Definition of FSD

The normal female sexual experience is commonly divided into one of three phases: desire or libido, excitement or arousal, and orgasm. A fourth aspect of this sequence is now simply referred to as “satisfaction”: the woman’s perception of how satisfying the overall sexual experience has been for her. FSD includes disorders of desire, arousal, orgasm, painful sex, and overall satisfaction. A significant percentage of desire, arousal and anorgasmia disorders may relate to testosterone insufficiency, with attention to the timing of onset of symptoms being of great importance.

Women with low desire throughout their reproductive lives (primary dysfunction) should likely be referred to a mental health practitioner with specialized expertise in sexuality. FSD problems that present with a specific time of onset following a period of normal functioning (secondary dysfunction/acquired dysfunction) may relate to changes in hormonal milieu as well as emotionally important, psychologically significant events. These distinctions may facilitate more expeditious, proper treatment.

Desire disorders

Hypoactive sexual desire disorder (HSDD) is a syndrome defined in the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-IV R) classification as “personal distress resulting from a diminished feeling of sexual interest, sexual thoughts and distress with the lack of one’s responsive desire beyond what would be considered normal for time of life and duration of the relationship.” According to the consensus of the Sexual Function Health Council of the American Foundation for Urologic Disease, HSDD is defined by persistent or recurrent deficiency of sexual fantasies, thoughts and/or desire for, or receptivity to, sexual activity resulting in personal distress [10]. While the actual prevalence of HSDD remains elusive, recent figures indicate about 50% of female sexual dysfunction is based on these criteria in a gynecology outpatient cohort, of which HSDD is the most prevalent [11].

HSDD is most often multifactorial in origin. When patients complain of low libido, their concerns must be validated, with an approach that invites dialogue, appreciating the multiple potential elements in her experience. Although androgen deficiency may be a contributing factor, important additional psychological factors may come to light during the course of evaluation. Should sexual abuse, trauma, or mood disorders be revealed, it is important to acknowledge them and refer the patient for appropriate psychological therapy (a wide variety of mental health professionals specialize in addressing such concerns, such as International Society for the Study of Women’s Sexual Health [ISSWSH] or American Association of Sexuality Educators Counselors and Therapists [AASECT] certified practitioners).

A history of HSDD onset with anorexia, bulimia, severe anxiety, premenstrual depressive disorder, postpartum blues or depression, infertility, premature ovarian failure, postoperative surgical bilateral oophorectomy, or administration of contraceptive hormones, perimenopause or menopause may be particularly associated with low androgen levels [12,13]. Administration of many antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) or serotonin–norepinephrine reuptake inhibitors (SNRIs), can create negative sexual side effects (particularly anorgasmia) and may require pharmacologic consultation with a medicating psychiatrist.

Anorgasmia

Anorgasmia is the absence of being able to achieve orgasm, defined as “a variable, transient peak sensation of intense pleasure creating an altered state of consciousness, usually accompanied by involuntary, rhythmic contractions of the pelvic striated circumvaginal musculature, often with concomitant uterine and anal contractions and myotonia that resolves the sexually-induced vasocongestion (sometimes only partially), usually with an induction of well-being and contentment” [14]. The presence of a normal sexual excitement phase is a prerequisite for female orgasmic disorder. In other words, if the absence of orgasm follows a time of decreased desire for sexual activity, an aversion to genital sexual contact, or a decreased lubrication-swelling response, diagnoses such as hypoactive sexual desire disorder, sexual aversion disorder, or female sexual arousal disorder, respectively, might be more appropriate, even if anorgasmia is the common final outcome.

Upon ruling out physiologic or biologic causes of anorgasmia, such as Turner’s syndrome, primary depression, underlying psychological factors such SSRIs, substance abuse including alcohol, and a relationship problem, we are left with the diagnosis of primary anorgasmia. It is significantly less common than low libido or HSDD, and can result from insufficient levels of free, biologically available testosterone. An increased frequency of this less common FSD is observed in women in the lowest quartile of free testosterone as measured in serum. While systematic investigation of testosterone for the treatment of isolated orgasmic disorder is lacking, many studies document the improvement in orgasmic dysfunction in women with HSDD when given testosterone.

Painful intercourse

If intercourse is experienced as painful, it is likely to create negative associations and lead to decreased desire for sex. As clinicians, we must be systematic in elucidating the cause. It is exceedingly rare to remediate dyspareunia with correction of low testosterone levels alone. If pain is experienced upon entry/vaginal penetration, etiologic considerations include vulvar pathology (atrophy, infection, dystrophy, vestibulitis, or vulvodynia or provoked vestibulodynia) as well as urethral anomalies (diverticulum), or vaginal/genital/urethral atrophy. This is especially frequent in menopausal women not receiving estrogen therapy, local or systemic.

Although lichen sclerosis et atrophicus was formerly treated with topical testosterone preparations, testosterone deficiency per se does not cause this condition nor is it associated with this diagnosis, which is now uniformly treated with topical corticosteroids. Urethritis and cystitis (with urinary infections) can be a frequent source of acute onset painful intercourse and must be ruled out. This infectious urinary tract complication is associated with the effects of low estrogen concentrations in these tissues, not androgen deficiency per se. However, as the vestibule and vestibular glands (Bartholin’s, Skene’s, etc.) are rich in androgen receptors, and derived from embryonic endoderm, they are highly sensitive to androgens. As such, topical estrogen and and androgen may have a more effective outcome than estrogen therapy alone [15]. If pain is elicited deeper into the vagina or at its apex, other considerations may include endometriosis, ovarian cyst, pelvic inflammatory disease, malpositioned IUD, as well as vaginal canal atrophy associated with very low serum estrogen levels and should be investigated. Rarely, severe uterine retroversion can be associated with dyspareunia with deeply posterior penetration, which is not associated with androgen deficiency.

Comorbidities on examination

Background and hormonal measurements

HSDD is not highly correlated with androgen levels as measured in serum, supported by data from the USA and other countries. A recently published cross-sectional study in a cohort of 1423 Australian women found no significant correlation of circulating androgen levels with self-reported perception of sexual desire and sexual satisfaction [6]. In spite of this lack of correlation, it is unfortunate that commercially available testosterone assays are notoriously unreliable and imprecise in women. Using total testosterone or bioavailable testosterone may be better than measured or calculated free testosterone, as the normal ranges are greater in menstruating and perimenopausal women. Individual perimenopausal patients may exhibit wide variations, depending on the cycle in which testosterone is measured as levels fluctuate rapidly.

While the authors wish to dissuade the reader from relying upon testosterone assays in the assessment of therapeutic response, there are several approaches which can help to reduce the variability of such assay measurements. The suggested timing for minimizing cyclic variation in menstruating women (i.e., perimenopause) is cycle days 7–10, avoiding early menstrual cycle levels when free and total testosterone are at their nadir. Blood sampling at this time also avoids the pre-ovulatory peak in testosterone unless women have less than a 25-day cycle length. Data support trials of testosterone supplementation in women whose testosterone levels are in the lower 25–33% of normal range [22].

Pre- and perimenopause

Actual androgen deficiency is difficult to explain in normal premenopausal women with regular menses, as androgens are requisite for normal menstrual function. The benefits of testosterone therapy in perimenopausal women with low sexual desire have been demonstrated in clinical trials by Goldstat et al. [23]. Other comorbidities can cause androgen deficiency in these women (such as hypothalamic amenorrhea, adrenal insufficiency, etc.). Functional hypoandrogenism could be the result of hormonal contraception with suppression of both granulosa (estrogen-producing) and theca (testosterone-secreting) cells in the ovary. Decreased sexual desire is a relatively common complaint for perimenopausal women in spite of mostly adequate androgen production prior to full menopause [24]. As previously stated, there can be measurable benefits of testosterone therapy in HSDD perimenopausal women with low serum testosterone levels. Although hypoandrogenemia is less common, it can occur in pre- and perimenopausal women [23].

Thus a strictly biologic explanation for this phenomenon in women who continue to maintain functional ovulatory cycles is not substantiated, as there is no concomitant fall in serum testosterone levels. One hypothesis in this subgroup suggests that the evolutionarily beneficial midcycle surge in testosterone and its associated increase in libido may be absent in perimenopausal women [25]. Both ovarian testosterone and adrenal androgens (DHEA, DHEA-S, and androstenedione) fall gradually from the early twenties, dropping to about 50% of their peak adult values by the onset of menopause, which might offer an explanation for this phenomenon [26,27]. The Princeton Consensus Statement (see Table 4.2) published in 2002 by US and Australian experts defined female androgen deficiency syndrome (FADS) as the presence of decreased well-being and libido, occurring in a woman with androgen levels in the lower quartile of the normal female range and adequate levels of estrogen [28]. However controversial the diagnosis of true androgen deficiency may be in menstruating or perimenopausal women, correcting low testosterone or DHEA levels can help eliminate these “endocrinopathies” as a potential source of HSDD.

Postmenopause

HSDD (estimated as low desire with distress) occurs in 9–14% of postmenopausal women, a large number as greater longevity has increased the population of older women [4]. Numerous studies validate the therapeutic sexual benefits of testosterone in postmenopausal women who experienced loss of libido. Clinical data support the usefulness of transdermal testosterone administration for women with both low sexual desire and difficulties with arousal [29]. Clinically, such low-libido patients are common. They may not present primarily with sexual complaints, which often need to be elicited by more thorough questioning in the clinical setting. Persistent and unexplained fatigue without symptoms of depression or hypothyroidism may be the presentation, with concomitant complaints of muscle weakness and/or lack of muscle definition with previously adequate exercise efforts. These women are more likely to be surgically menopausal as removal of ovaries further decreases low androgen concentrations in older women, even though sexual ideation in some studies did not differ in oophorectomized older women [28,30].

Testosterone treatment

The route of testosterone administration is important. Oral testosterone results in deleterious effects on lipids in women due to first-pass hepatic metabolism (decreased HDL cholesterol primarily). Replacement via transdermal or subcutaneous routes, with serum levels within the physiologic range, is the desired goal. The strongest evidence for use of testosterone replacement for HSDD was generated with the development of the transdermal testosterone patch (TTP) (Intrinsa; Procter & Gamble/Warner Chilcott). Initially, 75 surgically menopausal women on oral estrogen, conjugated equine estrogen, were randomized to placebo or TTP. Those on TTP demonstrated improved sexual function [29]. Subsequently, several other studies have demonstrated the efficacy and safety of this form of treatment [31,32; see below].

No US FDA approval of available preparations: a significant challenge

At present, no preparation for testosterone replacement therapy in women has been licensed by the US FDA. Previous testosterone regulatory applications aimed at the treatment of HSDD have been rejected, primarily due to concerns with the lack of long-term safety data, and whether the improvement satisfied “meaningful clinical benefits.” Several testosterone products for women are licensed by the European Medicines Agency (EMA). They include the testosterone patches Intrinsa (Procter & Gamble, OH, USA) and Livensa (Warner Chilcott, Dublin, Ireland). AndroFeme (Lawley Pharmaceuticals, Perth, Australia) is a 1% testosterone cream licensed by the state of Western Australia. These products are approved for the treatment of HSDD in surgically menopausal women or similar indications. Due to lack of profitability, Warner Chilcott has suspended distribution of the Intrinsa testosterone patch in the EU.

Bioidentical compounded testosterone cream

A robust “compounded bioidentical testosterone cream” industry has sprung forth in the USA. The quality of such products, clinical parameters of absorption, and distribution and metabolism remain highly variable. Individual compounding pharmacies ideally obtain Pharmacy Compounding Accreditation Board (PCAB) certification of purity and dose reliability of their products to optimize quality and clinical outcomes for both prescriber and consumer [36]. Disappointingly, only a small percentage of compounding pharmacies belong to PCAB and achieve the quality assurance PCAB certification indicates.

Typical starting prescriptions for correcting androgen deficiency include: 0.5 mg/0.5 mL of testosterone cream. Some women will have satisfactory results with this low dose, and others may require 1–2 mg twice daily application in order to achieve therapeutic efficacy with serum testosterone levels in the mid-to-upper third of the normal reproductive female range. Morning application is encouraged to mimic the natural peak testosterone diurnal maximum concentration in the morning, nadir at night.

Serum testosterone testing in this setting is encouraged with the aforementioned provisos, as variability and potential for overdosage should be avoided. As serum testosterone concentrations do not typically require fasting, morning administration with late afternoon phlebotomy to approximate average to nadir testosterone serum levels (between 4 and 6 p.m.) make monitoring easier. If higher doses of testosterone are needed to achieve clinical improvement and optimize patient satisfaction, minimal volumes can be delivered with an increase in testosterone concentration rather than by prescribing large volumes of cream. Common doses ranges are 1.0 mg/0.5 mL to 2 mg/mL for long-term maintenance of clinically satisfactory testosterone concentrations.

For consumer safety, unsubstantiated “take it on faith” creams and gels are to be avoided. Patients may bring such unlabeled pump vials to the office requesting replacement. Serum testing is necessary to assess levels achieved with “mystery products” as well as to prescribe appropriate dose ranges to achieve desired clinical effects and avoid undesired adverse events as well as potential future litigation.