HORMONE REPLACEMENT THERAPY: PHARMACEUTICAL COMPOUNDING OR OTHER NATURAL CHOICES

 In the year 2020, an estimated twenty million women entered menopause in the United States. For many women, this life changing event required symptom treatment and a sympathetic ear. The actor Suzanne Sommers authored a book in the late 1990s or early two thousand called “The Sexy Years”. The book is part anecdotal, part medical research and offers a lot of personal experience and advice. If you are familiar with this actor, you know she has aged beautifully. Her hormone connection and advice on replacement therapy helped put compounding pharmacies on the map. The work is a good educational tool for women curious about the therapy and the diverse types. It can serve as a guide to the compounding pharmacist and technicians interested in the subject matter. It will help you differentiate between bioidentical and synthetic hormones as well as suggest natural alternatives. It educates on how hormones regulate weight gain, sex drive, sleep, and body temperature.

What is all the hype about? Shouldn’t women accept natural aging processes of the body? If we believe that then we are rejecting the remedies that nature has given us. Throughout history women have used black cohosh to alleviate menopause symptoms. Here is a delightful story about herbal and native medicine in Appalachia where I fostered a love of knowledge of anything medicinal.

“Catfish A Man of the Woods”

When I was a child, I remember my grandparents taking me to see an Appalachian herbalist named Catfish Man of the Woods (his real name was Clarence Gray, but everyone called him Catfish). He was quite the stereo type, to say the very least until you heard him speak.

 He lived in Mason County, which is very rural today. He could barely read, having been declared a child who could not be educated by the third grade, and he talked fast so you had to listen carefully to understand what he was saying, but he had a pharmacopeia knowledge of herbal medicine. His knowledge of herbs was so ahead of his time, in fact, that a documentary on his life was created, and he was even once a guest on a popular late night talk show. The video can is on You Tube.

Some people have said that Catfish was an autistic savant. When he was a child, an autistic child would (incorrectly, obviously) indeed have been considered ineducable, especially in rural schools. I cannot say if her was an autistic savant, but he exhibited some of the signs. However, having met him on many occasions, what I can say is that it is very possible, and even probable. Either way, Catfish was a gentleman, very funny and very friendly – he never met a stranger – and I thought the world of him. He taught me so much.

Catfish combined traditional Appalachian folk medicine with traditional Native American medicine, and many people traveled to seek his treatments including a former First Lady, even now, many folks in West Virginia use traditional Appalachian herbal medicine, including me. Catfish was a frequent guest speaker presenting on herbal pharmacology to Marshall University Medical students.

When some of the native residents hit menopause and started getting severe hot flashes, they did not go to the doctor for hormone replacement therapy. Instead, they started taking an herb called Black Cohosh, which I had learned about many years ago from Catfish. Not only does it completely alleviate hot flashes without the need for hormones, but there are no side effects, and no known cases of anyone ever being harmed by taking it. It is therefore far safer than hormone replacement therapy, and I would highly recommend it to any ladies out there who are going through menopause. It has the additional benefit of alleviating some of the mood effects of menopause as well. When combined with over-the-counter progesterone cream a few days per month as birth control pills would be dosed, the benefits are realized. Another alternative is Maca root. It is effective for male and female hormone balance. Maca is a native Peruvian root vegetable that has been used for centuries to promote health and balance hormone levels, helping women with conditions like PMS, PCOS and oestrogen dominance, as well as improve fertility, libido and stress management. Maca has also been used during menopause to reduce symptoms of hormonal fluctuations like hot flushes, mood swings, anxiety and to return inner harmony and balance to the body.  Always seek the advice of your physician before adding a nutraceutical or supplements.

 With more prescriptions being written for Premarin than for any other medication in the United States, the market is obviously present for hormone replacement therapy. This is also supported by the recent activities among pharmaceutical companies to market their own brands of conjugated estrogens. Individualized patient care rather than mass treatment is one issue here. The question is, what degree of individualization of care is really needed? What can be provided? Who can provide it? Another question to answer is whose decision is it…. the patient’s, her health care providers, or the third-party payers? As the baby boomers (born during WW II) moved into mature adulthood, this area increased in importance. I am presenting this information for the support of quality compounding of natural hormone replacement preparations.

 DEFINITIONS AND ABBREVIATIONS

ERT is estrogen replacement therapy and involves treatment using a number of different estrogens that are available.

 HRT is hormone replacement therapy and involves a combination of hormones, including estrogens, progestins and even androgens. Natural (bio-identical) hormones refer to those hormones that are molecularly identical to those made in the human body and have the same exact chemical structure. Plant-derived refers to those hormones that are chemically derived from precursors found in yam or soy plants. Chemically, they will have the same chemical structure as those that are Loyd V. Allen, Jr., Ph.D., R. Ph (My mentor when I learned to compound). totally synthesized. Synthetic (Patented, Conventional, Artificial) hormones are those that are not usually found in humans and are chemically different from the naturally occurring human hormones. They are not identical in structure or activity to the natural hormones they are designed to emulate. The Natural Hormones include estrone (E1), estradiol (E2), estriol (E3), progesterone, testosterone, dehydroepiandrosterone, pregnenolone and androstenedione. In humans, the estrogens are primarily composed of 10-20% estradiol (E2), 10-20% estrone (E1), and 60-80% estriol (E3). For comparison, Premarin® is composed of 5-19% estradiol (& others), 75-80% estrone and 6-15% equilin.

THE MENSTRUAL CYCLE

In a woman’s life, between puberty and menopause, the menstrual cycle is regular and predictable and can be divided into about seven phases, each lasting the approximate number of days as indicated in Table 1. During the distinct phases of the cycle, there is a constant changing of the amount of estrogens, progesterone, LH and FSH in the body. The estrogens are responsible for normal growth and development of female sex organs, maintenance of secondary sex characteristics, promoting the proliferation and growth of specific cells in the body, protection against bone loss and protection against heart disease. Progesterone (1) is important for promoting secretory changes in uterine endometrium (counteracting the prolific action of the estrogens), (2) is necessary for maintaining pregnancy (maintains the uterine lining and decreases uterine contractions), (3) prepares the breasts for lactation, stimulates osteoblast-mediated new bone formation (increases bone mass and density) and, (4) is metabolized to other active hormones. Testosterone serves to enhance libido, provides cardiovascular protection (lowers cholesterol), enhances bone building (increases calcium retention), and improves the energy level and mental alertness. Estrogens, progestins and androgens are important endogenous hormones that produce numerous physiological actions.

TREATMENT

The treatment of menopause is, to some degree, seeking an elusive answer to hormone imbalance. The patient and health care provider are, in many cases, seeking a simple answer to a complex problem, or set of symptoms. One simple answer does not exist. A few general rules can be stated related to hormone replacement therapy:

1. There is no right answer or single approach to HRT.

 2. Treat each patient as an individual.

 3. HRT may be difficult and is time consuming.

 4. One cannot successfully treat hormone imbalances with hormones alone. The decision to use HRT is a personal one, based on the individual’s particular risks. The goal of natural HRT is to:

(A) alleviate the symptoms caused by the natural decrease in production of hormones by the body

(B) replace the hormones to the extent to provide positive benefits

(C) bring the body back to normal hormonal balance, and

(D) imitate the body’s natural processes as much as possible. The natural aging process results in a decrease in selected hormone levels in the body. These natural hormones are made by the body and have contributed to survival and longevity throughout the life span of humans. These hormones are not dangerous and have not subjected women to disease and it is not likely that we will develop a better synthetic drug to take their place. Consequently, it only makes sense to provide back to the body the exact chemical hormones to replace the lower levels that occur because of menopause.

The benefits of natural HRT include:

 (1) minimizing symptoms of menopause prevention of osteoporosis,

 (2) improved lipid profiles

, (3) reduced risk of heart disease,

 (4) reduced risk of endometrial and breast cancer, and

 (5) prevention of Alzheimer’s disease.

HORMONES AND DOSING

Postmenopausal dosing guidelines vary with the patient and what is presented is only a guide. Each patient must be individually assessed, dosed, and followed. Dosing of Double Estrogens or Triple Estrogens is in the range of 0.625 to 5 mg given once or twice daily. Progesterone is usually dosed in the range of 25 to 200 mg daily. Testosterone is often dosed in the range of 0.25 to 2 mg daily. Obviously, these doses can be lowered or raised based upon the response of the patient and the dosage form that is used. The Double Estrogen mixture consists of 80% estriol and 20% estradiol. The Triple Estrogen mixture consists of 80% estriol, 10% estrone and 10% estradiol. Various routes of administration are used, including oral, transdermal, nasal, vaginal, sublingual, buccal and others. In the oral administration of capsules, the release rate of the hormone is often retarded using a cellulose polymer that forms a gel when the capsule shell dissolves.

The gel slowly releases the hormone over a few hours, and this minimizes high peaks that may occur when a lactose filler is used, and the drug is rapidly released. Transdermal delivery of hormonal steroids offers a number of advantages over other modes of administration; it normally allows the use of lesser amounts of the hormone for a long-lasting effect by avoiding chemical or metabolic degradation of drugs that may occur in the gastrointestinal tract. Moreover, by bypassing the liver, transdermal delivery eliminates the potential drawbacks associated with hepatic steroid metabolism.3 However presence is necessary for normal development and maturity.

As one emerges from childhood to adolescence, these hormones are responsible for many of the physiological changes that occur to prepare one for adulthood. Throughout one’s adult life, these hormones are usually kept in balance but may be modified through the administration of additional hormones, as in the case of contraception. Nonetheless, adult life is characterized by the presence of circulating levels of these hormones. As one continues to mature into the fifth decade or so of life, these hormones start decreasing in prevalence and changes in the adult body begin to occur to prepare one for mature adulthood. These changes involve a decrease in these hormones leading through a change in life termed the menopause.

While most think of menopause as related to women, there are also changes in the male at about the same time in life. The symptomatology associated with these changes is not comfortable for many patients and they seek medical help. Since the hormones, the body has been producing and responding to involve estradiol, estriol, estrone, progesterone and testosterone, these are termed “natural,” and their replacement is termed “natural hormone replacement therapy.” This is compared to the administration of other estrogen, progestins and androgens that are commercially available that are chemically modified products, even though they may come from natural animal (nonhuman) sources.

As the natural hormones are not patentable substances, there has been little historical interest from the pharmaceutical industry in promoting their use. However, as compounding pharmacists, this provides an opportunity for meeting patient needs on an individual basis.

THE STAGES OF A WOMAN’S LIFE

A woman’s life can be divided into four distinct stages as it relates to menopause.

1. Pre-menopause occurs at the onset of the first menstrual period and is characterized by routine fluctuations of estrogens, progesterone, luteinizing hormone, and follicle stimulating hormone.

 2. Perimenopause occurs between the onset of changes in the hormonal secretions and the onset of menopause. There are fluctuating hormonal secretions due to intermixed normal and abnormal menstrual cycles. This is also called the period of estrogen dominance.

 3. Menopause occurs at the termination of the menstrual periods and is defined as missing twelve consecutive periods. It should be noted that not all women experience problems associated with menopause.

 4. Post menopause is the period following the last menstruation. During this time, HRT can be used to aid in heart protection, improve the lipid profile and enhance bone mass.

SIGNS AND SYMPTOMS OF MENOPAUSE

The reduction of endogenous estrogens and progestogens after menopause results in a variety of vasomotor symptoms in women. These often-experienced signs and symptoms of menopause are listed in Table 2 (Symptoms associated with a decrease in estrogen) and Table 3 (Symptoms associated with a decrease in progesterone). Menopause is not an illness, but a natural occurrence in a woman’s life that may lead to increased risks, including heart disease, specifically, myocardial infarction and angina. Osteoporosis is another major health problem as well as vaginal atrophy and Alzheimer’s disease. er, there are no wide range-controlled studies to monitor and verify the pharmacokinetics and biological effects of transdermal progesterone application in the general population makes it important to monitor the patients routinely.

Estradiol is a naturally occurring steroidal estrogen that occurs as white or creamy white, small crystals or as a crystalline powder. It is odorless, hygroscopic and is insoluble in water but has a solubility of about 35.7 mg/mL in alcohol at 25°C. It should be stored in tight, light-resistant containers. In the body, estradiol is reversibly oxidized to estrone and both estradiol and estrone can be converted to estriol. Estradiol is not used orally due to estradiol and estrone can be converted to estriol. Estrone is a naturally occurring steroidal estrogen prepared either from the urine of pregnant mares or from the Mexican yam (Dioscorea). It occurs as small, white crystal or as a white to creamy white, crystalline powder that is odorless and is insoluble in water. It is soluble to the extent of 4 mg/mL in alcohol and is soluble in vegetable oils. In the body, estradiol is reversibly oxidized to estrone and both estradiol and estrone can be converted to estriol. Estrone is used in the treatment of hypogonadism, primary ovarian failure, vasomotor symptoms of menopause, prostatic carcinoma, inoperable breast cancer, kraurosis vulvae, and abnormal uterine bleeding due to hormone imbalance.

Progesterone is a naturally occurring progestin that occurs as a white or creamy white, crystalline powder that is practically insoluble in water, soluble in alcohol, sparingly soluble in vegetable oils, and exists as a polymorph that melts at 121°C. Progesterone is extensively metabolized by the liver and is not usually given by the oral route, with some exceptions. Store in tight, light-resistant containers. Testosterone occurs as white or slightly creamy white crystals or crystalline powder that is odorless and stable in air. It is insoluble in water, soluble 1 g in 5 mL of ethanol, 2 mL of chloroform and 100 mL of ether. It is soluble in vegetable oils. It melts between 153 and 157°C. Testosterone is subject to photodegradation in the presence of light. Testosterone is not very bioavailable when given as an oral-swallow preparation, but it is absorbed when administered buccally and sublingually. The different esters of testosterone are hydrolyzed to free testosterone and, subsequently, are metabolized in the same way as testosterone itself. Testosterone is indicated as androgen replacement for delayed male puberty, postpartum breast pain and engorgement, inoperable breast cancer and male hypogonadism.

SIDE EFFECTS OF HORMONE REPLACEMENT THERAPY

 Side effects of HRT can often be minimized by alteration of the dose. It is important to determine if the side effects are estrogen or progesterone related and an appropriate adjustment made. With each dosage adjustment, sufficient time should be allowed for patient response before another adjustment.

PATIENT COUNSELING

 Inherent in the success of treating menopausal patients is taking the time for thorough education, which starts with patient assessment. One must know the patient’s history and the family history (presence of breast cancer, cardiovascular disease, or osteoporosis). Individual files should be maintained on each patient. Dietary recommendations are important and should include reduced fat and plenty of fresh vegetables, legumes, and whole grains. Another vital component is exercise, which helps in building stronger bones, increases the immune system function, decreases depression and anxiety, and can reduce many symptoms of premenstrual syndrome and menopause.

MARKETING HRT

Education programs can be provided to doctors and nurses as well as to the lay public. Promotional materials concerning educational programs can be provided to places where women gather. Formal or informal seminars have been successful in presenting the topic. Pharmacists providing these seminars begin with a short story of their pharmacy, the importance, and legal aspects of compounding, the purposes of estrogens, progestins and androgens, compliance issues and compensation and insurance billing. These are often followed up by one-on-one personal consultations. After a personal consultation, many pharmacists follow up with a communication to the physician and/or nurse by telephone or fax.

A consultation is an excellent way to start the process of patient history review and the use of a symptoms chart. In addition, laboratory test values can be maintained in this chart. While laboratory tests such as serum levels, saliva levels and urine monitoring have their place in patient evaluation, they do have limitations. However, using laboratory analysis in deficiency. This chart can be used during an initial patient consultation to determine a woman’s supplemental hormonal needs and then again on subsequent visits to determine if the woman’s prescribed dosages are meeting or exceeding her hormone extensive first-pass hepatic metabolism. Estradiol is indicated in the treatment of atrophic vaginitis, atrophic dystrophy of vulva, menopausal symptoms, female hypogonadism, ovariectomy, primary ovarian failure, inoperable breast cancer, inoperable prostatic cancer and mild to severe vasomotor symptoms associated with menopause.

Estriol is a naturally occurring estrogen and is claimed to have a selective action on the cervix, vagina and vulva and to have relatively little effect on the endometrium. It is often given in combination with estrone and estradiol in estrogen replacement therapy. It is a crystalline powder that is not water soluble but is soluble in alcohol and vegetable oil. In the body, estradiol is reversibly oxidized to estrone and both requirements. The symptoms list chart is a tool which can be used to evaluate patients for their starting hormone dosages and a tool that can be used to evaluate the effectiveness of current hormone regimes. Pharmacists wishing to help women with their hormone needs should use all available tools including but not limited to family history evaluation, symptoms list chart, serum or saliva levels, bone density monitoring and uterine lining monitoring to completely assess the needs of their patients.

COMMON HRT PREPS

 There are numerous HRT formulations being compounded today. Among the most common are Progesterone Capsules, Progesterone Topical Creams, Testosterone Topical Creams, Triple Estrogen Capsules, Triple Estrogen with Progesterone Capsules, Progesterone Slow-Release Capsules, Progesterone Vaginal Suppositories, Triple Estrogen with Progesterone and Testosterone Capsules, Progesterone in a Pluronic-Lecithin Organogel, Double Estrogen Capsules, Progesterone Troches, and Testosterone Capsules.

HORMONE REPLACEMENT FORMULATIONS

Rx Double Estrogen 2.5 mg Capsules (Estriol 2 mg, Estradiol 0.5 mg) Estriol 200 mg Estradiol 50 mg Lactose OR 39.75 g Starch OR 37.25 g Methocel E4M with 10 g Lactose 23.75 g Procedure for the above capsules (Each formula is for 100 #1 capsules)

 1. Blend the estriol and estradiol powders together.

2. Geometrically, incorporate the lactose or starch and mix thoroughly, OR

3. Geometrically, incorporate the Methocel E4M, then the lactose and mix thoroughly.

 4. Encapsulate 100 capsules, using a size #1 capsule.

5. Check the weights of at least ten capsules.

 6. Package and label. Rx Triple Estrogen 2.5 mg Capsules (Estriol 2 mg, Estrone 0.25 mg, Estradiol 0.25 mg)

Estriol 200 mg Estrone 25 mg Estradiol 25 mg Lactose OR 39.75 g Starch OR 37.25 g Methocel E4M with 10 g Lactose 23.75 g Procedure for the above capsules (Each formula is for one hundred #1 capsules)

1. Blend the estrone and estradiol powders together.

2. Incorporate the estriol and mix well.

3. Geometrically, incorporate the lactose or starch and mix thoroughly OR

4. Geometrically, incorporate the Methocel E4M, then the lactose and mix thoroughly.

 5. Encapsulate 100 capsules, using a size #1 capsule.

combination with clinical observation pharmacists can better recommend starting doses and dosage adjustments of hormone replacement for patients. The symptoms chart characterizes symptoms of estrogen excess, estrogen deficiency, progesterone excess and progesterone

 6. Check the weights of at least ten capsules.

 7. Package and label.

Rx Triple Estrogen 2.5 mg, Progesterone 100 mg and Testosterone 1 mg Capsules Estriol 200 mg Estradiol 25 mg Estrone 25 mg Progesterone 10 g Testosterone 100 mg Lactose 32.5 g (#1 capsule) Procedure for the above capsules (Each formula is for one hundred #1 capsules)

1. Mix the estradiol and estrone powders thoroughly.

2. Incorporate the testosterone powder.

3. Incorporate the estriol powder.

4. Incorporate the progesterone powder and mix.

5. Incorporate the lactose and thoroughly mix.

6. Encapsulate 100 capsules using a size #1 capsule.

7. Check the weights of at least ten capsules.

 8. Package and label.

 Rx Progesterone 5% Cream Progesterone, micronized 5 g Glycerin qs Dermabase 95 g Procedure:

 1. Levigate the micronized progesterone with a small quantity of glycerin to form a smooth paste.

 2. Geometrically, incorporate the Dermabase and mix until uniform and smooth.

 3. Package and label.

 Rx Progesterone 200 mg/mL in Pluronic Lecithin Organogel Progesterone, Micronized 20 g Propylene Glycol 20 mL Lecithin: Isopropyl Palmitate Solution* 20 g Pluronic F127 20% Gel** qs 100 mL Procedure:

1. Prepare a paste of the micronized progesterone and the propylene glycol.

2. Add the  Soy Lecithin: Isopropyl Palmitate Solution and mix well.

3. Add sufficient pluronic F127 20% gel to volume and mix well.

 4. Package and label

 Table 2. Symptoms associated with a decrease in estrogen.

• Anxiety
• Depression
• Dry skin
• Headache
• Heart palpitations
• Hot flashes
• Inability to reach orgasm
• Lack of menstruation
• Memory loss
• Mood swings
• Night sweats
• Painful intercourse
• Shortness of breath
• Sleep disorders
• Vaginal dryness
• Vaginal shrinkage
• Yeast infections

 *The Lecithin: Isopropyl Palmitate Solution can be prepared by mixing 10 g of soy lecithin and 10 g of Isopropyl palmitate; allow to stand overnight for complete dissolution to occur. **The Pluronic F127 20% Solution can be prepared by adding 20 g of pluronic F127 to sufficient cold (ice) water to make 100 mL. For complete dissolution, place in a refrigerator and allow to stand with periodic agitation.

Table 1. The phases of the menstrual cycle. Days Phase Hormonal Levels 1-4 Menstruation Rising estrogen levels 5-8 Postmenstruum Peaking estrogen levels 9-12 Late postmenstruum Falling estrogen levels 13-16 Ovulation Low estrogen levels Peak follicle stimulating hormones (FSH) Peak luteinizing hormones (LH) 17-20 Post ovulation Rising estrogen and progesterone levels 21-24 Early premenstruum Peak estrogen and progesterone levels 25-28 Premenstruum Falling levels of estrogen and progesterone

Table 3. Symptoms associated with a decrease in progesterone.

• Acne
• Asthma
• Anxiety
• Bloating
• Cramps
• Depression
• Early menstruation
• Emotional swings
• Food cravings
• Fuzzy thinking
• Headache
• Inability to concentrate
• Insomnia
• Irritability
• Low libido
• Moodiness
• Painful breasts
• Painful joints
• Swollen breasts
• Weight gain Table

4. Side effects associated with HRT.

• Bloating
• Breast enlargement and tenderness
• Craving for sweets
• Depression
• Fatigue
• Fibrocystic breasts
• Heavy/irregular menses
• Leg cramps
• Loss of sex drive
• Nausea
• Pounding headache, bilateral
• Premenstrual-like mood swings
• Recurrent vaginal yeast infections
• Thinning of the hair
• Vomiting
• Water retention
• Weight gain
• Yellow-tinged skin

 REFERENCES

1. Huddleston DS. Menopause: The hormonal replacement therapy decision. In McElmurry BJ, Parker RS (eds).

2. Annual Review of Women’s Health. New York, National League for Nursing Press, Vol. III, pp 33-45. 2. Algrimm M. Natural hormone replacement: Individualized treatment vs “one-size-fits-all” therapy. Am J Natural Med 1997; 4:6-7.

 3. Donaldson AS, Jeffcoate L, Sufi SB. Assays of oestradiol and progesterone in saliva in the assessment of ovarian function. Front Oral Physiol 1984; 5:80-86

. 4. McEvoy GK. AHFS Drug Information-99, Bethesda MD, American Society of Health-System Pharmacists, 1999, pp 2377- 2381, 2474-2476, 2695-2698, 2700-2702.

 5. Lacy C, Armstrong, LL, Ingrim NB, Lance LL. Drug Information Handbook, 4th ed., Lexi-Comp INC, Hudson OH, 1996, pp 445-447, 451-452.

 6. Hardman JG, Limbird LE. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 9th ed., New York, McGrawHill, 1996, pp 1411-1437, 1441-1455.

7. Reynolds JEF (ed). MARTINDALE. The Extra Pharmacopoeia, ed thirty. London, The Pharmaceutical Press, 1993, p 1192.

8. Testosterone, in Lund W, ed., The Pharmaceutical Codes, 12th ed., London, The Pharmaceutical Press, 1994, pp 1135-1136

9. Allen, Loyd, “The Art, Science and Technology of Pharmaceutical Compounding”

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