As men age, testosterone levels progressively fall and inflammatory biomarkers increase. The gradual decline in testosterone production with aging, known as andropause, is common and may have deleterious effects on men including decreased overall well-being, increased risk of cardiovascular disease and sarcopenia, reduced sexual function, and bone loss.
 
   Testosterone replacement therapy has long been a treatment for sarcopenia (loss of muscle tissue as a natural part of the aging process) in aging men. There is an inverse relationship between testosterone levels and matrix metalloproteinases, specifically MMP-2, which are potential biomarkers of atherosclerotic plaque vulnerability and cardiovascular disease. Strong links have been identified between testosterone deficiency and significant comorbid conditions (including Type 2 diabetes and other metabolic syndrome diseases).  Therefore, it comes as no surprise that an increasing number of men worldwide have begun requesting testosterone replacement therapy from their physicians.

   Occasionally, physicians may discourage male patients from getting testosterone replacement therapy based on a few recent studies indicating the therapy causes cardiovascular events, including myocardial infarctions. Yet, an extensive review of the testosterone replacement therapy literature reveals that the majority of clinical studies show that properly administered testosterone replacement therapy, in which estradiol and dihydrotestosterone levels are also controlled, has no adverse effects on myocardial infarction risk. The current state-of-the-art in testosterone replacement therapy is an aromatase inhibitor, such as anastrazole, to control estradiol levels; and a 5α-reductase inhibitor, such as dutasteride or finasteride, to control dihydrotestosterone (DHT).
 
   Dutasteride controls both Type I and Type II 5α-reductase while the older drug finasteride controls only Type II. If a patient receiving TRT has high DHT levels while taking finasteride, it may be helpful to switch to dutasteride.
 
   While testosterone is available in many forms, compounded troches offer several benefits:

• Convenience - easier than pellets or injections
• Decreased risk of cross contamination - men need not be concerned about others contacting the site of application, such as the arm or leg when a child or pet is held
• Rapid buccal or sublingual absorption means the dose can be a fraction of that required for topical forms of testosterone
• Patients can quickly achieve peak levels when desired

 

   Estradiol and progesterone are molecularly identical to endogenous hormones and are an option for women who prefer natural (bioidentical) hormones for the reduction of moderate to severe VMS frequency and severity. Several formulations combining estrogens and progestogens for hormone therapy (HT) have been approved worldwide for the treatment of menopausal symptoms, yet recent data indicate a decline in their use and an increase in compounded bioidentical HT. Women with a uterus who take exogenous estrogen are prescribed a progestogen to prevent endometrial cancer. Progestogens such as micronized progesterone have been shown to inhibit endometrial hyperplasia related to unopposed estrogen stimulation. Published data suggest that estradiol and natural progesterone have a safer profile when compared to conjugated equine estrogens (CEE) and progestins such as medroxyprogesterone acetate (MPA).

   Studies have shown that HT containing estrogen plus progesterone is better tolerated than HT containing MPA in terms of spotting/bleeding and quality of life. In a randomized 9-month study of women taking CEE plus either micronized progesterone or MPA, the progesterone group experienced fewer days of bleeding (4.3 vs 6.2 days) and less blood flow than the MPA group. This better bleeding profile observed with progesterone may be related to the effect of progestogens on several angiogenic factors in the glandular endometrium. In vitro studies in endometrial epithelial) cells demonstrated that progestins, but not progesterone, may alter the balance between angiogenic promoters and inhibitors. These alterations with progestins could induce a unique pro-angiogenic activity in the endometrial capillary plexus, with consequent aberrant vasculogenesis, which may result in irregular endometrial bleeding.

   In a cross-sectional study of 176 women who had previously switched from HT containing MPA to HT containing micronized progesterone, 71% had switched because of the better side effect profile, 35% because they believed the long-term risks would be fewer, and 23% because of intolerance to MPA. When evaluated at 1 to 6 months after switching, the women experienced significantly better quality of life, including less depression and anxiety, than with MPA. Patient satisfaction questionnaires also indicated that women preferred micronized progesterone over their previous regimen for better symptom control and fewer adverse effects. Sleep was significantly improved with no decreases in time spent awake after 6 months of CEE plus micronized progesterone but not with CEE plus MPA in a randomized study of 21 postmenopausal women tested in a sleep laboratory.
 
   The type of progestogen can also influence the incidence of breast cancer. Observational studies have reported that oral estrogens plus micronized progesterone is less likely to increase breast cancer risk than oral estrogens with various synthetic progestins. A more detailed analysis of the E3N study showed estrogens plus dydrogesterone significantly increased lobular breast cancer and that estrogens plus other progestins significantly increased ductal, lobular, pure lobular and mixed ductal/lobular cancer, but that estrogens plus progesterone did not increase any of these breast cancer subtypes.

   One reason for the use of synthetic progestins in the past was that effective absorption of oral natural progesterone was difficult to achieve. Studies have clarified that absorption is influenced by the vehicle used and progesterone particle size. Now, micronized progesterone which is well absorbed is readily available and can be compounded into various dosage forms to meet each woman's specific needs. Commercially available progesterone capsules contain peanut oil, a common allergen. Our pharmacy can compound hormones and other medications without allergens and other problem-causing excipients.

   No single product combining natural estradiol and progesterone has been approved by the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA) and therefore, these combinations must be compounded. A randomized, placebo-controlled phase 3 trial (REPLENISH) is underway to study an oral formulation of estradiol and natural progesterone combined in a single capsule for treating vasomotor symptoms (VMS) in postmenopausal women. The REPLENISH trial will evaluate the efficacy and safety of 4 different strengths of estradiol/progesterone: 1.0 mg/100 mg, 0.5 mg/100 mg, 0.5 mg/50 mg, or 0.25 mg/50 mg). The results will be compared to placebo and the endometrial safety of the combinations will be evaluated at 1 year.