement increases the risk of VTE in postmenopausal women with no previous thromboembolic events. Comparatively, non-oral estrogen use did not significantly affect their risk.

In the medical literature examining the relationship between VTE and hormone replacement in menopausal women, the route of administration has been primarily oral. However, studies have revealed that oral estrogen therapy may exert a prothrombotic effect through hepatic induction.^3,4 This is conceivably related to high concentrations of estrogen in the liver due to the liver’s “first-pass” effect. Likewise, a recent study revealed that compared with no hormone therapy, use of oral estradiol was associated with excess risk of VTE. In contrast, use of transdermal estradiol (most commonly used as a patch) was not associated with excess risk of VTE. In addition, the study authors concluded that “transdermal treatment appears to be underused, with the overwhelming preference still for oral preparations.”⁵

Furthermore, in addition to an increase in prothrombotic effects, studies have shown that oral estrogen use is related to other possible side effects^6–16:

Increase in blood pressure
Increase in triglycerides
Increase in estrone
Increase in occurrence of gallstones
Increase in liver enzymes
Increase in sex hormone binding globulin, which lowers available testosterone for the body to use
Interruption of tryptophan metabolism and consequently serotonin metabolism
Lower growth hormone levels
Increase in C-creative protein
Increase in carbohydrate cravings

Other medical trials that have compared oral and transdermal estrogen replacement also discovered that transdermally administered estrogen has little or no effect in increasing prothrombotic substances. Furthermore, transdermal estrogen may have beneficial effects on proinflammatory markers (such as C-reactive protein and prothrombin activation peptide) as well as antithrombin activity. It may have a suppressive effect on tissue plasminogen activator antigen and plasminogen activator inhibitor activity in contrast to oral estrogen as well, which would also be beneficial in many cases.^4,14,17–20

Other study authors also examined the risk of transdermal estrogen use compared to patients that did not use hormone replacement therapy and showed that there was no increased risk compared to nonusers.^21–25 Some research also suggested that transdermal estrogens may substantially improve the benefit/risk ratio of postmenopausal hormone therapy and should be considered as a safer option, especially for women at high risk for VTE.²¹ In fact, other studies revealed that women who were overweight⁸ and women who had prothrombotic mutations also had no increased risk of thrombosis with transdermal estrogen replacement therapy.²⁶

Lastly, researchers have also investigated whether patients with a previous thromboembolism, family history of thromboembolism or prothrombotic mutation could take estrogen replacement therapy. The studies revealed that the above were a strong contraindication to oral hormone replacement therapy, but transdermal estrogen could be considered after careful individual evaluation of the benefits and risks. Furthermore, these studies suggested that transdermal estrogen should also be the first choice for overweight and obese women requiring hormone replacement therapy.^27,28

Compounded Sublingual and Buccal Estrogen
When considering compounded estrogen delivery, there are several choices. The list includes multiple dosage forms, and two of the most common provide sublingual or buccal delivery and topical delivery (with or without permeation enhancement). While vaginal/labial applications, injections and pellets are also treatment options, we are going to focus on the more common ones.

Sublingual and buccal delivery are similar and often used in medicine for patients who either can’t swallow a solid dosage form or for specific medical reasons, such as hyperemesis (severe nausea and vomiting). Sublingual administration involves placing medication under the tongue to absorb through the mucosa into the bloodstream. Buccal administration involves placing a medication between the gum and the cheek, where it absorbs through the mucosa and into the bloodstream. Absorption is generally considered rapid and efficient, and these routes avoid first-pass metabolism, though many dosage forms that are intended for sublingual or buccal delivery commonly also allow oral intake through normal salivary action. Sublingual absorption occurs in part through the ventral surface of the tongue or the floor of the mouth into the reticulated vein. The main mechanism for the absorption of a drug into oral mucosa is via passive diffusion into the lipoidal membrane.

The sublingual area is more permeable than the buccal area, which is more permeable than the palatal area (top of the mouth). These differences are generally related to the relative thickness, blood supply and degree of keratinization of these membranes. For a drug to be absorbed completely through the sublingual route, it must have slightly higher lipid solubility for passive permeation, and luckily, estrogens are lipophilic (fat soluble).²⁹Notably, sublingual BHRT seems to be effective in reducing vasomotor, mood and quality-of-life symptoms experienced in postmenopausal women.³⁰

While compounders have prepared sublingual hormone drop formulas for years,³¹ troches are the most popular sublingual and buccal dosage form for BHRT. There is a lot of older pharmacokinetic data published on sublingual use from manufactured oral estradiol tablets.^32–34 This data clearly shows sublingual administration resulted in rapid absorption with significantly higher estradiol levels than did comparable oral dosing, and these increased levels fell rapidly over the first six hours, indicating the need for multiple daily doses considering the half-life of oral estradiol is approximately one to two hours at steady state. There are no similar pharmacokinetic studies for comparable compounded dosage forms (rapid dissolve tablets or tablet triturates), but assuming extremely close dissolution times, one could expect similar outcomes.

Even though sublingual and buccal absorption of estrogen is relatively rapid, troches dissolve more slowly than tablets (from 20 minutes to an hour depending on the formulation). Additionally, more than 50% of the troche is swallowed by the normal mechanism of saliva formation, and the remainder is absorbed transmucosally.³⁵ Because over half of the troche is swallowed, prescribers and compounders must be aware that estrogens given in this manner may have a similar risk of VTE as oral administration, and we therefore do not recommend estrogen troches for postmenopausal women.

Pamela Wartian Smith, MD, MPH, MS, spent 20 years as an emergency room physician with the Detroit Medical Center and then 24 years as an anti-aging/functional medicine specialist. She is a diplomat of the Board of the American Academy of Anti-Aging Physicians and is an internationally known speaker and author on the subject of metabolic, anti-aging and personalized medicine. She has been featured on CNN, PBS and many other television networks; has been interviewed in numerous consumer magazines; and has hosted two of her own radio shows. She is currently the Director of the Center for Personalized Medicine and the founder of The Fellowship in Anti-Aging, Regenerative, and Functional Medicine. Dr. Smith is also the co-director of the Master’s Program in Metabolic and Nutritional Medicine at the Morsani College of Medicine, University of South Florida. Additionally, she is the Director of Medical Education for the American Academy of Anti-Aging Medicine. She is the author of the best-selling books HRT: The Answers, What You Must Know about Women’s Hormones, and many others.

A version of this article originally appeared in PCCA’s members-only magazine, the Apothagram.

References
1.   Centers for Disease Control and Prevention. (2019). What is venous thromboembolism? Retrieved from https://www.cdc.gov/ncbddd/dvt/facts.html
2.   National Heart, Lung, and Blood Institute. (n.d.). Venous thromboembolism. Retrieved from https://www.nhlbi.nih.gov/health-topics/venous-thromboembolism
3.   Nabulsi, A. A., Folsom, A. R., White, A., Patsch, W., Heiss, G., Wu, K. K., & Szklo, M. (1993). Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women. The New England Journal of Medicine, 328(15), 1069–1075. https://doi.org/10.1056/NEJM199304153281501
4.   Lowe, G. D., Upton, M. N., Rumley, A., McConnachie, A., O’Reilly, D. S., & Watt, G. C. (2001). Different effects of oral and transdermal hormone replacement therapies on factor IX, APC resistance, t-PA, PAI and C-reactive protein — A cross-sectional population survey. Thrombosis and Haemostasis, 86(2), 550–556.
5.   Vinogradova, Y., Coupland, C., & Hippisley-Cox, J. (2019). Use of hormone replacement therapy and risk of venous thromboembolism: Nested case-control studies using the QResearch and CPRD databases. The BMJ, 364.https://doi.org/10.1136/bmj.k4810
6.   Smith, P. (2010). What you must know about women’s hormones. Garden City Park, NY: Square One Publishing, 2010.
7.   Ballagh, S. A. (2005). Vaginal hormone therapy for urogenital and menopausal symptoms. Seminars in Reproductive Medicine, 23(2), 126–140. https://doi.org/10.1055/s-2005-869480
8.   Canonico, M., Oger, E., Conard, J., Meyer, G., Lévesque, H., Trillot, N., … Scarabin, P. Y. (2006). Obesity and risk of venous thromboembolism among postmenopausal women: Differential impact of hormone therapy by route of estrogen administration. The ESTHER Study. Journal of Thrombosis and Haemostasis, 4(6), 1259–1265. https://doi.org/10.1111/j.1538-7836.2006.01933.x
9.   Chetkowski, R. J., Meldrum, D. R., Steingold, K. A., Randle, D., Lu, J. K., Eggena, P., … Judd, H. L. (1986). Biologic effects of transdermal estradiol. The New England Journal of Medicine, 314(25), 1615–1620. https://doi.org/10.1056/NEJM198606193142505
10.   Pansini, F., Bergamini, C. M., Bonaccorsi, G., Breveglieri, P., Calisesi, M., Valpondi, V., … Mollica, G. (1990). Control of carbohydrate metabolism in menopausal women receiving transdermal estrogen therapy. Annals of the New York Academy of Sciences, 592(1), 460–462. https://doi.org/10.1111/j.1749-6632.1990.tb30374.x
11.   Scarabin, P. Y., Alhenc-Gelas, M., Plu-Bureau, G., Taisne, P., Agher, R., & Aiach, M. (1997). Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Arteriosclerosis, Thrombosis, and Vascular Biology, 17(11), 3071–3078. https://doi.org/10.1161/01.atv.17.11.3071
12.   Vehkavaara, S., Silveira, A., Hakala-Ala-Pietilä, T., Virkamäki, A., Hovatta, O., Hamsten, A. … Yki-Järvinen, H. (2001). Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women. Thrombosis and Haemostasis, 85(4), 619–625.
13.   Vongpatanasin, W., Tuncel, M., Mansour, Y., Arbique, D., & Victor, R. G. (2001). Transdermal estrogen replacement therapy decreases sympathetic activity in postmenopausal women. Circulation, 103(24), 2903–2908. https://doi.org/10.1161/01.cir.103.24.2903
14.   Folsom, A. R., Lutsey, P. L., Astor, B. C., & Cushman, M. (2009). C-reactive protein and venous thromboembolism. A prospective investigation in the ARIC cohort. Thrombosis and Haemostasis, 102(4), 615–619. https://doi.org/10.1160/TH09-04-0274
15.   Rovinski, D., Ramos, R. B., Fighera, T. M., Casanova, G. K., & Spritzer, P. M. (2018). Risk of venous thromboembolism events in postmenopausal women using oral versus non-oral hormone therapy: A systematic review and meta-analysis. Thrombosis Research, 168, 83–95. https://doi.org/10.1016/j.thromres.2018.06.014
16.   Lissett, C. A., & Shalet, S. M. (2003). The impact of dose and route of estrogen administration on the somatotropic axis in normal women. The Journal of Clinical Endocrinology & Metabolism, 88(10), 4668–4672. https://doi.org/10.1210/jc.2003-022036
17.   Post, M. S., Christella, M., Thomassen, L. G., van der Mooren, M. J., van Baal, W. M., Rosing, J., … Stehouwer, C. D. (2003). Effect of oral and transdermal estrogen replacement therapy on hemostatic variables associated with venous thrombosis: A randomized, placebo-controlled study in postmenopausal women. Arteriosclerosis, Thrombosis, Vascular Biology, 23(6), 1116–1121. https://doi.org/10.1161/01.ATV.0000074146.36646.C8
18.   Margarido, P. F., Bagnoli, V. R., Maggio da Fonseca, A., Maciel, G. A., Soares, J. M., Jr., D’Amico, E. A., & Baracat, E. C. (2011). Transdermal estrogen therapy effects on fibrinogen levels in women with a past history of venous thromboembolism: A pilot study. Clinical and Experimental Obstetrics & Gynecology, 38(3), 232–235.
19.   Oger, E., Alhenc-Gelas, M., Lacut, K. Blouch, M. T., Roudaut, N., Kerlan, V., … Mottier, D. (2003). Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: A randomized trial. Arteriosclerosis, Thrombosis, and Vascular Biology, 23(9), 1671–1676. https://doi.org/10.1161/01.ATV.0000087141.05044.1F
20.   Eilertsen, A. L., Høibraaten, E., Os, I., Andersen, T. O., Sandvik, L., & Sandset, P. M. (2005). The effects of oral and transdermal hormone replacement therapy on C-reactive protein levels and other inflammatory markers in women with high risk of thrombosis. Maturitas, 52(2), 111–118.https://doi.org/10.1016/j.maturitas.2005.01.004
21.   Olié, V., Canonico, M., & Scarabin, P. Y. (2010). Risk of venous thrombosis with oral versus transdermal estrogen therapy among postmenopausal women. Current Opinion in Hematology, 17(5), 457–463. https://doi.org/10.1097/MOH.0b013e32833c07bc
22.   Minkin, M. J. (2004). Considerations in the choice of oral vs. transdermal hormone therapy: A review. The Journal of Reproductive Medicine, 49(4), 311–320.
23.   Laliberté, F., Dea, K., Duh, M. S., Kahler, K. H., Rolli, M., & Lefebvre, P. (2011). Does the route of administration for estrogen hormone therapy impact the risk of venous thromboembolism? Estradiol transdermal system versus oral estrogen-only hormone therapy. Menopause, 18(10), 1052–1059. https://doi.org/10.1097/gme.0b013e3182175e5c
24.   Renoux, C., Dell’aniello, S., Garbe, E., & Suissa, S. (2010). Transdermal and oral hormone replacement therapy and the risk of stroke: A nested case-control study. The BMJ, 340.https://doi.org/10.1136/bmj.c2519
25.   Scarabin, P. Y., Oger, E., & Plu-Bureau, G. (2003). Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. The Lancet, 362(9382), 428–432. https://doi.org/10.1016/S0140-6736(03)14066-4
26.   Straczek, C., Oger, E., Yon de Jonage-Canonico, M. B., Plu-Bureau, G., Conard, J., Meyer, G., … Scarabin, P. Y. (2005). Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration. Circulation, 112(22), 3495–3500. https://doi.org/10.1161/CIRCULATIONAHA.105.565556
27.   Pavičić Baldani, D., Skrgatić, L., Simunić, V., Elvedi Gasporavić, V., & Geršak, B. (2015). Hormonsko nadomjesno liječenje i venske tromboemolije [Hormone replacement therapy and venous thromboembolism]. Liječnički Vjesnik: Glasiol Hrvatskoga Lijenčničkog Zbora/Medical Journal: The Journal of the Croatian Medical Association, 137(1–2), 34–40.
28.   Tremollieres, F., Brincat, M., Erel, C. T., Gambacciani, M., Lambrinoudaki, I., Moen, M. H., … Rees, M. (2011). EMAS position statement: Managing menopausal women with a personal or family history of VTE. Maturitas, 69(2), 195–198. https://doi.org/10.1016/j.maturitas.2011.03.011
29.   Narang, N., & Sharma, J. (2011). Sublingual mucosa as a route for systemic drug delivery. International Journal of Pharmacy and Pharmaceutical Sciences, 3(Suppl. 2), 18–22.
30.   Ruiz, A. D., & Daniels, K. R. (2014). The effectiveness of sublingual and topical compounded bioidentical hormone replacement therapy in postmenopausal women: An observational cohort study. International Journal of Pharmaceutical Compounding, 18(1), 70–77.
31.   Allen, L. V., Jr. (2015). Estriol 2 mg and estradiol 0.5 mg per 0.1 mL sublingual drops. U.S. Pharmacist, 40(9), 50–51.
32.   Casper R. F., & Yen, S. S. (1981). Rapid absorption of micronized estradiol-17 beta following sublingual administration. Obstetrics & Gynecology, 57(1), 62–64.
33.   Burnier, A. M., Martin, P. L., Yen, S. S., & Brooks, P. (1981). Sublingual absorption of micronized 17β-estradiol. American Journal of Obstetrics & Gynecology, 140(2), 146–150. https://doi.org/10.1016/0002-9378(81)90101-0
34.   Price, T. M., Blauer, K. L., Hansen, M., Stanczyk, F., Lobo, R., & Bates, G. W. Single-dose pharmacokinetics of sublingual versus oral administration of micronized 17β-estradiol. Obstetrics & Gynecology, 89(3), 340–345. https://doi.org/10.1016/S0029-7844(96)00513-3
35.   Drisko, J. A. (2000). “Natural” isomolecular hormone replacement: An evidence-based medicine approach. International Journal of Pharmaceutical Compounding, 4(6), 414–420.

A New Anhydrous Base for Female Hormone Delivery

Fri, 11 Oct 2019 13:52:00 GMT

By PCCA

This morning at International Seminar 2019, attendees packed into the ballroom to hear our Chief Scientific Officer Gus Bassani, PharmD, deliver his PCCA Innovation presentation. This is where Gus reveals the much-anticipated new PCCA products every year. This time, he introduced the audience to VersaBase® Anhydrous HRT, the pharmacy compounding industry’s first proprietary anhydrous base developed specifically to deliver female bioidentical hormones through the skin, such as estriol, estradiol and progesterone.

PCCA Chief Scientific Officer Gus Bassani introduces
International Seminar attendees to VersaBase Anhydrous HRT.

This new base is the latest addition to the VersaBase family of vehicles, and it uses a patent-pending delivery system that improves both the solubility of hormones and their permeation into and through the skin. This is typically difficult to achieve with an anhydrous base, but our Director of Research and Development Daniel Banov, MS, RPh, and his team have spent their careers inventing products that surpass what most consider possible. This one is no exception. VersaBase Anhydrous HRT performed comparably to VersaBase Cream (the industry standard for women’s topical HRT) during in vitro testing that demonstrated it delivering our Special Micronized Progesterone into and through human skin tissue.

VersaBase Anhydrous HRT also complements our newer anhydrous bases that we first released in 2018 to address changing needs in the compounding industry. Like PermE8™ Anhydrous Gel and W06™ Anhydrous Topical Gel, this newest base has water activity lower than 0.6 (Aw < 0.6), which qualifies it as anhydrous according to the standards in the latest version of USP General Chapter <795>. Therefore, formulations in these bases have longer default beyond-use dates (BUDs), which the chapter allows for nonaqueous dosage forms. This can save compounders thousands of dollars per formulation because the medications do not have to be stability tested in order to have the longer BUD. It also makes compounds more convenient for patients, since they won’t have to return to the pharmacy as often for prescription refills. To increase efficiency further, most of the VersaBase Anhydrous HRT formulas that we have tested and published in the PCCA formula database do not require the use of an ointment mill, which reduces both compounding time and cleanup time.

Also on The PCCA Blog: Why Water Activity Matters in Pharmacy Compounding

PCCA members with Clinical Services access can visit our formula database to see the numerous VersaBase Anhydrous HRT formulas that we have already developed to help eet the needs of patients. If they have questions about compounding with this base, they can contact our clinical compounding pharmacists at 800.331.2498.

These statements are provided for educational purposes only. They have not been evaluated by the Food and Drug Administration, and are not to be interpreted as a promise, guarantee or claim of therapeutic efficacy or safety. The references cited did not necessarily evaluate PCCA products or formulas included in these statements. The information contained herein is not intended to replace or substitute for conventional medical care, or encourage its abandonment.

Micronized or Wettable: Which Type of Progesterone Should You Compound With?

Tue, 06 Aug 2019 14:05:46 GMT

by PCCA

In numerous discussions with compounders recently, the experts on our Clinical Services team have found that there is confusion around some of the different types of progesterone, specifically when to use a micronized progesterone powder and when to use a wettable progesterone powder. To help you determine the best choice, here are some considerations for choosing which progesterone to use.

Micronized or Wettable Progesterone?
For most compounded medications, our Clinical Services and Formulation Development teams recommend that compounders use a micronized progesterone. They specifically prefer our exclusive, USP-grade Special Micronized Progesterone, which has a particle size of 90% less than 5 μm and 100% less than 10 μm to promote better bioavailability. The USP monograph for progesterone does not specify micronization standards,¹ but ours meets or exceeds the monograph criteria and leads the industry in particle size, going beyond what is required.

However, we also offer a USP-grade wettable progesterone for certain situations. To further clarify when compounders should use which type of progesterone, we asked Melissa Merrell Rhoads, PharmD, Director of Formulation Development at PCCA. “Our Special Micronized Progesterone is versatile and can be used in almost any dosage form, from topical creams, oral capsules and troches to rapid dissolve tablets, suppositories and more,” she said. “We typically only recommend the use of wettable progesterone when a troche or suppository is needed at concentrations above 200 mg.” This is because wettable progesterone incorporates more easily into melted bases at these higher concentrations. “However, progesterone troches with concentrations above 100 mg are very bitter, so palatability and patient compliance could be an issue,” Melissa said. “There are really very few reasons not to use our Special Micronized Progesterone — it’s very high quality and less expensive than our wettable version.”

Some compounders have also shared with us that they believed wettable progesterone is less bitter than micronized progesterone, which is a consideration for troches and other dosage forms in which the patient’s taste is a factor. However, our clinical and formulations experts maintain that there is no difference in the bitterness of micronized and wettable progesterone powders. As Melissa indicated above, it is the amount of progesterone, regardless of the type, that will affect the bitterness of a compounded medication.

What Makes It Wettable?
If you do need to use a wettable progesterone, it’s also important to consider what makes it wettable. There are various options available in the compounding industry, but not all of them are USP grade. Even some that are labeled as USP grade contain additives, such as surfactants like sodium lauryl sulfate, that make them wettable. These are often listed on the chemical’s certificate of analysis or safety data sheet. Some USP drug substance monographs explicitly allow additives, and some do not. Thyroid USP’s monograph, for instance, states that “it may contain a suitable diluent such as lactose, sodium chloride, starch, sucrose, or dextrose.”² On the other hand, the USP monograph for progesterone does not explicitly mention an additive.¹ This calls into question whether progesterone powders with additives can, in fact, be USP grade.

Matt Martin, PharmD, PCCA Clinical Compounding Pharmacist, finds this concerning. He points out two sections in the General Notices and Requirements of the United States Pharmacopeia and National Formulary: Section 3.20, Indicating Conformance, and Section 5.20, Added Substances, Excipients, and Ingredients.

Section 3.20 states that “when a drug product, drug substance, compounded preparation, or excipient fails to comply with the identity prescribed in USP or NF or contains an added substance that interferes with the prescribed tests and procedures, the article shall be designated by a name that is clearly distinguishing and differentiating from any name recognized in USP or NF.”³ When considering this passage in relation to wettable progesterone, Matt wonders, “How does a chemical comply with the identity of the USP monograph when it has another chemical that is not discussed in the monograph?”

Section 5.20 states, “Added substances are presumed to be unsuitable for inclusion in an official article and therefore prohibited, if their presence impairs the bioavailability, therapeutic efficacy, or safety of the official article; or they interfere with the assays and tests prescribed for determining compliance with the compendial standards (see section 3.20 Indicating Conformance).”³ Even though this doesn’t rule out additives unless they impair bioavailability, therapeutic efficacy or safety, or they interfere with determining compendial compliance, Matt again raises questions. “How can a company supplying the progesterone with an additive prove that the additive does not create any of these issues?” he says. “Do they have data that can prove this?”

Fortunately, our USP-grade wettable progesterone does not contain additives, but instead is rendered wettable through its manufacturing process. PCCA customers will not find any additives listed on our wettable progesterone certificates of analysis or safety data sheets for this reason.

Soy Source? Not to Worry
Aside from questions about using micronized or wettable progesterone, compounders have also voiced concerns about the fact that some bioidentical hormones — our wettable progesterone included — are derived from soy sources. They are rightly concerned because some patients have allergies or sensitivities to soy. However, even though we list the soy origin of some of our bioidentical hormones, they do not actually contain soy allergen. This is due to the chemical manufacturing process. While the manufacturers may use soy as the starting material to begin chemical synthesis of the bioidentical hormones, the processing steps involved mean that the end product is far removed from the starting material, so much so that they have no detectible soy content.

To prove this, we submitted some of our hormones to an independent lab for allergy testing. (You can see which ones here.) The lab tested specifically for soy content, and the controlled tests found no soy-based allergens with a limit of detection of 2.5 parts per million, or 0.00025%. This means that it would be incredibly unlikely for one of these hormones to cause an issue for a patient with a soy allergy.

Gus Bassani, PharmD, PCCA’s Chief Scientific Officer, wasn’t surprised with the results. “With the pure, pharmaceutical-grade drug substances that we carry, the expectation was that there would not be any soy-based impurity present, despite the fact that soy sterols were used as the starting material to begin chemical synthesis to the bioidentical sex hormones,” he said.

The Bottom Line
With so many choices for chemicals in the pharmacy compounding industry, many of which claim to be of the highest quality, it can be difficult at times to determine which ones are the best choice for your patients. When it comes to progesterone, our experts recommend a USP-grade, micronized progesterone in most cases — specifically Special Micronized Progesterone because of its unparalleled particle size, and because it, like all of our active pharmaceutical ingredients, goes above and beyond minimum requirements and meets The PCCA Standard™. If you need to compound with a wettable progesterone, such as when incorporating it into a melted base at a high concentration, we recommend using one that is USP grade and that does not contain additives. And even if we indicate that one of our bioidentical hormones has a soy source, it is very unlikely that a patient with a soy allergy or sensitivity will have issues with it.

As always, if PCCA members with Clinical Services access have questions about compounding with progesterone, they can contact our clinical compounding pharmacists at 800.331.2498.

References
1.   United States Pharmacopeial Convention. (2019). Progesterone. In United States pharmacopeia and national formulary (USP 42nd ed. & NF 37th ed.). Rockville, MD: United States Pharmacopeial Convention, Inc.
2.   United States Pharmacopeial Convention. (2019). Thyroid. In United States pharmacopeia and national formulary (USP 42nd ed. & NF 37th ed.). Rockville, MD: United States Pharmacopeial Convention, Inc.
3.   United States Pharmacopeial Convention. (2019). General notices and requirements. In United States pharmacopeia and national formulary (USP 42nd ed. & NF 37th ed.). Rockville, MD: United States Pharmacopeial Convention, Inc.

These statements are provided for educational purposes only. They have not been evaluated by the Food and Drug Administration, and are not to be interpreted as a promise, guarantee or claim of therapeutic efficacy or safety. The references cited did not necessarily evaluate PCCA products or formulas included in these statements. The information contained herein is not intended to replace or substitute for conventional medical care, or encourage its abandonment.

Why VersaBase Cream Is Your Best Choice for Women’s HRT

Wed, 17 Apr 2019 18:08:16 GMT

VersaBase Cream is a stable, pharmaceutically elegant base that can accommodate a broad range of active ingredients for customized, patient-specific medications. Compounding pharmacies have been using it for many applications over the years, but where it stands out is in topical and vaginal hormone replacement therapy (HRT). Our Clinical Services, R&D and Formulation Development departments continually research, test and formulate with VersaBase Cream, and independent researchers have worked with it as well. This makes it one of the most studied bases in the pharmacy compounding industry with a substantial portfolio of supporting data and materials, giving compounders incredible support in using it to help their patients.

VersaBase by the Numbers

5 publications to support its use in compounded medications

230+ formulas, offering a plethora of potential treatment options

20 formulas with extended beyond-use dates (BUDs)

13 bracketed formulas with extended BUDs to expand the possibilities for pharmacy and patient

7 related marketing resources to help in discussions with prescribers]

It’s Been Studied
Both PCCA and independent researchers have been studying VersaBase Cream for over a decade, giving compounders support when they recommend it in compounded medications. It has been included in the Journal of Women’s Health Care, where a peer-reviewed, in vitro study showed that it delivered our Special Micronized Progesterone into and through human skin. An independent, peer-reviewed study published in Gynecologic and Obstetric Investigation evaluated the absorption of estriol, estradiol, progesterone, DHEA and testosterone in VersaBase Cream, among other experimental factors. The International Journal of Pharmaceutical Compounding recently published an independent case study showing transdermal delivery of testosterone in this base, and another study evaluating the chemical stability of a range of estriol concentrations in a VersaBase vaginal cream. U.S. Pharmacist has also published an independently developed compounding formulation of progesterone in this base.

It’s Backed by Numerous Formulas
Not only is VersaBase Cream well studied, but we have also supported it with numerous formulations as well, offering compounders, practitioners and patients a host of potential treatment options. We have developed over 230 formulas in total that use VersaBase Cream. Of those, 20 have gone through our FormulaPlus™ program, so they have extended BUDs supported by stability-indicating assays. This can save compounders thousands of dollars in stability testing, it makes compounds more convenient for patients because they won’t need to refill prescriptions as often. We provide the data behind each BUD study as well. Of those formulas, 13 are bracketed, meaning that they offer the compounder a range of active ingredient concentrations with the same extended BUD, substantially expanding their value for the pharmacy and the patient. PCCA members can easily access all of these under the formula tab of the VersaBase Cream page on the Members-Only Website.

It Has Marketing Support
We have also developed various marketing materials to help pharmacies that compound topical and vaginal HRT with VersaBase Cream. PCCA members have access to the product information sheet, customizable top formula cards, a customizable PowerPoint presentation and much more. They can find all of them on the Marketing Resources page of the Members-Only Website.

If PCCA members have questions about compounding with VersaBase Cream, they can contact our Clinical Services department at 800.331.2498.

What happens in Vegas, Stays in Vegas? Not When It Comes to HRT Education

Fri, 05 Apr 2019 18:10:33 GMT

By Ranel Larsen, PharmD, RPh, PCCA Clinical Compounding Pharmacist

This is the saying that comes to mind of when we think about Las Vegas. But, in the case of PCCA’s HRT Symposium, what happens in Vegas does not, in fact, stay there.

“HRT Vegas,” as we often call it, happens each year in February and focuses on hormone replacement therapy (HRT). It is the compounding industry’s biggest hormone replacement event, and this year was no exception. The same can be said of all PCCA Education. At each event, we ask for feedback on suggested topics, speakers and ideas to make the next event bigger and better. This year, HRT Vegas was exceptional, with engaging topics and an incredible line-up of speakers tailored to the needs of our attendees. One of the advantages of compounded HRT is being able to customize the therapy for each patient’s specific needs because, as we know, one size does not fit all. HRT is also a complex topic and should not be considered without a thorough understanding of how all the body’s hormones interact with each other. This is what attendees learn at HRT Vegas, plus much more. Let’s look at some highlights.

HRT and Safety
When we talk about hormones, one of the first things that is usually brought up is safety. Estradiol may improve cognition¹and lower the risk of Alzheimer’s disease,^2,3cardiovascular disease, osteoporosis and other comorbidities in postmenopausal women. With heart disease being the number one cause of death in women, why are more not using HRT? There are two reasons: A poor understanding of the science by physicians and the general public, and a fear of breast cancer. Let’s take a minute to look at a few key studies.

We will start with the Women’s Health Initiative (WHI) study. It is important to have a thorough understanding of this study, as it contains valuable information, and it had and still has a huge impact on the use of hormones. If you look at the estrogen-only arm involving conjugated equine estrogen (CEE), the results showed a decreased risk of breast cancer, coronary heart disease, colorectal cancer and death.⁴ In addition, the WHI 18-year follow-up data showed a significant reduction in breast cancer incidence with CEE alone, and a significant increase in breast cancer incidence with CEE plus medroxyprogesterone.⁵ So it seems that medroxyprogesterone is likely the suspect here.

The Journal of the American College of Cardiology published a study that concluded that natural progesterone, not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women.⁶ This suggests that there is a major difference between progesterone and medroxyprogesterone. Just take a look at the chemical structure of each, and you can see how truly different they are. Then, compare the structures of estradiol and testosterone. Look at how a small change can drastically change the chemical. It’s not too surprising that progesterone and medroxyprogesterone have such different actions.

And finally, one of the most substantial pieces of evidence that hormones are safe is the North American Menopause Society (NAMS) Hormone Therapy Position Statement, 2017. It concluded that hormone therapy is the most effective treatment for vasomotor symptoms and genitourinary symptom management and has been shown to prevent bone loss and fracture. In addition, they state, “The risks of hormone therapy differ depending on type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used.”⁷

The Route Is Important
The Kronos Early Estrogen Prevention Study (KEEPS), which involved more than 700 women, looked at transdermal estradiol and oral progesterone and found no increase in breast cancer risk. It also concluded that the therapy relieved many of the symptoms of menopause, improved mood and improved several markers of cardiovascular risk.⁸ Another study showed that oral but not transdermal estrogen replacement therapy is associated with risk of venous thromboembolism in postmenopausal women, suggesting that transdermal therapy might be safer than oral therapy with respect to thrombotic risk.⁹ A recent study also highlighted that the transdermal route avoids the hepatic first‐pass metabolism, resulting in fewer adverse effects on coagulation markers compared to oral estrogens and does not increase risk of deep vein thrombosis.¹⁰

It’s a Symphony
PCCA’s HRT Symposium has evolved to a more functional medicine approach over the years, looking at the body as a whole and working to treat the cause instead of simply treating the symptoms. So not only did we learn about estrogen, progesterone and testosterone, but also about thyroid, adrenals and the gut, and how it is all connected.

Why Patients Need a Compounding Pharmacy
Compounders have something that is not offered anywhere else. We have the ability to customize and to use estriol and testosterone, which are not commercially available. We can make different strengths and dosage forms of estrogen and progesterone, and we can make it easy for patients by combining multiple active pharmaceutical ingredients into one dosage form. And most of the time, this means increased compliance and affordability, which means happy patients. “Happy wives equal happy lives,” right? Well I say that happy menopausal patients make for happy pharmacists and practitioners!

This is just a small sampling of what HRT Vegas provided. In addition, our speakers presented many formulas, compounding tips and tricks, and updates on public affairs and regulatory issues. The event brings together pharmacists, marketers and practitioners from all over the U.S. and Canada, building lasting professional relationships and empowering each other. HRT Vegas brings us together, helps us make connections and increases our knowledge to better serve our patients. When you come to PCCA’s HRT Symposium in Las Vegas, what happens in Vegas does not stay in Vegas!

Can’t wait until next year? PCCA members can join us for our Nashville HRT Symposium from August 8–10, 2019. They can also earn their HRT Specialist designation by taking our C4 HRT Online Course, which starts May 13, 2019, and attending the Nashville HRT Symposium.

Ranel A. Larsen, PharmD, RPh, PCCA Clinical Compounding Pharmacist, is a graduate of the Roseman University School of Pharmacy, where she obtained her Doctor of Pharmacy degree in 2006. After working in retail pharmacy for three years, she transitioned to a compounding-only pharmacy, where she worked for over four years. Ranel joined the PCCA staff in April 2014. Her areas of interest include hormone replacement therapy for men and women, veterinary medicine, pain management and dermatology.

References
1.   Hogervorst, E., Williams, J., Budge, M., Riedel, W., & Jolles, J. (2000). The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women: A meta-analysis. Neuroscience, 101(3), 485–512.
2.   Nilsen, J., Irwin, R. W., Gallaher, T. K., & Brinton, R. D. (2007). Estradiol in vivo regulation of brain mitochondrial proteome. Journal of Neuroscience, 27(51), 14069–14077. https://doi.org/10.1523/JNEUROSCI.4391-07.2007
3.   Wharton, W., Gleason, C. E., Lorenze, K. R., Markgraf, T. S., Ries, M. L., Carlsson, C. M., & Asthana, S. (2009). Potential role of estrogen in the pathobiology and prevention of Alzheimer's disease. American Journal of Translational Research, 1(2), 131–147.
4.   Anderson, G. L., Limacher, M., Assaf, A. R., Bassford, T., Beresford, S. A., Black, H., … Wassertheil-Smoller, S. (2004). Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women's Health Initiative randomized controlled trial. JAMA, 291(14), 1701–1712. https://doi.org/10.1001/jama.291.14.1701
5.   Manson, J. E., Aragaki, A. K., Rossouw, J. E., Anderson, G. L., Prentice, R. L., LaCroix, A. Z., … Wactawski-Wende, J. (2017). Menopausal hormone therapy and long-term all-cause and cause-specific mortality: The Women's Health Initiative randomized trials. JAMA, 318(10), 927–938. https://doi.org/10.1001/jama.2017.11217
6.   Rosano, G. M., Webb, C. M., Chierchia, S., Morgani, G. L., Gabraele, M., Sarrel, P. M., … Collins, P. (2000). Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women. Journal of the American College of Cardiology, 36(7), 2154–2159.
7.   The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. (2017). The 2017 hormone therapy position statement of The North American Menopause Society. Menopause, 24(7), 728–753. https://doi.org/10.1097/GME.0000000000000921
8.   Cobin, R. H., & Goodman, N. F. (2017). American Association of Clinical Endocrinologists and American College of Endocrinology position statement on menopause–2017 update. Endocrine Practice, 23(7), 869–880. https://doi.org/10.4158/EP171828.PS
9.   Scarabin, P. Y., Oger, E., & Plu-Bureau, G. (2003). Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet, 362(9382), 428–432. https://doi.org/10.1016/S0140-6736(03)14066-4
10.   Mikkola, T. S., Savolainen-Peltonen, H., Venetkoski, M., & Ylikorkala, O. (2017). New evidence for cardiac benefit of postmenopausal hormone therapy. Climacteric, 20(1), 5–10. https://doi.org/10.1080/13697137.2016.1262839

These statements are provided for educational purposes only. They have not been evaluated by the Food and Drug Administration, and are not to be interpreted as a promise, guarantee or claim of therapeutic efficacy or safety. The references cited did not necessarily evaluate PCCA products or formulas included in these statements. The information contained herein is not intended to replace or substitute for conventional medical care, or encourage its abandonment.