INTRODUCTION:
Female sexual dysfunction ( FSD ), as I understand it is a complex set of conditions with multiple anatomical, physiological and psychological components. Data suggests that it affects 20 to 25% of women, and, menopause can worsen the problem.
A simplistic classification of FSD includes the following four categories:
1) Diminished sexual desire
2) Decreased sexual arousal
3) Orgasmic dysfunction
4) Difficult or painful intercourse
There is obviously overlap between the categories. The commonest FSD in the climacteric is Hypoactive Sexual Desire Disorder ( HSDD ).
One risk with emerging treatments for HSDD, such as testosterone patches, is that they may be seen as a panacea for what is a very complex condition with multiple contributing factors and co-morbidities that need to be diagnosed and addressed in individual women.
It is important to note that HSDD should only be considered a clinical problem if the lack of desire is persistent and causes personal or inter personal distress.
PHYSIOLOGY OF ANDROGENS:
All types of androgens decrease with age. Fifty percent of circulating testosterone comes from ovarian and adrenal production, and this amounts to about 300 micro grams daily. The remaining 50% comes from the conversion of androgenic precursors derived from the adrenal gland and ovary. The target organs for this action is the skin, liver and adipose tissue
In the post menopausal woman, the contribution of the ovaries to the testosterone pool increases significantly from 25% to 50%. The question arises: How do testosterone levels decrease, if the ovary steps up its contribution in the post menopause? The production of testosterone prohormone DHEA and DHEAS by the adrenal gland decreases to the extent where the increased production by the ovaries cannot correct the deficit, resulting in a net decline in testosterone levels. Therefore, in surgical menopause, there is a dramatic and permanent decrease in testosterone levels.
Sex Hormone Binding Globulin ( SHBG ) binds onto testosterone more strongly than to estrogen. Only 1 to 2% of testosterone is free and physiologically active. The bound fraction includes 66% tightly bound to SHBG and 33% weakly bound to albumin.
THE PROBLEMS OF TESTOSTERONE MEASUREMENT:
This whole topic is bedevilled by the difficulty in measuring testosterone, especially in females. Liquid chromatography tandem mass spectrometry is the gold standard for measuring total testosterone. Equilibrium Dialysis is the most accurate method of measuring free testosterone, but its widespread use is limited by its labour intensity and thus cost, and is used mainly in research settings. Therefore, mathematical formula, such as the Sodergard equation is used to calculate free testosterone. The levels of total testosterone, SHBG and albumin are needed for the calculation to be done. The correlation is good with equilibrium dialysis.
A further complicating factor is that weakly bound testosterone can easily dissociate from albumin at tissue level. Therefore serum levels may not accurately define dynamics at a cellular level.
MECHANISM OF ACTION OF TESTOSTERONE:
Physiologically available testosterone enters the cytoplasm of genital smooth muscle cells ( eg. Clitoris ) and is converted to dihydro testosterone (DHT) by the enzyme 5 alpha reductase. DHT binds to the androgen receptor and the complex translocates to the nucleus, where it binds to specific portions of DNA. These binding regions, known as hormone response elements, influence the transcriptional activity of certain genes which will code for growth factors that maintain the adult form of the genital structures.
In the scenario of decreased bio available testosterone, especially as seen in surgical menopause, the resultant decrease in growth factors will lead to atrophy and regression of the female genitals to the juvenile pre pubertal state.
THE INFLUENCE OF ANDROGENS ON MOOD, WELL BEING AND LIBIDO:
Before we ascribe HSDD to be purely hormonal in aetiology, we have to exclude other causes; and they include psychosocial issues, psychological disorders, mental conditions and pharmacological agents. This involves taking a detailed history and allowing the patient time to express herself to practioners with a non judgemental attitude towards sexual issues.
The role of estrogens must not be forgotten. The alleviations of hot flushes, ensuring better sleep patterns and thus less fatigue, and its role in the treatment and prevention of vaginal atrophy may be enough to reverse a negative sexual cascade.
Understanding desire, its components and its role in female sexuality is key to determining whether testosterone therapy is appropriate for HSDD. There are 3 components to desire: drive, expectations and beliefs and motivation.
Drive is the biological dimension and it refers to the underlying spontaneous sexual interest. Its intensity is variable, it declines naturally with age and is affected by co-existing medical conditions and medications.
A person’s beliefs and values shape the sexual nature of that person. This underlies the importance of looking after the sexuality of our patients in the younger years, so that they enter the climacteric in a positive sexual frame of mind.
The motivation refers to the psychological factors that create a person’s willingness to be sexual, and this is proportional to the strength of the relationship. A woman’s sexual drive may be very high, but if she is having relationship problems, she is not going to want to be sexual. In contrast, a woman with low sexual drive who has an excellent relationship with her partner wants to be sexual for intimacy based reasons. The cornerstone of the Basson sexual response model is emotional intimacy.
Androgens heighten response to psychosexual stimulation. They also cause external genitalia to become more sensitive leading to more consistent sexual gratification. Overall, it induces a greater sense of well being.
EVIDENCE BASE FOR ANDROGEN THERAPY:
Treatment with testosterone and estrogen combined has been shown to improve sexual desire in surgically menopausal women, and is more effective than estrogen alone. This applies to all routes of testosterone therapy; but the transdermal testosterone patch ( TTP ) has the advantage that it avoids first pass hepatic metabolism and delivers consistent physiological doses of testosterone.
The Shifren Study was the first randomised controlled study using a TTP. 75 women who had surgically induced menopause and had been on oral estrogen therapy for at least 8 weeks were enrolled in the study if they answered positively to the following 3 questions: 1) at any time before surgery would you have characterised your sex life as active and satisfying; 2) since your surgery has your sex life become less active or less satisfying; 3) would you prefer your sex life to become more active or more satisfying than it is now? The 3 categories were placebo, 150 mcg and 300mcg used over a 12 week period. The 300 mcg patch showed significant improvement in all domains of sexual function.
Braunstein et al increased the treatment period to 24 weeks and added a further category of a 450 mcg patch. The sample number increased to 318. Entry criteria were similar to the Shifren study. The conclusions from the Braunstein study was that the 150 mcg patch was not effective; the 450 mcg patch was not superior to the 300 mcg patch; and the treatment was safe for 24 weeks. Adverse events were similar in frequency in all groups and included mainly application site reactions. There were no major adverse events. Other adverse events to look for with testosterone therapy include acne, alopecia and voice deepening. They are usually mild, dose dependent and reversible. Virilization is only seen with supra physiological doses of testosterone.
The INTIMATE SM 1 and SM 2 ( Investigation of Natural Testosterone in Menopausal women Also Taking Estrogen in Surgical Menopause ) involved 562 and 532 women respectively. There was a pre treatment baseline period of 8 weeks on estrogens, followed by multicenter, randomised , double blind placebo-controlled treatment for 24 weeks consisting of a TTP, 300 mcg per day, or placebo. A major component of both studies was the use of validated instruments to assess female sexual function: Sexual Activity Log (SAL), Profile of Female Sexual Function (PFSF), and Personal Distress Scale (PDS). The primary endpoint of both studies was the change in frequency of totally satisfying sexual activity. The secondary endpoint looked at personal distress which is a critical component of HSDD. The endpoints in these phase 3 studies were constructed from aspects of sexual functioning that were important to patients with HSDD. Both studies demonstrated an increase in the number of satisfying sexual episodes per month, improvement in all domains of sexual function and a decrease in personal distress. The clinical relevance of these studies was further explored using a statistical tool known as the anchoring technique in a subset population. This amplified the differences between the groups. Significantly, patients who benefited from treatment stated that they would continue using it.
PLACEBO RESPONSE
The high placebo response is not unexpected in patient centered studies. Factors involved in the placebo response include the women’s desire to improve their sex lives by their voluntary participation in trials, regular contact with health care providers, constant visible presence of a transdermal patch and increased communication between partners regarding their sexuality.
THERAPEUTIC DILEMAS FACING THE CLINICIAN:
Despite the efficacy evidence, the FDA ( Federal Drug Administration ) has not approved intrinsa (TTP) use in the United States of America. They cite the need for more studies regarding chronic use of testosterone. To assess the long term safety of testosterone, 2 separate phase 3 efficacy studies and 1 safety study are currently ongoing testing a testosterone gel, which is absorbed transdermally when applied to the skin once daily ( 300 mcg daily ). The long term safety study will include a treatment period of 12 months with a 48 month follow up. They aim to recruit 3000 women. The primary safety outcome measures include a combined incidence of pre defined cardiovascular events ( death, non fatal stroke and myocardial infarction ). The secondary outcome measures looked at breast carcinoma in situ, atypical breast hyperplasia and breast density as a surrogate marker for cancer risk
CARDIOVASCULAR RISK OF TESTOSTERONE:
Testosterone implants make no difference to clotting factors. The effects on lipids depends on the route of administration of testosterone, with the oral routes adversely affecting lipoprotein profiles. TTP trials showed no difference in carbohydrate metabolism.
ENDOMETRIAL EFFECTS OF TESTOSTERONE:
There has been concern that testosterone can cause endometrial proliferation after conversion into estrogens via aromatise activity that endometrial cells exhibit. To date, no endometrial cancer case has been reported in patients on physiological testosterone therapy
TESTOSTERONE AND THE BREAST:
There are androgen receptors in the breast and the stromal tissue has the aromatase enzyme system.
Shufelet and Braunstein writing in Menopause International stated that “Epidemiological studies, controlled for endogenous estrogen levels, showed either a decreased or no increased risk of breast cancer with testosterone replacement therapy.”
Hopefully the ongoing safety study will provide answers.
ENDOCRINE SOCIETY OF AMERICA – POSITION:
It states in its clinical practice guidelines: “ Although evidence exists for short term efficacy of testosterone in selected populations, such as surgically menopausal women, we recommend against the generalised use of testosterone by women because the indications are inadequate and evidence of safety in long term studies is lacking”
In response to the latter statement, Traish, Feeley & Guay ( J of Sexual Medicine; 2009;6:334-351 ) stated “ that we must proceed with caution is not a new concept in medicine” “however caution must not take the form of denying patients a valuable treatment option”
CONCLUSION:
Testosterone therapy for women is a complex and ongoing debate. The European Union approved the use of TTP ( intrinsa ) in 2007. Personally, I feel that testosterone therapy can be safely used after excluding` other causes of HSDD and informing patients that it is still off label therapy in South Africa. Owing to the unavailability of TTP in South Africa, I use testosterone implants. I start off with a dose of 25 milligrams. In the literature there are recommendations for a 50 milligram dose; but I have found an adequate response with the smaller dose in the majority of patients, and presumably less chance of side effects. The dose is repeated at 6 months if there has been a definite response. There is no point continuing androgen therapy in the absence of a change in HSDD. In patients who exhibit tachyphalaxis to implant therapy, I measure the free testosterone index, and only repeat the dose if the level is in the lower quartile of the normal range.
Testosterone therapy is usually given to patients after ensuring that they are well estrogenised.
REFERENCES
1: Kingsberg SA, Simon JA, Goldstein I Journal of Sexual Medicine, 2008 (suppl 4) 182 – 193.
2: Shifren JL, Braunstein GD et al NEJM 2000; 343: 682-8
3: Braunstein GD, Sundwall DA, et al Arch Intern Med. 2005;165:1582-9
4: Obstet Gynecol 2005;105:944-52
5: J Clin Endocrinop Metab 2005;90:5226-33
6: Shuflet CL, Braunstein GD Menopause Int 2008:14:117-22
7:Traish,Feeley & Guay J Sex Medicine; 2009;6:334-351