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Anthony E. Karpas, MD Case 1—Androgen supplements in young castrated women A 42-year-old female P2 G2 presented with loss of sex drive. Her recent history was significant for a hysterectomy and bilateral salpingo-oophorectomy for endometriosis four months previously. Immediately following surgery, she had experienced severe hot flashes. She was treated with a 0.5mg estrogen patch that partially relieved her symptoms. Although she did have some vaginal dryness and needed a lubricant for sexual activity, her pain and discomfort with intercourse was gone. Even though she had less pain once her endometriosis was treated, her desire for sex and her sexual satisfaction had decreased markedly since surgery. She denied any depression and was not taking other medications. Lab tests showed low estradiol and testosterone levels, an elevated FSH and a normal DHEAS. In other words, she had normal adrenal androgens and low ovarian steroids from inadequate replacement. The patient was started on esterified estrogen 0.625 and methyl- testosterone 1.25mg (Estratest-HS®). She reported some improvement in her symptoms but still was not satisfied. This patient still needed higher doses of both estrogen and testosterone. The patient was given estrogen and testosterone pellets consisting of 50mg of estradiol and 75mg of testosterone. An alternative therapy might include high dose patch therapy combined with the testosterone doses outlined below. These dosages restored her estradiol and testosterone blood levels to physiological pre-menopausal levels and, within six weeks, she reported that she was back to normal. Discussion Clearly the major factor in this patient’s problem is the removal of the ovaries. In addition to estrogen, the ovaries produce large quantities of male hormones. D-4-androstenedione a weak androgen is produced by the theca cell of the ovary as the precursor to estrogen is transformed to estrogen in the granulosa cell. Large quantities of D-4-androstenedione are also released in to the circulation. This, in addition to DHEA, produced by the adrenal gland, are the major sources of androgen for females. While there is some evidence for direct action of these hormones, most of their effects are mediated by their conversion to testosterone. Many studies have shown that testosterone is a major factor in sexual function in both males and females. Removal of the ovaries therefore results in a loss of a major source of androgens. Androgen therapy in women has been used for 50 years but has never been approved by the F.D.A. Combination therapy of estrogen and testosterone have been available but never formally studied in placebo-controlled trials until recently. In my clinical experience, there are fewer problems with re-activation of endometriosis when testosterone is given concurrently with estrogen. Testosterone is effective, especially where the loss of hormones was dramatic, in improving sex drive and general mood and quality of life. Various other forms of therapy have been tried. Combinations of esterified estrogen and methyl testosterone have been available and are often effective; testosterone and estrogen in the form of pellets have been used with great success in Europe and Australia but are only available as compounded substances in the USA. Recently studies have been conducted using transdermal testosterone patches. They did show a clinical benefit at one dose but curiously no additional benefit at higher doses. The estrogen dose in this study was constant. It would have been interesting to study the effect of varying this dose. Transdermal testosterone therapy for men is available but the doses need to be drastically reduced for female use. . I have found that testosterone 1% gel (Androgel® or Testim®) 5 mg tube or pack every 3- 5 days is effective. We have used a compounded gel with 1cc of 4% testosterone, which is effective. This patient was premenopausal at the time of surgery and therefore adapted to a high estrogen and androgen environment. It is important to consider the estrogen replacement as well, the lab test showed an FSH of 75 indicating that the estrogen level was too low for this 42 year old. In general I have found that testosterone replacement in the absence of adequate estrogens is ineffective. A major factor to consider in this patient is the fact that her symptoms were sudden and was related to removal of her ovaries at a young age. While some authors argue that hysterectomy can be psychologically traumatic, this generally occurs at a younger age when childbearing was still an option. This patient had two children and was pleased with the pain relief post surgery. Replacing hormones in a young woman with an oophorectomy with dosages designed for older women going through natural menopause is inadequate. Treating women, whose hormonal balances have not been restored to physiological levels, with anti-depressants and tranquilizers is also inappropriate. Case 2—Menopause, Depression of Ovarian Androgens and Communication Issues between Partners A 57-year-old female was seen for decreased sexual function. Until four years ago, she reported normal sexual feelings. Now it had diminished. Her last menstrual period was at the age of 49. She did not have severe hot flashes and elected not to use estrogen therapy. A few years later she had vaginal irritation and dysparunia. She was started on low dose conjugated estrogens (Premarin®) and topical Premarin® cream with resolution of the problem. Vaginal atrophy caused by estrogen deficiency is a vexing problem associated with menopause. It is caused by the shrinkage of the vaginal epithelial cells to small basal cells. Loss of moisture also contributes to the problem; vaginal irritation and dryness are often confused with yeast infections. Microscopic exam showing basal and parabasal cells should make the diagnosis obvious. The use of topical estrogen is usually effective in treating this problem. Vaginal exam is necessary to rule out lichen sclerosis which can be pre-malignant Observing vaginal smears under the microscope is helpful in diagnosing and monitoring treatment. I have found it necessary to suggest vaginal dilators for more advanced cases. After a few months, she began to complain of loss of libido again. Ovarian hormone production can be maintained despite amenorrhea for several years post-menopause. Androgen production may actually increase perimenopausally and continue for a few years post menopause due to surviving theca cells in the ovary. Elevated LH levels due to loss of estrogen may augment this secretion. Hormone replacement therapy with estrogen may suppress the elevated LH as well as elevate sex hormone binding globulin (SHBG). This inhibits ovarian androgen production and diminishes sex drive. Adding testosterone to the HRT is usually successful in improving function. The patient was than treated with Estratest® with initial success. A few months later, the patient was still unhappy. Further questioning revealed that the patient’s partner was having problems after starting antihypertensive drugs. The patient was reassured that this was not unusual and to suggest a PDE inhibitor, such as Viagra®, to be discussed with her partner’s physician. Sexual dysfunction is usually a complex problem involving relationship issues as well as mechanical problems. It has been said that the commonest cause of sexual dysfunction in women is sexual dysfunction in men. Many patients I have taken care of needed reassurance that there were multiple causes of male impotence including declining hormones, vascular changes, and medications. Many patients take this personally as a loss of attractiveness, which lowered their self-esteem. Counseling helps reestablish romance and good communication. These patients’ problems were resolved after treating her husband’s problem with a PDE inhibitor and by some basic counseling about sexuality. Case 3-- Side Effects of Common Medications May Reduce Libido A 30-year-old female P1G1 presented with sexual dysfunction shortly after the birth of her 1st child. The patient had breast fed for three months and weaned at that time due to “exhaustion”. She reported being depressed and was placed on an anti-depressant. She had one period before being started on drosperinone-containing oral contraceptive (Yasmin®). Additional history included asthma treated episodically with prednisone as well as daily steroid inhalants. She was happy in her current relationship but expressed concern that her husband was becoming impatient with her. Laboratory tests revealed low testosterone, FSH, LH and DHEAS, and elevated SHBG levels. Her estrogen levels are more than adequate but unmeasurable since the ethinyl estradiol in her oral contraceptive is not measured by estradiol assays. Discussion There are several issues involved in this case. 1) The patient probably had post partum depression, which could have caused her initial problem. Depression in women has been reported to be a major cause of sexual dysfunction. While the depression responds to SSRI medications, the sexual side effects can get worse. Many antidepressants, especially those with serotonin re-uptake inhibiting activity such as Paxil®, Zoloft®, and Prozac®, cause both a loss of sex drive and inhibition of orgasm. It has been reported that some agents active in Parkinson’s disease, such as pramipexole dihydrochloride (Mirapex®) and ropinirole hydrochloride (Requip®), may reverse these problems. Unfortunately, I have not had consistent results with these medications. If the antidepressant medications are beneficial the patient may have to be counseled to be patient for six months before attempting to wean off of them. 2) The intermittent use of oral and inhaled steroids may suppress the adrenal androgen production by decreasing DHEAS production. In addition, the use of oral contraceptives may suppress ovarian androgen production. It has been reported that drosperinone, which blocks androgen receptors, intensifies this effect. This patient is profoundly hypo-androgenic and should benefit from some treatment. Use of a more androgenic pill, such as those containing norethindrone, such as Ortho 1/35® or levo-norgestrol, such as Seasonale®, could be helpful. It should be noted that the androgen suppressing effect of oral contraceptives might persist for several months after discontinuation. The use of DHEA, which is available over-the-counter but preferably by a compounding pharmacy, will also be beneficial in 20-25mg dosages daily. 3) Patients who are of reproductive age and ovulatory and who are not on oral contraceptives should not be treated with androgens because of potential damage to the ovary. Exogenous androgen administration has been associated with polycystic ovarian syndrome due to alteration of the LH/FSH ratio. In addition there may be serious consequences to a fetus that is exposed to excess androgens. Side effects of excess androgens can include hair growth, acne, virilization, clitoromegally and androgenic alopecia. Case 4—Reduced Libido without Endocrinopathy A 28-year-old P0 G0 presents with problems with sexual function. She gives a history of poor libido and minimal response to stimulation. She had been married but is currently divorced. She is in a new relationship and is concerned that her decreased sexual desire will create problems. Menstrual history is unremarkable. She had been on birth control but uses condoms at the present time. Her physical exam is unremarkable. Vaginal exam revealed some vaginismus at the entrance to the vagina with a speculum exam. The cervix was nulliparous but normal No tenderness was present on manual examination. Laboratory studies showed a testosterone of 30, DHEAS of 175, LH 5, FSH 6, and SHBG 60 -- all within normal range. Since this patient was having regular periods, it was unlikely that she had an endocrinopathy. Discussion The benefits of laboratory testing in the diagnosis of female sexual dysfunction are questionable unless one has a suspicion of an endocrine problem. Normal low range levels for testosterone in women of reproductive age have not been established. No low normal range exists for DHEAS. Most testosterone assays have been set up to measure male levels and are not sensitive enough to measure normal low range female levels. RIA or radio-immune assays lack enough sensitivity at their lower end to even measure high normal female levels and are very inaccurate in the normal female range. Further complicating things is SHBG or sex hormone binding globulin binds 1/3 of androgens. Albumin loosely binds another 1/3. Changes in SHBG can profoundly affect serum androgen measurements in women. Measurements of free testosterone should correct this problem but most labs use an estimate based on the SHBG and testosterone rather than a direct measure. This is inaccurate and, since the testosterone level is usually inaccurate, this only compounds the problem. Currently only one lab (Nichols®) uses high pressure liquid chromatography and mass spectometry to directly measure testosterone and free testosterone with any accuracy. Even for this assay, normal levels have not been established. In summary, androgen assays were initially developed to measure higher levels of testosterone and they are inaccurate in the low ranges commonly measured in women. Measurement of free testosterone can be useful to follow post-menopausal women on treatment with pellets or Transdermal gels or patches. A range of 6 to 12 is desirable. Unfortunately methyl-testosterone is not measured in testosterone assays. This makes it difficult to monitor women on oral therapy. No correlation has been found between testosterone levels and libido. There is a weak relationship with DHEAS. Unfortunately this is a classic presentation for this problem. Female sexual dysfunction is multifactorial and rarely can be solved with a simple treatment. Counseling with a trained sex therapist can be beneficial in many cases. 50% of women do not report overt sexual fantasies but function well with direct stimulation. Many patients lack even a rudimentary knowledge of their sexual anatomy and are not aware that sexual intercourse without some direct clitoral stimulation is unlikely to be satisfying. Fewer than 50% of women report orgasm with vaginal intercourse alone; Changes in anatomy following childbirth may also contribute to the problem. Female sexual function is analogous to male sexual function physiologically. The clitoris is similar to the glans penis in function and nerve derivation. The labia minora are constructed of spongy tissue like the corpus spongiosum of the penis. In response to direct stimulation, blood flow increases to this area as well as the anterior vagina. Fluid secretion, providing lubrication to the area, increases and the vagina dilates. A buildup of sensation occurs followed by climax. L4 and L5 are the primary spinal nerves involved in the process. Central stimulation such as visual, olfactory and fantasy involve L4 while local response to caressing and direct stimulation is mediated by L5. A local spinal reflex, which involves parasympathetic nerves, is responsible for the increase in blood flow while sympathetic nerves control climax. Injury or drugs that interfere with the action of these nerves could interfere with the process. Diabetic neuropathy has been shown to negatively effect nocturnal engorgement in women. Methods for measuring neural and reflex response are sadly lacking. Patients should be encouraged to know their own anatomy. Stimulants such as vibrators may be very useful. Recently there has been promotional advertising for a locally applied gel, which contains substances such as menthol that act as mild stimulants. The effectiveness of this is unknown. Many issues exist of self-esteem or guilt that is best dealt with by licensed counselors. The art of treating patients successfully for sexual dysfunction lies in making the diagnosis of a physical versus psychological cause and treating with the appropriate solution. References 1. Basson, Rosemary. Sexual Desire and Arousal Disorders in Women . New England Journal; 2006;354:1497-1506. 2. Laumann EO, Nicolosi A, Glasser DB, et al. Sexual problems among women and men aged 40-80 y: prevalence and correlates identified in the Global Study of Sexual Attitudes and Behaviors. Int J Impot Res 2005;17:39-57. 3. Hartmann U, Philippsohn S, Heiser K, Rüffer-Hesse C. Low sexual desire in midlife and older women: personality factors, psychosocial development, present sexuality. Menopause 2004;11:726-740. 4. Buster JE, Kingsberg SA, Aguirre O, et al. Testosterone patch for low sexual desire in surgically menopausal women: a randomized trial. Obstet Gynecol 2005;105:944-952. 5. Braunstein G, Sundwall DA, Katz M, et al. Safety and efficacy of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial. Arch Intern Med 2005;165:1582-1589. 6. Simon J, Braunstein G, Nachtigall L, et al. Testosterone patch increases sexual activity and desire in surgically menopausal women with hypoactive sexual desire disorder. J Clin Endocrinol Metab 2005;90:5226-5233. 7. Caine VS, Johannes CB, Avis NE, et al. Sexual functioning and practices in a multi-ethnic study of midlife woman: baseline results from SWAN. J Sex Res 2003;40:266-276. 8. Avis NE, Zhao X, Johannes CB, Ory M, Brockwell S, Greendale GA. Correlates of sexual function among multi-ethnic middle-aged women: results from the Study of Women's Health Across the Nation (SWAN). Menopause 2005;12:385-398. 9. Bancroft J, Loftus J, Long JS. Distress about sex: a national survey of women in heterosexual relationships. Arch Sex Behav 2003;32:193-211. 10. 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A prospective study of the effects of oral contraceptives on sexuality and well-being and their relationship to discontinuation. Contraception 2001;64:51-58. 17. Panzer C, Wise S, Fantini G, et al. Impact of oral contraceptives on sex hormone-binding globulin and androgen levels: a retrospective study in women with sexual dysfunction. J Sex Med 2006;3:104-13. 18. Arlt W, Callies F, van Vlijmen JC, et al. Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med 1999;341:1013-1020. 19. Barnhart K, Freeman E, Grisso JA, et al. The effect of dehydroepiandrosterone supplementation to symptomatic perimenopausal women on serum endocrine profiles, lipid parameters, and health-related quality of life. J Clin Endocrinol Metab 1999;84:3896-3902. 20. Basson R, McInnes R, Smith MD, Hodgson G, Koppiker N. Efficacy and safety of sildenafil citrate in women with sexual dysfunction associated with female sexual arousal. J Womens Health Gend Based Med 2002;11:367-377. 21. Lobo RA, Rosen RC, Yang HM, Block B, Van Der Hoop RG. Comparative effects of oral esterified estrogens with and without methyltestosterone on endocrine profiles and dimensions of sexual function in postmenopausal women with hypoactive sexual desire. Fertil Steril 2003;79:1341-1352. 22. Davison SL, Bell R, Donath S, Montalto JG, Davis SR. Androgen levels in adult females: changes with age, menopause, and oophorectomy. J Endocrinol Metab 2005;90:3847-53. 23. Taylor MJ, Rudkin L, Hawton K. Strategies for managing antidepressant-induced sexual dysfunction: systematic review of randomised controlled trials. J Affect Disord 2005;88:241-254. 24. North American Menopause Society. The role of testosterone therapy in postmenopausal women: position statement of the North American Menopause Society. Menopause 2005;12:497-511.
Dr. Anthony Karpas recently retired from the practice of endocrinology and reproductive medicine. If you have any questions about his article please call Andrew B. Dott MD MPH 993 D Johnson Ferry Rd Atlanta GA 30342 404 250 1350 email: drdott@midlife-passages.com
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