Obstetrics and Gynecology
1. What every clinician should know
- 2. Diagnosis and Differential Diagnosis
- 3. Management
- 4. Complications
5. Prognosis and outcome
6. What is the evidence for specific management and treatment recommendations
1. What every clinician should know
Menopause matters. In the United States, approximately 37 million women are at or near menopause with some 45.5 million women beyond menopause.
Menopause is the last menstrual period at the end of a woman's normal reproductive life cycle. The diagnosis is retrospective because it is made one year after that last flow. Median age for menopause is 50 to 52 years.
Perimenopause is the endocrine transition beginning with the first irregular flow ending one year after the last menses. Duration of perimenopause is approximately five years, and the normal range of this interval for 95% of women is two to eight years. The average age of onset is 46 years with 95% occurring between 39 and 51 years.
Climacteric defines the time during which a woman passes from regular ovulatory cycles to postmenopause.
Menopause, the perimenopausal transition, and the climacteric are not pathological. They are normal endocrine transitions of aging associated with significant clinical disruptions of normal life that fall into three groups: 1. estrogen depletion, 2. estrogen excess, or 3. androgen depletion.
Clinical disruptions of perimenopausal and menopausal life are closely linked to endocrine transformations of this passage: estrogen depletion, estrogen excess, and androgen depletion.
Results from gradual decrease in ovarian follicular competence expressed as widening intermenstrual intervals followed by total cessation of ovulation with the last menses signaling total loss of ovarian estrogen production. Estrogen withdrawal is expressed clinically as menstrual irregularities, vasomotor instability (hot flashes), pelvic atrophy, and aggravation of age-related systemic disorders.
Menstrual irregularities: As perimenopause approaches, intermenstrual intervals become shorter because follicular maturation is accelerated from early selection of aging dominant follicles. Thus, intermenstrual intervals of the 20s of 28 to 30 days generally decrease by two to four days to 24-28 days in the 40s. With continued aging, intramenstrual intervals widen as ovulations decrease in frequency and become erratic. Flows decrease in frequency, finally ending in the last menstrual flow defining menopause. With the occurrence of the last menstrual period, a diagnosis of menopause is made one year later.
Vasomotor symptoms (VMS): Hot flashes result from sudden increased blood flow in the skin over the head, neck, and chest. They are preceded with an aura, increased heart rate and perspiration, and are followed with an increase in core body temperature. Duration can be several minutes, even up to an hour. They are more frequent at night. The aura and the event are highly disruptive to the orderly conduct of a woman's life. In addition, symptoms are associated with loss of sleep, memory lapses, irritability, mood swings, and lethargy. Flashes can disrupt life for many years and, for some women, can be highly debilitating. They decrease over the years if untreated. They occur in over half the women going through the menopausal transition. The connection between estrogen withdrawal and vasomotor symptoms is firmly established, and replacement with estrogen suppresses or ablates them in a great majority of menopausal women.
Pelvic Atrophy: Estrogen withdrawal induces atrophy in the vaginal epithelium. Vaginal dryness with increasing dyspareunia is a common effect of estrogen withdrawal. Atrophic vaginitis results in persistent vaginal irritation, pain, and discharge. Dyspareunia results in declining sexual desire. Other complications include atrophy and inflammation of the vulvar skin and urethra resulting in urinary urgency, frequency, urethritis, and cystitis.
Age-related systemic disorders: Osteoporosis with deformities and fractures result from estrogen depletion. Similarly, atherosclerotic cardiovascular disease is aggravated by and associated with estrogen depletion.
Estrogen excess may cause persistent uterine bleeding long after exhaustion of ovarian follicles. Estrogen excess is more commonly seen in women who are overweight. Androgens normally secreted by the postmenopausal ovary and adrenal gland are converted to estrogens by extraglandular aromatization in peripheral tissues, particularly body fat. Estrogen excess, without luteal progesterone results in chronic hyperstimulation of endometrium and bleeding after menopause. These same endocrine mechanisms are also associated with excessive breast cancer risk.
Erratic perimenopausal flows may persist between ovulatory cycles or cause postmenopausal bleeding because of excess extraglandular conversion of androgens into estrogens. Rare cases of congenital adrenal hyperplasia are reported to produce persistent bleeding after menopause.
Endometrial hyperplasia results directly from estrogen excess, may cause of persistent bleeding, and may evolve into endometrial cancer.
Endometrial cancer occurs with increasing prevalence in women with chronic estrogen excess. These women are usually overweight with insulin resistance. In some cases, endometrial cancer pathogenesis is not related to estrogen excess.
Androgen depletion results from diminishing testosterone secretion of the anovulatory postmenopausal ovary and from atrophy of the reticularis zone of the adrenal cortex associated with advancing age.
The premenopausal ovary secretes a mid-cycle surge of testosterone that is associated with ovulation. This surge is linked with measurable increases in sexual desire at midcycle. With menopause, the midcycle surge in testosterone is lost. Although the postmenopausal ovary does produce some testosterone, it is significantly diminished. Ovarian testosterone is believed to be important in the maintenance of normal sexual desire in women. Decreased testosterone production is a consequence of oophorectomy and is associated with loss of sexual desire.
The adrenal androgen cortex (zona reticularis) secretes an abundance of dehydroepiandrosterone sulfate (DHEA-S), a testosterone precursor. DHEA-S secretion, genetically determined, is characteristic within families. DHEA-S production reaches maximum levels during adolescent years and into the early 20s and then attenuates gradually with advancing age. It continues to decline through menopause as the adrenal reticularis continues to undergo age-related apoptosis. With some women, who are genetically inclined, the age-related apoptosis is marked and results in depressed intracellular, total system testosterone production. Loss of ovarian midcycle testosterone with menopause, or oophorectomy, further aggravates the drops in total system testosterone production associated with age-related adrenal reticular zone apoptosis.
2. Diagnosis and Differential Diagnosis
Diagnosis of menopause is not difficult, except when it is untimely. When the last menstrual flow occurs at the appropriate time in association with classic symptoms, the event is easily and correctly identified. Most women can recall the month, even the date, of their menopausal flow.
Menopause, the last menstrual flow is diagnosed retrospectively when no menstrual flow has occurred for one year at the end of the normal reproductive cycle.
Perimenopause is not so clearly defined. It diagnosed by the onset of irregular menses at the end of the normal reproductive cycle. Its onset is the first time that such an irregular flow is observed. This diagnosis is usually made by a patient's own observation of time of her initial menstrual irregularities.
Laboratory tests are frequently not helpful. FSH and estradiol measurements are highly variable because it is nearly impossible to obtain blood at exactly the right moment in the hormonal chaos of perimenopause. A single FSH level exceeding 40 mIU/mL is considered consistent with the diagnosis of postmenopause, but an optimally timed blood sample can be difficult to obtain before the last menstrual flow. Inhibin is an index ovarian follicular mass. Its decline begins around age 35 and accelerates through age 40. There is no fixed value of Inhibin that identifies pre- or postmenopausal women. Both inhibin and anti-mullarian hormone can be undetectable during or after menopause. In general, when there have been several months of amenorrhea, a single FSH level over 40 mIU/mL is the most reliable diagnostic aid for declaring to a patient that she is postmenopausal.
Differential diagnosis of menopause can be challenging, particularly if it is premature. Questions are most likely to occur over differential diagnosis of VMS. Causes besides hypoestrogenism can be psychological, hypothyroidism, and acute infections, pheochromocytoma, carcinoid, leukemia. and some occult malignancies. When VMS is not occurring on the perimenopausal scenario, these differential diagnoses need to be investigated.
Ovarian failure-associated perimenopause and menopause is an inevitable, natural event. No technology is available to modify its course. Thus, the menstrual disturbances encountered in the normal perimenopause to menopause scenario follow a predictable course. Initially, menses are very regular, become more frequent, and become closer together. They then become farther apart as ovarian failure occurs, intervals widen, and flows become scanty. Management of these changes rarely requires more than an expectation setting explanation. Deviations from this pattern, however, may signal significant pathological diagnoses that include benign conditions such as adenomyosis, polyps, and myomas, or malignancies that include endometrial carcinoma or even myometrial sarcoma. When a deviation from the expected menstrual pattern is reported, diagnosis of the underlying gynecological disease is needed and specific treatment is rendered.
Management is for symptoms related to:
Managing Estrogen Depletion
Vasomotor symptoms (VMS) are directly related to withdrawal of estrogens from ovarian failure. VMS is most efficiently managed by replacing estrogens, the hormones that are deficient. During the hot flush, a woman's body undergoes a complex autonomic thermoregulatory dysfunction that is associated with an aura, increased heart rate, flushing, perspiration, and increasing core body temperature. The symptoms are unsettling and disruptive for women during their most productive hours when they are working in public or managing complexes technical tasks. At night the hot flashes disrupt normal sleep patterns. VMS is correlated with loss of REM sleep, which is directly related to loss of memory, lethargy, and fatigue starting in the morning and persisting throughout the day. Estrogens are the most effective available for reducing VMS and associated menopausal symptoms. In 2002, concerns increased markedly over adverse reactions associated with oral estrogens because of the Women's Health Initiative Study.
This study linked oral estrogens and progestins to cardiovascular complications including deep vein thrombosis, coronary occlusion, and strokes. There was also a small increase in breast cancer, but this was principally linked to the progestin component in the drug under investigation, which was a mixture of equine estrogens plus medroxyprogesterone acetate. These findings combined with many years of retrospective analysis led to a series of guidelines that supported continued use of estrogens for VMS but to administer them at lowest doses possible to alleviate symptoms. This logic has affected the most popular strategies, which include delivering estrogens through the skin in doses much lower that with oral administration.
Transdermal estradiol, developed over the past 20 years, includes estradiol, the exact molecular form of estrogens secreted by the premenopausal ovary, directly into the microvascular circulation. The advantage of transdermal delivery is that hepatic portal system is bypassed and liver does not metabolize estradiol through the skin. This is in contradistinction to oral estrogens where the "first-pass effect" is a mechanism by which several complications associated with oral estrogens are associated.
Estrogens, regardless of the delivery method, are highly effective in the suppression of VMS, more effective than any other therapy. The preparations differ in efficacy and side effects.
Transdermal estradiol is available as patches, gels, and sprays.
Estradiol patches currently available for clinical use are listed on
The Matrix patch, a more advanced technology, utilizes a suspension of estrogen within a polymer or textile pad that is held in direct contact with the skin. The adhesive is applied only to the perimeter of the patch and makes the patches associated with fewer skin reactions. Most recent designs utilize a Dot Matrix system that combines the drugs in a single layer and can be incorporated in a small and thinner design than earlier patches. Skin reactions to these patches are even lower. Transdermal patches were designed to improve compliance to oral therapy by providing once or twice weekly dosing. Occasional skin irritation occurs. Up to 10% of the patches may fall off, become soiled, or leave behind a sticky residue or be undesirable for cosmetic reasons. Estradiol patches are highly effective for suppressing VMS in randomized clinical trials.
Estradiol gels available for clinical use are listed on
Estradiol spray is currently available in the United States and is listed in
Transdermal estradiol preparations currently available by prescription
Oral estrogens available for clinical use as listed on
Oral estrogen preparations currently available by prescription
|Compound||Brand Name||Estrogen Type||Dosage||Comments|
|Conjugated estrogens||Premarin||Oral, conjugated estrogen||0.625 mg/day||Mare's urine|
|Ethinyl estradiol||Estinyl||Oral, EE||0.02-0.05 mg/day|
|Micronized estradiol||Estrace||Oral,E2||0.5-2 mg/day|
|Estrone||Ogen, Ortho-Est||Oral, E1||0.625-2.5 mg/day|
Oral estradiol is dosed at 0.3 to 0.6 mg per day. Higher doses may be required to suppress hot flashes. Oral estradiol is highly effective in suppressing hot flashes and has been demonstrated repeatedly in clinical trials going back 30 to 40 years.
Oral estrone sulfate is administered much like oral estradiol. Preparations for this are listed on
Conjugated estrogens are a mixture of estrone, estradiol, and equilin sulfate extracted from biological fluids. Doses range from 0.3 to 0.625 mg, or higher doses are administered if required. Conjugated estrogens are highly effective in suppressing hot flashes.
In situations where estrogens are contraindicated or declined by the patient, there are alternatives although none are as effective as estrogens. These include:
Selective serotonin reuptake inhibitors ((SSRIs): SSRIs are customarily used to treat depression and anxiety. From clinical trials, however, low doses of SSRIs have been shown effective in decreasing hot flashes. Venlafaxine (Effexor), paroxetine (Paxil), and fluoxetine (Prozac) are all effective in managing hot flashes but they all are associated with troublesome side effects characteristic of this class of drugs.
Clonidine (Catapres): Clonidine is customarily used for blood pressure control, but it has potentially annoying side effects, such as dry mouth, constipation, drowsiness, or difficulty sleeping. Clonidine effectively relieves hot flashes in some women but is completely ineffective in others.
Megestrol acetate (Megace): Megace is a progestin that can be effective in relieving hot flashes, but can only be taken over the short term (for several months). Serious effects can occur if the medication is abruptly discontinued, and it is not usually recommended as a first-line drug to treat hot flashes. Megestrol use can also lead to weight gain.
Medroxyprogesterone acetate (Depo-Provera): Medroxyprogesterone acetate, administered by 3 monthly injections, is effective in suppressing hot flushes. This drug can be used long-term but may have side effects that include weight gain and bone loss.
Gabapentin (Neurontin): Gabapentin is primarily used for the treatment of seizures that appears to be moderately effective in treating hot flushes. The drug often causes drowsiness.
Black cohash is a popular herbal remedy available without prescription in health food stores.
Atrophic conditions from lack of estrogens impact vaginal mucosa and produce dryness of the vagina, atrophy of the vulvar skin, repeated infections, and dyspareunia. Vaginal gels and creams delivering local estradiol are highly effective at reversing vaginal atrophy. The relief of dyspareunia is remarkable. Efficacy with vaginal rings is similar to vaginal gels and they are less messy. Vaginal DHEA administered in ovules is also effective in reversing vaginal atrophy. It also restores sexual desire. Vaginal DHEA is in clinical trials. Its major advantage is lack of estrogen exposure.
Osteoporosis and accelerated cardiovascular disease are the most significant long-term complication from lack of estrogen. Oral and transdermal estradiol are both effective at reducing bone loss and are commonly used for this purpose. Bisphosphonates work via an entirely different mechanism than estrogens. Serious side effects are reported with bisphosphonates and their popularity is declining.
Managing Estrogen Excess
Postmenopausal bleeding and endometrial hyperplasia are the most common clinical problems related to chronic estrogen excess. Particularly in overweight women, there is excess conversion of androgen precursors to estrogen. In addition, the administration of postmenopausal replacement estrogens (particularly in higher doses) produces chronic estrogen excess resulting in endometrial hyperplasia and uterine carcinoma.
Oral progestins are used to treat or prophylax against endometrial hyperplasia and its consequences.
Oral micronized progesterone may be administered at 100 to 200 mg per day depending on indication. As prophylaxis against endometrial hyperplasia, it may be administered chronically or intermittently to induce light and timely menstrual flow-or no flow at all. Thus, micronized progesterone is commonly given one week every two to six months. This avoids estrogen-induced endometrial proliferation and thus allows the clinician to give otherwise unopposed estrogen. Many women find side effects of progestins undesirable and prefer unopposed estrogen for as long as possible.
Oral medroxyprogesterone acetate, available for many years, has indications similar to that of micronized progesterone.
Oral megestrol is similar to medroxyprogesterone acetate. It is a slightly more potent medication.
Managing Androgen Depletion
Hypoactive sexual desire disorder(HSDD) is a complication of declining androgen production. Sexual desire is thoughts and fantasies about sexual matters. Sexual desire is at the center of the human sexual cycle. HSDD is the most common sexual disorder in older women and is at the core of several other female sexual dysfunctions. Other dysfunctions are resolved or easier to manage when HSDD is successfully treated.
Testosterone is effective in treating HSDD linked to declining androgens. Oral testosterone is not given to women because of the first-pass effect similar to that encountered with oral estrogens. Various non-oral methods including transdermals, injections, and implants have been developed over the last two decades. Transdermal testosterone, first reported as a Matrix patch in the 1990s, is becoming the most widely accepted approach to replacing androgens in treatment of HSDD. There is abundant high-quality evidence to indicate that transdermal testosterone is effective treatment of HSDD from androgen depletion. Numerous transdermal delivery systems or are undergoing investigation in research protocols and believed safe for use in postmenopausal women. One testosterone Matrix patch has been approved for clinical use by the European Drugs Agency but has not been approved by the FDA for use in the United States. These are listed in
Testosterone preparations for women currently available by prescription, as custom formulations, or in clinical trials
|Testosterone Matrix Patch(women)||Intrinsa (investigational)||Proctor &Gamble Pharmaceuticals|
|Testosterone Matrix Patch (men)||Androderm 2.5, 5 mg (off label)||SmithKline Beecham|
|Testoderm 5 mg (off label)||Alza|
|Testosterone Cream (men)||Androsorb (off label)||Novavax, Inc.|
|Testosterone Gels (men)||Androgel (off label)||Solvay Pharmaceuticals, Inc|
|Testosterone Gels (women)||Tostrelle (investigational)||Cellegy Pharmaceuticals, Inc|
|LIbigel (investigational)||Biosante Pharmaceuticals|
|PLOGel custom formulations|
|Testosterone Pellets||Custom formulations, 25, 50, 100 mg|
|Testosterone Injections||Testosterone enanthate 25-100 mg (off label)|
|Oral Methyltestosterone plus conjugated estrogens||Estratest (off label)||Solvay Pharmaceuticals, Inc|
|Sublingual testosterone (men)||Micronized (investigational) Striant|
|Vaginal DHEA||No name||Endoceutics|
A testosterone patch for women, currently available in Europe, is listed in
Testosterone gels and creams for men are used off label for women. Androgel and Testim are transdermal testosterone gels that are FDA approved. Off-label dosing for women is a 1/5th to 1/10th dose. Testosterone delivery is not precise in gels and creams and blood testosterone levels are needed to manage these doses safely. Custom formulated gels (e.g., testosterone in PLO gel) dosed for women are available from compounding pharmacies.
Testosterone pellets (implants) are available in the United States at doses of 25 to 75 mg. They are obtained at compounding pharmacies. They are inserted through a trocar and are effective for three to four months. There is extensive evidence from prospective trials supporting the efficacy of testosterone implants in the treatment of HSDD.
Intramuscular testosterone injection products. approved for use in men, can be used for women in lower doses They are injected in slow-release forms as testosterone esters, Cypionate, proprinate, and enanthate. Doses are 25 to 50 mg every two to four weeks, sometimes higher. It is important to to monitor the patient for virilizing effects.
Menopause itself is not complicated. There are downstream complications, however, from the hormonal dysfunctions it produces and from the replacement regimens used by physicians to avoid those complications. Thus complications of greatest concern are those related to estrogen and testosterone replacement.
Safety of Estrogens
Transdermal estradiol appears safer than oral. This assertion is based on observational studies that compare biophysical and metabolic measurements and on epidemiological studies that compare adverse events. Thus, transdermal estradiol has few, if any, effects on hepatic proteins and lipids. Oral estrogens do cause aberrations not associated with transdermal hormones.
Triglycerides are increased with oral estrogens whereas transdermals decrease them
Hepatic proteins are directly impacted by oral estrogens because the large steroid load passed through the portal system Thus, coagulation factors and platelets are directly impacted by oral estrogens. Transdermals have little or no effect on coagulation factors. C-reactive protein (CRP) is an inflammatory index predicting cardiac events and tissue damage from those events. Oral estrogens produce a two-fold rise in CRP in one study while the transdermal had no effect. In other studies transdermal estrogens are associated with decrease inflammatory markers. Growth factors, leptin:adiponectin ratio, and insulin resistance in metabolic syndrome are reportedly adversely affected in women ingesting oral estrogens. Transdermal estrogens appear to have few adverse effects on these parameters
Hormone binding proteins, such as SHBG, TBG, and CBG, are increased with oral estrogens but not with transdermals.
Effects on SHBG are particularly noteworthy because it decreases the bioavailability of circulating testosterone; this effect has been linked to significant decreases in sexual desire that are associated with oral estrogens.
Three major epidemiological studies described increased adverse events versus women using oral estrogens; these same adverse events are not seen with use of the transdermal estrogens.
The Women's Health Initiative was at first the most definitive clinical trial to show a strong epidemiological connection between oral estrogens and thrombogenetic events. Similar increases in coronary artery disease, stroke, and venous embolism were established for oral estrogens, alone or in combination with progestins, in these studies.
A Danish national register study comparing oral, vaginal, and transdermal estrogens failed to show an increase in myocardial infarction on estrogens overall. However, for women using transdermals and vaginal estrogens, the risks for myocardial infarction was reduced by 38% and 44%, respectively.
The ESTHER Study examined the differences between oral estrogens, transdermal estrogens, and controls. Designed as a retrospective case control analysis, the estrogen study compared the use of oral estrogen, transdermal estrogens, and non-use of hormone therapy. The relative risk with adjusted risk ratio for thrombembolism with use of oral estrogen was 4.2 by contrast, the odds ratio was 0.9 with transdermal preparation and by definition was 1.0 for non-users. For patients with a high risk of deep vein thrombosis in association with prothrombotic mutation, the difference between oral and transdermal preparation was even more striking. For patients with a mutation, the overall odds ratio for thromboembolism with oral estrogen was 25.5 compared with odds ratio of 4.1 to 4.4 for non-use in transdermal estrogen, respectively.
Safety of Testosterone
Transdermal testosterone given in doses that result in physiological to slightly super physiological serum testosterone concentrations do not increase cardiovascular risk in women with alteration of blood pressure, vascular reactivity, blood viscosity, hemoglobin concentrations, coagulation factors, or insulin sensitivity.
Consensus reports from the Endocrine Society and North American Menopause Society have been cautionary. Similar to the issues raised by the FDA advisory committee hearing, the FDA have opined that transdermal testosterone in physiological or slightly super physiologic testosterone is ineffective but the degree of increased sexual desire is not sufficiently justified given potential long-term complications that are not fully known. Despite recent reports with transdermal testosterone patches in exposure transcending four years, there is a dearth of experience recorded beyond this time.
In 60 years of publications and FDA transcripts, testosterone administered to woman appears to be a safe practice when doses are moderated sufficiently to virilization. In other reviews report serious adverse side effects due to transdermal implanted testosterone in physiologic doses, or moderately super physiologic doses are not problematic.
Information gleaned from controlled studies carried up to four years as well as observational reports obtained from women receiving testosterone as part of postmenopausal hormone therapy or from testosterone-treated female-to-male transgender persons provide reassurance. Excess dosing will cause virilization, and this is a major source of adverse reactions. Monitoring for excess dosing is critical.
5. Prognosis and outcome
Perimenopause and menopause are inevitable. They are not a disease, nor are they mortal, nor are they fatal. No known technology will stop or retard the events leading to menopause. The intervention benefit to patients is in containment of downstream effects of the chaotic endocrinology with estrogens and with androgens, both of which significantly enhance life quality.
Menopause matters. When patients request it, we should treat.
Estrogens are highly effective at containing symptoms of estrogen depletion. In addition, there is compelling evidence that estrogens continued for many years aid in containment of osteoporosis and cardiovascular disease.
Androgens are more of a lifestyle issue. Sexual functioning is important in some passages of life and not in others. It is likely that androgen therapy is more of a short-term issue being used as women go through personal passages benefitted by enhanced sexual activity and intimacy.
6. What is the evidence for specific management and treatment recommendations
Buster, JE. "Transdermal menopausal hormone therapy: delivery through the skin changes the rules". Expert Opin Pharmacother. vol. 9. 2010. pp. 1489-1499.(The article tabulates evidence demonstrating safety of transdermal delivery.)
Buster, JE, Kingsberg, SA, Aguirre, O. "Testosterone patch for low sexual desire in surgical menopausal women: a randomized trial". Obstet Gynecol. vol. 105. 2005. pp. 944-952.(Article among the largest,most definitive trials demonstrating efficacy of transdermal testosterone in women.)
Rotter, JL, Wong, FL, Lifrak, ET, Parker, LN. "A genetic component to the variation of dehydroepiandrosterone sulphate". Metabolism. vol. 34. 1985. pp. 731-736.(First article to demonstrate genetic basis of DHEA-S production.)
Davis, SR, Moreau, M, Kroll, R. "Testosterone for low libido in post-menopausal women not taking estrogen". N Engl J Med. vol. 359. 2008. pp. 2005-2017.(This is the first article to demonstrate continued efficacy of testosterone therapy without estrogen.)
Buster, JE, Koltun, WD, Pascual, ML. "Low dose estradiol spray to treat vasomotor symptoms: A randomized controlled trial". Obstet Gynecol. vol. 111. 2008. pp. 1343-1351.(This is the first article to demonstrate efficacy of estradiol transdermal spray.)
Godsland, IF. "Effects of post-menopausal hormone replacement therapy on lipid, lipoprotein and apolipoprotein (a) concentrations: Analysis of studies published from 1974-2000". Fertil Steril. vol. 75. 2001. pp. 898-915.(This article summarized data supporting minimal lipid changes with transdermal hormone delivery.)
DiCarlo Tommaselli, GA, Sandmartin, A. "Serum lipid levels and body composition in post-menopausal women: effects of hormone therapy". Menopause. vol. 11. 2004. pp. 466-473.(Review of impact of hormone therap on serum lipids.)
Rossouw, JE, Anderson, GL, Prentice, RL. "Risks and benefits of estrogen plus progestin in healthy post-menopausal women: principal results from the Women's Health Initiative randomized controlled trial". JAMA. vol. 288. 2002. pp. 321-333.(Review of findings from the women's health initiative.)
Canonico, M, Oger, E, Plu-Bureau, G. "Hormone therapy and venous thrombemobolism among post-menopausal women: impact of the route of estrogen administration and progestogens: the ESTHER Study". Circulation. vol. 115. 2007. pp. 840-845.(Studies showing no additive risk of deep vein thrombosis from transdermal hormone replacement therapy.)
Canonico, M, Oger, E, Conrad,. "Obesity and risk of vernous thrombembolism among postmenopausal women: differential impact of hormone therapy by route of estrogen administration. The ESTHER Study". vol. 4. 2006. pp. 1259-1265.(Studies showing no additive risk of deep vein thrombosis from transdermal hormone replacement therapy.)
Canonico, M, Oger, E, Conrad,. "Obesity and risk of venous thrombembolism among postmenopausal women: differential impact of hormone therapy by route of estrogen administration. The ESTHER Study". J. Thromb Haemost. vol. 4. 2006. pp. 1259-1265.(Studies showing no additive risk of deep vein thrombosis from transdermal hormone replacement therapy.)
Davis, SR, McLoud, P, Strauss, BJ, Berger, H. "Testosterone enhances estradiol effects on postmenopausal bone density and sexuality". Maturitas. vol. 6. 2008. pp. 17-26.(Report showing testosterone supports and enhances bone denisity.)
Schufelt, CL, Braunstein, GD. "Safety of testosterone use in women". Maturitas. vol. 63. 2009. pp. 63-66.(Review of articles supporting safety of testosterone.)
Naunton, M, AL Hadithy, A, Jacobus, RB, Archer, DF. "Estradiol gel: review of thepharmacology, pharmakenetics, efficacy, and safety in menopausal women". Menopause. vol. 13. 2006. pp. 517-527.(Review article.)
Buster, JE. "Transdermal matters: Update on menopausal hormone replacement". The Female Patient. vol. 35. 2010. pp. 1-4.(Review article.)
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