Bronwyn G A Stuckey
Menopause is universal and leads to dramatic changes in estrogen status and corresponding changes in female sexual function (see Chapters 6.1—6.3 of this book). However, there are other, less common conditions associated with disturbances in hormones which may require specific management, constituting difficult endocrine management problems.
As in other portions of this textbook relating to difficult case management, all efforts have been made to protect the privacy of patients and to maintain the management strategies utilized in the case for teaching purposes.
An 18-year-old woman presented with failure of progression into puberty and the accompanying sign of anosmia. The history was consistent with Kallmann’s syndrome, and subsequent genetic studies have confirmed this diagnosis. Gonadotropins and estradiol were undetectable. The free androgen index was within the low normal range. Puberty and menses were induced by exogenous estrogen and progestin therapy. The patient married and returned at age 25 years with a request for ovulation induction to achieve pregnancy. There had been no complaint from the patient of impaired sexual function. Ovulation induction was attempted first with pulsatile gonadotropin-releasing hormone and subsequently with exogenous gonadotropins. After several cycles of therapy, pregnancy was achieved. The patient reported, in retrospect, markedly improved sexual function during ovarian stimulation with both gonadotropinreleasing hormone and gonadotropins compared to that experienced on exogenous estrogen and progestin therapy. When she returned to the former estrogen/progestin regimen, she was concerned by the fall in her feelings of sexual interest.
Question: is there an indication for androgen therapy, together with estrogen and progestin, in such patients?
Isolated hypogonadotropic hypogonadism is associated with lack of pituitary drive to the ovaries while the pituitary-adrenal axis remains intact. It may be secondary to congenital conditions such as Kallmann’s syndrome; to drug therapy such as opioids, especially when administered intrathecally; or to hyperprolactinemia.1-3 Central or secondary hypogonadism is associated with greater deficiency of ovarian sex hormone secretion, particularly androgen secretion, than is associated with normal menopausal aging.4 Although this is recognized, it has not been addressed in clinical studies of combined estrogen and androgen therapy in this patient group, with sexual function as an endpoint. This may be partly because of the difficulty in recruiting adequate numbers of patients in this category.
Panhypopituitarism is associated with a lack of stimulatory drive, not only to the ovaries, but also the adrenal gland, the other major site of sex hormone production.4 Despite demonstrated sex hormone deficiency, including androgen deficiency, there is a paucity of data addressing sexual function in this group. In one study of 38 women with hypopituitarism, dehydroepiandrosterone was used in doses of 30 mg daily for those younger than 45 years and 20 mg daily for older women.5 Patients were asked to report sexual interest and activity as reduced, unchanged, or increased. No significant effect of dehydroepiandrosterone was observed in the 6-month randomized part of the study.
A 45-year-old woman presented with galactorrhea, insomnia, and dyspareunia. She had had a hysterectomy 16 years previously for menorrhagia. Prolactin was 3000 mU/l (<500). Gonadotropins and estrogen were suppressed. Magnetic resonance imaging scan showed a small pituitary microadenoma consistent with a prolactinoma. Dopamine agonist therapy in the form of cabergoline was commenced, with rapid suppression of her prolactin, a return of biochemical evidence of ovulation, and an improvement in sexual function. At the age of 51, she became postmenopausal and commenced estrogen and progestin hormone therapy for menopausal symptoms. Dopamine agonist therapy was continued for the next 3 years. Since the pituitary tumor was small and the patient was postmenopausal, a decision was made by her physician that the dopamine agonist was serving no purpose and could be withdrawn. There was a subsequent rise in serum prolactin to 2000 mU/l (< 500) and a fall in sexual interest and response. Sexual function improved with the reinstitution of dopamine therapy.
Question: does high prolactin adversely affect sexual function, independently of changes in sex hormones, in such patients?
Hyperprolactinemia may be caused by prolactin-secreting pituitary tumor (prolactinoma), pituitary stalk disruption by space- occupying lesions, psychotropic medication, or renal failure. The secretion of prolactin is under inhibitory control by hypothalamic dopamine, which binds to D2 receptors on lactotrophs. Increased prolactin secretion by the pituitary inhibits release of hypothalamic gonadotropin-releasing hormone and, consequently, of gonadal sex hormones.
Hyperprolactinemia caused by a prolactinoma produces menstrual disturbance, leading to an earlier diagnosis in women than in men.6 Both menstrual disturbance and decreased libido have been documented with high prevalence in women with a prolactinoma.7,8 Treatment with a dopamine agonist such as bromocriptine or cabergoline will usually restore normal endocrine function and induce tumor shrinkage. Studies of dopamine agonist therapy in men confirm a brisk response of sexual dysfunction to therapy.9 Whether the early response relates to the fall in prolactin or the institution of dopamine is not known. No such confirmatory studies exist in women partly because of the small numbers of study participants.8
A 29-year-old woman with schizophrenia presented with amenorrhea, galactorrhea, dyspareunia, and loss of libido. She had required hospitalization and was being treated with thioridazine. Soon after commencing this medication, she had experienced amenorrhea. She became aware of decreased sexual function and galactorrhea. Serum prolactin was 2674 mU/l (< 500), and gonadotropins and estradiol were suppressed. Her attending physician treated her with cabergoline, resulting in a fall of prolactin, return of menses, and improvement in sexual interest. However, she experienced a relapse in her psychiatric symptoms, and the dopamine agonist was withdrawn, with subsequent return of her sexual symptoms.
Question: what is the optimal management of psychotropic-induced hyperprolactinemia and sexual dysfunction?
Hyperprolactinemia induced by psychotropic medication is commonly associated with sexual dysfunction in both men and women. The mechanism of antipsychotic therapy is to block dopaminergic action in the mesolimbic system. Side effects of the blockade of dopaminergic action elsewhere include movement disorders, caused by blockade of dopamine action in the striatum, and hyperprolactinemia, caused by blockade of dopamine D2 receptors in the pituitary. All conventional antipsychotic medications cause elevation in prolactin.10,11 Among the newer antipsychotic agents, risperidone also causes significant hyperprolactinemia, but other agents, such as clozapine, olanzapine, quetiapine, and aripiprazole, cause very little, if any, elevation of prolactin.12
Again, the effects of psychotropic-induced hyperprolactinemia have been more widely studied in men than in women. However, the rise in prolactin is more marked in women and is associated with galactorrhea, amenorrhea, hypo- estrogenism, vaginal dryness, and reduced libido.13,14 In a study of sexual dysfunction in men and women taking conventional psychotropic medication, hyperprolactinemia was found to be strongly related to sexual dysfunction in females.15 However, it is unclear whether the sexual side effects are secondary to the elevation of prolactin or to the dopamine blockade.
It is conventional wisdom that the institution of dopamine agonists to treat hyperprolactinemia in such patients is contraindicated because it may lead to loss of psychotropic control. This view is supported by data showing increased dopaminergic activity in schizophrenia and by evidence of dopamine-induced psychosis in patients treated for Parkinson’s disease.16,17 Despite this belief, small studies have reported a low incidence of deleterious psychiatric effects of dopamine agonists used to treat psychotropic-induced hyperprolactinemia.1 21
Nevertheless, newer selective, “prolactin-sparing” antipsychotic agents are preferred when hyperprolactinemia and its side effects, including sexual dysfunction, are recognized. In a study of 20 female patients with risperidone-induced hyperprolactinemia, amenorrhea, and sexual dysfunction, the change to olanzapine produced a significant fall in prolactin and improvement in sexual function.22 In a smaller study of five patients, four of whom were female, a switch to quetiapine produced improvements in hyperprolactinemia and in sexual side effects associated with conventional antipsychotic therapy.23
Sexual dysfunction associated with hyperprolactinemia induced by antipsychotic medication may be unreported by patients unless sought in the clinical history, and may be an important cause of noncompliance with medication. However, studies of therapeutic intervention with change of antipsychotic therapy or dopamine agonist therapy are very few and uncontrolled.
A 33-year-old woman had a history of acute renal failure after exposure to a plant-derived nephrotoxin. She rapidly required dialysis and had been having dialysis for 9 years when she presented. Initially, she had felt so unwell that sexual activity was not considered a priority for her or her husband. However, her feeling of well-being had improved, and she sought help for her lack of sexual drive and response. She had had no menses since she had been on dialysis. Her creatinine (predialysis) was 600 |Jmol/l (50-95). Serum prolactin was 2900 mU/l (< 500), luteinizing hormone was < 1 mU/l, and estradiol was < 100 pmol/l. Cabergoline was prescribed, but it was not tolerated and led to no decrease in serum prolactin.
Question: what is the mechanism and the management of hyperprolactinemia in renal failure?
Hyperprolactinemia is also common in patients with renal failure, secondary to increased production more than impaired clearance.24 Hyperprolactinemia appears to worsen, rather than improve, after the institution of peritoneal or hemodialysis.25 Women with advanced renal failure usually have amenorrhea and hypoestrogenemia, especially if there is hyperprolactinemia present, and studies have identified reduced sexual function in patients undergoing dialysis.26,27 Although the debility of the disease may be responsible for diminution in sexual interest and drive, this may be at least partly attributable to hypogonadism and hyperprolactinemia.28
The mechanism of the rise in prolactin and its role in sexual function in renal failure have been poorly understood. Although a fall in prolactin with bromocriptine therapy had been reported, prolactin in chronic renal failure appears to be less responsive to either stimulation or suppression than it is in patients without uremia.29,30 Recent studies have focused on the role of the prolactin receptor as a member of the cytokine/hemopoietin receptor superfamily. Prolactin promotes expression of the erythropoietin receptor and thereby promotes erythropoiesis. It has been suggested that, in renal failure, hyperprolactinemia is a compensatory response to the reduced availability of renal-derived erythropoietin.31 This hypothesis is supported by studies showing a fall in prolactin with erythropoietin therapy, although not all are confirmatory.32-34 Improvements in gonadal and sexual function, together with a fall in prolactin, have also been reported in patients with renal failure after commencement of erythropoietin therapy.35,36 However, it is not clear that these improvements are dependent on changes in prolactin rather than improved well-being.37,38
In a nonblinded study, estrogen and progestin therapy has been shown to improve sexual function in amenorrheic, hypo- estrogenic women on renal dialysis, compared with women receiving no sex hormone therapy.39 This study reported an increase in frequency of intercourse, sexual satisfaction, and libido. Interestingly, prolactin fell in those patients treated with estrogen and progestin, and the relative contribution of these changes to the improvement is unclear.
Finally, renal transplantation is associated with a fall in prolactin and an improvement in sexual function in women undergoing dialysis.40-42 The contribution of the fall in prolactin after transplant is undoubtedly a small part of the overall improvement in quality of life and sexual function.
A 40-year-old woman developed fatigue, weight loss, and skin pigmentation. Plasma cortisol was low and did not rise with synthetic ACTH (1-24) (cosyntropin) stimulation. Addison’s disease was diagnosed, and she was treated with replacement glucocorticoid and mineralocorticoid therapy. A few years later, she entered early menopause, and combined estrogen and progestin therapy was prescribed. She complained of dwindling sexual interest. Serum dehydroepiandrosterone sulfate was low, consistent with adrenal failure and reduced adrenal androgen production.
Question: what evidence supports dehydroepiandrosterone therapy for the treatment of sexual dysfunction in patients with adrenal failure?
Several studies have shown impaired quality-of-life measures, including measures of sexual function, in patients with adrenal insufficiency, despite adequate glucocorticoid and mineralo- corticoid replacement.43,44 This impairment seems to be greater for females than for males, and it is proposed that dehydro- epiandrosterone therapy is an important factor missing in conventional adrenal replacement regimens. 45
Dehydroepiandrosterone and dehydroepiandrosterone sulfate are major secretory products of the adrenal and are low in adrenal insufficiency of either primary or secondary origin. In the periphery, dehydroepiandrosterone functions as a prohormone, being converted to testosterone via hydroxysteroid dehydrogenase, or to estradiol by aromatase.46 In women, it leads to a rise in circulating testosterone. However, there is also evidence of dehydroepiandrosterone synthesis and metabolism in the brain, where it appears to exert effects on neuronal growth.47
Four studies of dehydroepiandrosterone therapy in adrenal insufficiency have directly addressed sexual function in women. There is variability in the adequacy of the measures of sexual function used. The study by Johannsson et al., showing no benefit of dehydroepiandrosterone in women with adrenal insufficiency secondary to pituitary disease, has been discussed above.5 Arlt et al. demonstrated a significant effect of dehydro- epiandrosterone 50 mg daily on sexual thoughts, interest, and mental and physical satisfaction.48 This study included 24 patients with both primary and secondary adrenal failure in a crossover design with a visual analog scale to assess sexual function. However, these findings could not be replicated in a similar crossover design study, using the same dose in 24 women with primary adrenal failure.49 Similarly, a parallel-group, placebo-controlled study, using dehydroepiandrosterone 25 mg daily in 36 women with predominantly primary adrenal failure, also failed to show any benefit of treatment.50
The lack of uniformity of findings in studies of dehydro- epiandrosterone replacement in a condition where there is documented deficiency highlights the complexity surrounding all studies of female sexuality. Moreover, it suggests that uniformity is not likely to be found in studies of dehydroepiandros- terone in patients without documented deficiency.
This group of conditions encompasses difficult cases of endocrine causation of female sexual dysfunction. They include diseases, such as hypoadrenalism, either primary or secondary, where deficiencies of hormones or prohormones have been identified, but therapeutic trials of replacement have failed to provide conclusive evidence of benefit. They also include conditions, such as drug-induced or uremia-associated hyperprolactinemia, where conventional therapeutic intervention is either contraindicated or ineffective. In all of these conditions there is a lack of recognition by practitioners and a lack of quality data on best-practice management.
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