Women's Sexual Function and Dysfunction. Irwin Goldstein MD

Biogenesis of sex steroid hormones

In women, the biogenesis of sex steroid hormones from cholesterol occurs in the ovaries and the adrenal glands via distinct and overlapping A4 and Д5 metabolic pathways1 (Fig. 6.3.1). The A4 pathway yields progesterone, 17-OH progesterone, androstenedione, and testosterone, while the A5 pathway produces pregnenolone, 17-OH pregnenolone, dehydroepiandrosterone (DHEA), and A5 androstenediol, and the latter can be converted into testosterone. As can be seen in Fig. 6.3.2, the A4 and A5 pathways are represented in both organs, but the A4 pathway predominates in the ovaries and the A5 pathway predominates in the adrenal glands.2 Moreover, the majority of dehy- droepiandrosterone is converted into dehydroepiandrosterone sulfate (DHEA-S), in the adrenal glands by a sulfotransferase.Thus, dehydroepiandrosterone sulfate is considered an adrenal hormone and is converted back to dehydroepiandrosterone on demand by the sulfatase enzyme. Approximately one-half of the testosterone in the plasma in women is derived directly from precursors in the ovaries and the adrenal glands. The other half is the result of peripheral conversion of androgenic precursors to testosterone in various target tissues.2

Progesterone

Progesterone, which is produced cyclically during the menstrual cycle, is a critical hormone during the reproductive years, as it is a prerequisite for normal menstrual cycling and for achieving pregnancy. This cyclical production of progesterone is lost after menopause, but progesterone is still detected in serum and in the brain.4 Animal studies have shown that estrogen and progesterone act in the hypothalamus to regulate neuronal networks that control female sexual behavior.5 A similar effect in humans is inferred but has yet to be proven, although there is a suggestion that progesterone, when given to postmenopausal women, does have some effect on mood and sexual behavior.6

Figure 6.3.1. Steroid metabolism pathways in the female ovary and adrenal glands, emphasizing the A4 and A5 pathways. CYP = Human Cytochrome P450. HSD = hydroxysteroid dehydrogenase. StAR = Steroidogenic Acute Regulatory protein. Reprinted with permission from Grumbach and Conte.1

Figure 6.3.2. The A4and A5 metabolic pathways of androgenic hormones and their precursors in women during the reproductive years. From Davis.3

Progesterone is an important sex steroid intermediate in the A4 pathway, but does not appear to have any appreciable conversion to either estrogen or an effective androgen when administered orally or transdermally.7 No apparent effectiveness in sexual function was noted when progesterone was given in a clinical trial.8 One important clinical aspect is that progestins have little effect on sex hormone-binding globulin (SHBG) levels and may minimize the ability of estrogens to raise sex hormone-binding globulin.9 This would minimize any effect of estrogen in lowering free testosterone levels. Another view is that progesterone may exert androgenic effects by displacing testosterone from sex hormone-binding globulin, thereby allowing increased conversion to its high-affinity active metabolite 5a-dihydrotestosterone (5a-DHT).10 Ovarian dysfunction will primarily affect progesterone levels, but adrenal disorders can further decrease circulating amounts.

Dehydroepiandrosterone and androstenedione

Dehydroepiandrosterone is converted to androstenediol and then directly to testosterone in the biosynthetic organs, the adrenal glands and the ovaries, but most of the conversion to other sex steroids occurs in the peripheral tissues. Depending on the specific enzymes in the various target tissues, dehydroepiandrosterone may be converted to androgens and subsequently to estrogens, depending on the target tissue.2 In addition to conversion to estradiol, estrone, or testosterone, dehydroepiandrosterone may be converted to the very potent androgen, A5 androstanediol,11 which may have unique and dual function in genital tissue.11

Androstenedione, a weaker androgen, is produced in more significant quantities in the ovaries than the adrenal glands, and has several distinctive features.12 It is the only circulating androgen that is higher in premenopausal women than in men and, like dehydroepiandrosterone, less than 4% of this steroid is bound to sex hormone-binding globulin. Its androgenic potency is approximately 10% that of testosterone, while that of dehydroepiandrosterone is 5%. Serving as a prohormone, androstenedione is readily converted to testosterone and/or estrone, and both steroids are precursors for estradiol via aroma- tization.

Estrone

Estradiol is the potent estrogen in women and may be the more important estrogen in the premenopausal state, while estrone is less potent and more predominant in the postmenopausal state.14 Estrone can be derived from androstenedione as well as from estradiol. Both estradiol and estrone may be the product of aromatization of testosterone, directly or indirectly. Therefore, factors which contribute to estradiol or testosterone deficiency would equally contribute to estrone deficiency.

Estrogen and androgen deficiency

Conversion of androgens to estrogens via the enzyme aromatase occurs both peripherally and in the various sex steroid- producing glands. We have evaluated the relationship between female sex steroids (Table 6.3.1) and symptoms of female sexual dysfunction.

Table 6.3.1. Symptom-related laboratory evaluation of female sexual dysfunction

Symptom

Consider

Measure

Diminished libido

Androgen deficiency

Testosterone

Free testosterone by dialysis SHBG

Free testosterone index DHEA-S

Dyspareunia

Estrogen deficiency

FSH

Estradiol

Sexual apathy

Depression

Hypothyroidism

Beck index TSH

Menstrual

irregularity

Pituitary-ovarian

dysfunction

Estradiol

Prolactin

FSH

Galactorrhea

Pituitary adenoma Drug effect

Prolactin

Review medication list

DHEA-S, dehydroepiandrosterone sulfate; FSH, follicle stimulating hormone; SHBG, sex hormone-binding globulin; TSH, thyroid stimulating hormone.

Symptoms of female sexual dysfunction are observed mainly with deficiencies in estradiol and testosterone rather than excesses in these steroids. Since estradiol is derived from testosterone (Figs 6.3.1 and 6.3.2),14 the deficiencies are often simultaneous, although more attention has been given over the past few decades to estrogen deficiency. Research in testosterone deficiency in women is in its infancy owing to a multiplicity of causes. One is the limited sensitivity of current testosterone assays to measure the low levels of testosterone present in women.15 The other is the paucity of data outlining normal ranges of testosterone by age in women. It is known that testosterone levels, and those of their precursors, decline with age in men and women.16 Several attempts have been made to determine normal levels of dehydroepiandrosterone and testosterone in premenopausal women.17 A decrease in dehydroepiandros- terone with age has been well established (Fig. 6.3.3);16,1 21 however, clinical correlations with sexual function have rarely been made, even though plasma assays for dehydroepiandrosterone are reproducible, not controversial, and fairly accurate even in the lower ranges.

Symptoms of estrogen and androgen deficiency

Common symptoms of estrogen (Table 6.3.2), and testosterone deficiency (Table 6.3.3) in women share some similarities. There are also certain similarities between the symptoms of testosterone deficiency in men and women. Androgen deficiency-related symptoms are more reliably ascribed in women if such patients had adequate physiologic levels premenopausally or were treated with estrogen postmenopausally.22 Varying combinations of these signs and symptoms are seen in women with sex steroid deficiency from a variety of causes, necessitating a search of one or more of the possible etiologies that are noted in Table 6.3.4.

Table 6.3.2. Common symptoms of estrogen deficiency, and associated medical conditions

Potential causes of sex steroid deficiency

If the sources of production of estrogens and androgens, and of their precursors, are the adrenal glands and the ovaries, any condition that impairs the anatomy or function of these glands will lead to a deficiency of both androgens and estrogens.

Figure 6.3.3. Relationship between the decrease in dehydroepiandrosterone sulfate (DHEA-S) and increase in age in women. From Guay et al.18 Copyright 2004. International Journal of Impotence Research. Reproduced with permission.

Table 6.3.3. Common symptoms ascribed to androgen deficiency

Ovarian pathology

The ovaries produce androgens and estrogens, directly and via the sex steroid precursors dehydroepiandrosterone and androstenedione. The most common cause is natural menopause, although surgical removal will produce the same results, albeit more acutely.23 Premature menopause occurs earlier with more severe symptoms. There is some debate about the ability of the postmenopausal ovary to produce sex steroids. A commonly held theory is that the elevated gonadotropin levels during the menopause stimulate estradiol and testosterone production, especially from ovarian interstitial cells.24 Recently, Couzinet25 made an excellent argument for a lack of testosterone production in the menopause due to lack of hormone, enzymes, and receptors in ovarian tissue homogenates. The difference of opinion may be explained by the fact that Couzinet’s study was performed in women further along in menopause. In addition, about 50% of ovarian testosterone production is from dihydroepiandrosterone sulfate and Couzinet’s study was undertaken in women with adrenal insufficiency who therefore had low dihydroepindrosterone sulfate levels.

Varying degrees of ovarian hormone production can be seen with destruction from chemotherapy and radiation therapy. Suppression of steroid production from estrogen therapy is more complicated, whether it is from the use of oral contraceptives in younger women or from estrogen replacement during the menopause. In these cases, not only does estrogen therapy suppress estradiol and testosterone production from the ovary, but sex hormone-binding globulin production is stimulated from the liver, causing an increased binding of testosterone, and to a lesser extent estradiol, preventing them from being available to peripheral target tissues.26

Sexual difficulties with ovarian pathology

With loss of ovarian function from any cause, there is a decrease in both androgens and estrogens. A decrease in sexual function occurs, ranging from a decrease in sexual desire and mood disturbances to a decrease in receptivity and arousability. Since estrogens are derived from androgens, it has long been debated whether symptoms and benefit with therapy should be attributed to the particular androgen or estrogen. It is debated as to whether aging or decreased ovarian function contributes more to sexual dysfunction, especially in older women during the perimenpausal years.

Table 6.3.4. Some major causes of sex steroid (estradiol and testosterone) deficiency

Longitudinal studies are preferable to cross-sectional ones in evaluating changes in hormones and symptoms. Burger27 studied women during these transitional years and found a decrease in sexual function. The declining sexual function seemed to relate more to declining estradiol levels than to androgen levels. The investigators were also able to compare changes caused by aging and changes due to the menopause. Sexual responsivity was adversely affected by both aging and the menopause. However, other aspects of sexuality, especially sexual frequency and libido, were more related to the postmenopausal state.

There is no doubt that estrogen therapy improves vasomotor and other general symptoms28,29 after the loss of ovarian function. The common menopausal findings of decreased vaginal lubrication and genital atrophy respond very nicely to systemic or local estrogen therapy.30 The fact that estrogen therapy helps sexual receptivity and satisfaction may, however, be more related to relief of sexual discomfort, than to any direct effect of the estrogen.29,31 Androgen therapy is thought by some to be more important in sexual desire and receptivity.32 One limitation is the observation that when supraphysiologic levels of estrogens are used, there seems to be a definite link to fantasy, libido, and sexual satisfaction.33

Sexual difficulties with adrenal pathology

The adrenal glands also produce androgens via the precursors dehydroepiandrosterone and androstenedione, but the Д5 steroid pathway predominates, through the production of pregnenolone and dehydroepiandrosterone. Sulfation of dehydroepiandros- terone occurs exclusively in the adrenal glands, so that dehydro- epiandrosterone sulfate is considered an adrenal androgen. Clinical measurement of dehydroepiandrosterone is generally ordered through dehydroepiandrosterone sulfate because of its more stable serum levels due to a much longer half-life.

Adrenalectomy decreases androgen levels, especially dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone.34 The loss of estrogen with the loss of the adrenal glands is minimal and comes mostly from the loss of those estrogens that are converted in peripheral tissues. Symptomatology will involve more loss of sexual desire, but decreased lubrication and arousability, making orgasmic ability difficult, are also seen with the loss of adrenal hormones. The levels of androgens are lower than those seen with the normal decline in these androgen levels with age that have been reported by numerous authors35,36 (Fig. 6.3.3).

Adrenal insufficiency, either as an isolated organ failure, or as part of a polyendocrine deficiency syndrome, will produce a deficiency of adrenal androgens as well as a deficiency of corti- sol.35-37 Estrogens are a minor factor here also, as many women with adrenal deficiency maintain normal menstrual cycles. Blocking adrenal androgen production by the use of cortisol medication will also decrease androgen production.38,39 Excess cortisol from Cushing’s syndrome will have the same effect.40 Severe systemic illnesses, including anorexia nervosa,41,42 and even acute stress43 will also affect androgen production. It is felt that the body, in trying to conserve energy to survive, will decrease the production of reproductive hormones in favor of the life-saving corticosteroids and mineralocorticoids.

Sexual difficulty with pituitary pathology

If pituitary function is compromised, functions of both the ovaries and the adrenal glands will be affected. Therefore, a substantial or a total loss of estrogen and androgen hormones will be seen. This fact has been well outlined in both premenopausal and postmenopausal women, both with and without estrogen replacement44 (Fig. 6.3.4).

Decreased pituitary function, causing decreased or absent gonadotropins, luteinizing hormone, and follicle-stimulating hormone, as well as decreased adenocorticotropic hormone, can be caused by a variety of conditions (Table 6.3.4).Destruction of the pituitary gland may occur from pituitary adenomas and other tumors, both primary and metastatic. Tumors may become so large that they impinge on their blood supply, creating autodestruction of the tumor and destruction of surrounding normal pituitary tissue, a condition termed pituitary apoplexy, which usually presents with acute symptoms of headache, nausea, vomiting, and visual impairment. A similar condition, called Sheehan’s postpartum pituitary necrosis, may occur during pregnancy. Enlargement of the pituitary gland occurs normally during pregnancy, but damage can occur at the time of delivery when complications, such as excessive bleeding and hypotension, occur. Autoimmune destruction of the pituitary gland may occur as an isolated phenomenon or as part of a multiple endocrine syndrome. Lymphocytic hypophysitis is a variation of autoimmune destruction, which is now known to occur in men, but which has been described mostly in women during the peripartum period.45

Sexual symptoms with hypothalamic pathology

Pituitary function is dependent on hormonal and neural stimulation emanating from the hypothalamus. Therefore, diseases or destruction of the hypothalamus will cause a decrease in pituitary function that will then affect hormonal production of the ovaries and the adrenal glands. The most common cause of hypothalamic malfunction is a functional suppression due to stress from anxiety, acute illness, chronic illness, or medica- tions.46,47 Some chronic illnesses, but mostly acute illnesses, cause suppression of gonadotropin-releasing hormone and subsequently the pituitary gonadotrophs, luteinizing hormone and follicle-stimulating hormone.48 Similar medications that suppress the pituitary, ovaries, and adrenal glands, i.e., cortisone products and estrogen preparations, will also suppress hypothalamic function, as feedback androgen and estrogenic receptors are found in both the hypothalamus and the pituitary gland. The adrenal androgens are affected by acute disease stress, but cortisol production is either not affected or is increased, so that total adrenal insufficiency is rarely seen in these conditions.49 Many chronic illnesses, such as metastatic cancer and acquired immune deficiency syndrome wasting, can cause chronic suppression of the hypothalamic hormones.50 The central nature of this suppression has been demonstrated by a positive response of ovarian hormone to human chorionic gonadotropin stimula- tion.26 At times, tumors can destroy hypothalamic tissue, especially those that have a predilection for the suprasellar area, such as craniopharyngionoma.

Figure 6.3.4. Testosterone levels in women with pituitary disease, outlined by menopausal status and by presence or absence of estrogen replacement. Reproduced with permission.44

Miscellaneous situations

Increase in sex hormone-binding globulin

Sex hormone-binding globulin is closely related to sex steroids because many forms of estrogen increase its biosynthesis in the liver and increase its plasma levels. The free, active, or bioavailable levels of sex steroids are determined by the equilibrium between binding and dissociation from sex hormone-binding globulin. Thus, increased plasma levels of sex hormone-binding globulin will bind sex steroids and reduce the bioavailable, and vice versa. Sex hormone-binding globulin may be considered as a measure of estradiol or testosterone clearance from the body. The binding affinity for steroids by sex hormone-binding globulin is dihydrotestosterone > testosterone > androstenediol > estradiol > estrone. Dehydroepiandrosterone is weakly bound, but dehydroepiandrosterone sulfate is not bound at all.51 The availability of testosterone to the tissues is clinically more relevant in the discussion of sex hormone-binding globulin metabolism. Under normal physiologic conditions in women, only 1-2% of the total circulating testosterone is free or immediately bioavailable. The rest is bound, 66% bound tightly to sex hormone-binding globulin and 30% bound loosely to albumin.52

Oral administration of estrogens, whether as postmenopausal therapy or premenopausal oral contraception, will elevate sex hormone-binding globulin, which will bind more sex steroids, causing less to be available to the tissues.53 Oral androgen therapy will decrease sex hormone-binding globulin, and allow more hormones to act on the peripheral tissues. Parenteral delivery of sex steroids will affect sex hormonebinding globulin much less, and therefore will allow the delivery of more hormones to target tissues. An important difference is the oral contraceptive patch containing norel- gestromin and ethinyl estradiol, which raises sex hormone binding globulin markedly (Ortho-McNeil Pharmaceutical, Inc.

In addition to oral estrogen therapy, sex hormone-binding globulin may be increased by pregnancy, cirrhosis or other forms of liver disease, hyperthyroidism, anorexia nervosa, or antiepileptic drugs. Apart from oral androgen therapy, sex hormone-binding globulin levels may be decreased by hypothyroidism, obesity, hyperinsulinemia, and growth hormone.54 Several authors have found a clear-cut fall in sex hormonebinding globulin related to the menopause,28,55 but not all.56 Thus far, no difference in sex hormone-binding globulin levels has been noted during the premenopausal years.17,56

Miscellaneous or idiopathic?

Diagnosis of premenopausal women with sex hormone insufficiency is extremely difficult and controversial, especially in the absence of usual causes such as drug therapy or medical or surgical ovariectomy. Estrogen deficiency is diagnosed readily in most cases due to cessation or irregularity of menstrual periods. Any moderately severe and acute illness may cause this to happen.42 A confusing observation is that catabolic illnesses may also be observed in women who still have regular menses.57

There is early evidence that premenopausal women with regular menses may have symptoms of sexual dysfunction along with androgen deficiency. Guay et al. studied healthy young women who had no identifiable cause for sex steroid deficiency, but who had symptoms of sexual dysfunction. They had significantly lower Д5 adenal androgens and precursors than an age- matched control group.58 These androgen levels were distinctly lower than the range of normal androgens described in a previous healthy population of premenopausal women screened for the lack of sexual dysfunction symptoms.17 A study by Goldstat et al. evaluated the results of androgen treatment in healthy premenopausal women, with regular menses, complaining of decreased libido.59 The authors reported a significant improvement in well-being, mood, and sexual function with testosterone therapy over that of placebo. Doubt has been expressed about the supraphysiologic levels of androgens reached in the study.60 If the data are compared with a normal population of premenopausal women screened for sexual dysfunction reported by decade,17 the free androgen index of Goldstat’s patients is seen to be low at 2.0nmol/l, as compared with the low-normal value of 2.04nmol/l reported for women in their thirties, the mean age of Goldstat’s patients. Using the same normal criteria, the post-treatment free androgen index was only slightly elevated at 5.5 nmol/l, where the upper normal free androgen index for women in their twenties was found to be 4.96 nmol/l. Normal ranges of androgens in women are still to be considered estimates until more data are determined.

Measuring androgen levels in men and women

Total testosterone and free testosterone levels

Considerable energy has been devoted to determining what is the best way to determine whether a woman is capable of producing sufficient testosterone for her physiologic needs. In the woman, testosterone is partly of gonadal origin, i.e., produced within the ovarian theca cells and released into the circulation, and partly of adrenal origin. In women, testosterone is tightly bound to sex hormone-binding globulin and loosely bound to albumin. Free testosterone is that fraction of testosterone that actually interacts with androgen receptors. Measuring free testosterone has proven to be difficult. Several different free testosterone assays are now available, some with greater and others with less reliability (Table 6.3.5).

The free testosterone assays

Several free testosterone assays are currently available:

(1) free analog testosterone assay (free testosterone)

(2) free testosterone by equilibrium dialysis (free testosterone by dialysis)

(3) bioavailable testosterone (BT)

(4) free testosterone index (FTI)

(5) free testosterone by mass action-Sodergard equation

Which free testosterone assay is best and most reliable?

In an academic setting, the free testosterone by dialysis has emerged as the reference standard, the assay to which all other assays are compared. The free testosterone by dialysis assay may be too expensive and time-consuming, and is unlikely to provide the rapid turnaround clinicians have come to expect from their laboratories.

Table 6.3.5. Comparison of normal ranges of testosterone (T) provided by assay vendors and observed in clinical practice. Adapted with permission from Miller KK, Rosner W, Lee H et al. Measurement of free testosterone in women with androgen deficiency: comparison of methods.. Adapted from ref 61.

Assay

Normal range provided

Normal range observed

Total T by RIA nM after column chromatography

0.35-1.91

0.14-0.98

Total T by direct RIA nM

0.35-2.77

0.35-1.23

Free T by dialysis pM

3.82-21.6

1.73-8.67

Free T analog

1.56-11.0

1.73-8.67

SHBG RIA nM

30-95

26.1-63.4

For clinicians who want a cost-effective test that correlates well with the free testosterone by dialysis in women, the free androgen index may be more readily available. For clinicians, the free androgen index (FAI) may be the most readily available and reliable assay to provide an estimate of female androgen sufficiency or insufficiency.

FAI = Total testosterne in ng/dL x 0.347 x 100/SHBG in nmol\L

(normal range in premenopausal women found in ref. 17)

What is a normal hormone level?

For a few hormone measurements, such as prolactin and follicle- stimulating hormone, there is a general consensus of what is a below normal and excessive hormone level, so that the diagnosis of hormone sufficiency or insufficiency is relatively easy. Unfortunately, this is not the case with many of the hormones important for normal female sexual function, so the diagnosing and treating physician must rely on a package of tests to determine whether a disruption in hormone secretion is contributing to the patient’s sexual distress. The patient is then at the mercy of the local laboratory that has “purchased a normal range” from the vendor supplying the materials needed to perform the specific hormone assay. When these assays are “ field tested” in women of known age and medical status, the reported normal range provided by assay vendors does not always correlate with clinical observations.

Compare, for example the differences between normal ranges provided by assay vendors and actual levels of total testosterone, free testosterone, and sex hormone-binding globulin levels (Table 6.3.5). In all instances, the hormones of importance for female sexual function conform to a narrower normal range than previously suspected. When studies are expanded to include women who do or do not have sexual dysfunction, the normal range can be even more precisely defined.

For the clinician confronted with a woman with complaints of sexual dysfunction, a focused examination, as well as a symptom-specific checklist followed by targeted laboratory tests (Table 6.3.1), is the most efficient way to determine whether a treatable hormone abnormality is present and responsible for her sexual distress.

Conclusion

Sex steroid hormone deficiency in women occurs as a result of pathophysiologic changes in the ovaries, adrenal glands, or peripheral organs. Such pathophysiologic changes may be attributed to either destruction of endocrine glands and organs, or changes in the function of the hypothalamus and pituitary that regulate the biosynthesis of sex steroid hormones via protein and peptide hormones such as adrenocorticotropic hormone, luteinizing hormone, and follicle-stimulating hormone.

Similarly, the loss of function of sex steroid hormone- producing organs may be manifested by infection, medication, and illnesses or by severe emotional stress. Furthermore, factors that affect the synthesis and plasma level of sex hormonebinding globulin may also modify the bioavailability of estrogens and androgens, and this also alters their function. It has been suggested that healthy, premenopausal women, not taking medications, may also exhibit symptoms of androgen deficiency. These initial observations remain to be confirmed and related to sexual function. One key hurdle to assessment of sex steroid hormones in women, especially androgens, is the lack of analytic bioassays with reliable, sensitive, and valid measures to detect low levels of testosterone and other androgen metabolites on routine clinical and laboratory bases.

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