Friday, September 14, 2007

Effect Of Premature Menopause On Sexuality

Premature menopause, that is, menopause – spontaneous or iatrogenic – occurring at or before the age of 40 years, affects sexual identity, sexual function and sexual relationships. The woman's health, wellbeing and achievement of life's goals may be variably impaired.

Factors modulating the individual's sexual outcome after premature menopause include: etiological heterogeneity of premature menopause and associated medical and sexual comorbidities; psychosexual vulnerability to premature menopause and associated infertility in survivors of childhood and adolescent cancers; impact of premature menopause on women's sexual identity, sexual function – particularly the biological basis of desire, arousal, orgasm and vaginal receptivity – and sexual relationships; partner-related factors; fertility issues; and preventive/therapeutic measures.

Hormone therapy is indicated but long-term safety data are lacking. An interdisciplinary medical and psychosexual approach comprises appropriate counseling, fertility protection, when
feasible, individualized hormone therapy and specific psychosexual treatment(s). Further research on fertility protection and the safety of long-term hormone therapy after premature menopause is needed.

Premature menopause (PM) refers to hyper-gonadotropic amenorrhea occurring at or beforethe age of 40 years. It may be spontaneous, usually referred to as 'premature ovarian failure'(POF), or iatrogenic, secondary to surgicalremoval of both ovaries (bilateral oophorec-tomy) or to the irreversible ovarian damagecaused by chemotherapy or radiotherapy (sys-temic, i.e., total-body irradiation, or pelvic). The term POF currently encompasses allmodalities of ovarian exhaustion when theovaries remain in situ.

The incidence of POF is increasing, largelydue to improved survival rates of cancer patientstreated with radiation and chemotherapy. Delayed diagnosis and management of POFleads to suboptimal outcomes. Anticipationand early detection of this condition in high-riskwomen is a critical step towards prevention andeffective treatment of associated psychosexualissues. This goal may be achieved by means ofovarian function testing, followed by early insti-tution of appropriate management to improvehealth-related and sexual outcomes. Choice ofstrategies should vary depending on the age ofonset, associated symptoms and fertility aspira-tions of the individual, and should change withthe patient's advancing age.

PM is a major turning point in a woman's life:the younger the woman, the higher the risk of sig-nificant health and psychosexual impact. Morbidity and mortality from cardiovascular dis-ease, stroke, accelerated brain aging andosteoporosis present a greater risk in PM womencompared with controls. A higher frequencyof psychosexual disorders and more significantpersonal distress are reported amongst PMwomen. The woman's overall sense of well-being and achievements of life goals may bevariably affected.

To prevent such negative outcome from pre-mature loss of sex hormones, clinicians usuallyconsider hormone therapy (HT). The three mostcredited international scientific associations onmenopause currently recommend HT to be con-tinued until the age of natural menopause, 51 years, with the exception of women with hor-mone-dependent cancers or obvious major con-traindications. However, scientific dataregarding benefits and risks of long-term HT inthis cohort of often very young women with PMof diverse etiology are minimal.

Therefore, this review focuses on the maincharacteristics of PM and its impact on the threemajor dimensions of human sexuality: sexualidentity, sexual function and sexual relationships. After reviewing the main factors modulatingsexual issues after PM, the paper analyzes:

  • Psychosexual development and sexual identityissues in survivors of childhood andadolescent cancers
  • Women's sexual identity after PM, with focuson femininity and fertility issues
  • Women's sexual function, with special atten-tion given to the consequences of iatrogenicmenopause in terms of sexual desire, arousal, orgasm and dyspareunia
  • Sexual relationships and main couple's vulner-abilities
  • Impact of ethnicity, both on prevalence andpsychosexual outcome of PM
  • Options for fertility protection and ovo-donation when feasible, accepted and legallyavailable
  • Medical and psychosexual management ofpre-existing or PM-associated female sexualdisorders (FSD)


A Medline search was carried out, with the searchterms PM, premature ovarian failure, iatrogenicmenopause, etiology, endometriosis, Turner'ssyndrome, fragile X syndrome, galactosemia, eth-nicity, childhood cancer survivors, adolescent sur-vivors, leukemia, Hodgkin's disease, breast cancer, gynecologic cancer, chemotherapy, radiotherapy, bone marrow transplantation, fertility protection, cryopreservation, sexual identity, sexual function, sexual relationships, desire disorders, arousal dis-orders, dyspareunia, orgasmic disorders, coupleissues, HT, estrogen therapy, androgen therapyand psychosexual therapy


The evidence specifically analyzing the relation-ship between PM and sexual dysfunctions, andbetween PM and available treatment options islimited, with the exception of new randomized, controlled trial (RCT) data on the effect of test-osterone patches on sexuality in surgically meno-pausal women (Level I). This review isbased on these new studies, and on Level II-2and Level III evidence (as per the US Preventa-tive Services Task Force), along with the clinicalexperience of the author (implied when no dataare referenced).

Prevalence of premature menopause & associated sexual disordersSpontaneous POF affects on average 1% ofwomen aged under 40 years, although per-centages as high as 7.1% have recently beenreported. The Study of Women Across theNation (SWAN), indicates that POF wasreported by 1.1% of women. By ethnicity, 1.0% of Caucasian, 1.4% of African–American, 1.4% of Hispanic, 0.5% of Chinese and 0.1% of Japa-nese women experienced POF. The differencesin frequency across ethnic groups were statisti-cally significant (p = 0.01). Lifestyle-relatedsociocultural factors, besides genetic factors, maybe important contributors to age at menopause, as well as modulators of its impact on sexuality. By convention, menopause that occurs at ages40–45 years is considered 'early' and occurs inapproximately 5% of women.

Iatrogenic PM, caused by benign and malig-nant conditions, affects 3.4–4.5% of womenaged under 40 years. The 5-year survivalfor all malignancies in childhood and adolescenceis 72% (up to 90% for some cancers), and an increasing number of survivors are facingthe challenges of adulthood deprived of theirgonadal hormones, unless an appropriate HT isprescribed. Some 25% of breast cancer patientsare premenopausal at diagnosis, and 15% areyounger than 45 years.

Systematic studies on the prevalence of FSDin women affected by PM are limited. A recentEuropean survey of 2467 women (in France, UK, Germany and Italy) showed that in the agecohort from 20–49 years the percentage ofwomen with low sexual desire is 19%, but is sig-nificantly higher (32%) in women who haveundergone surgical menopause. This differencedisappears when comparing naturally post-menopausal women (aged 50–70 years) and age-matched surgically menopausal women (46 and48%, respectively). The percentage of womendistressed by their loss of desire, and thus definedas having Hypoactive Sexual Desire Disorder(HSDD), was 27% in fertile women and 28%after surgical menopause in the age cohort20–49 years, compared with 11% in womenwith natural menopause and 14% in those withsurgical menopause in the age cohort50–70 years. Thus, although the probabilityof HSDD increases with age, the distress associ-ated with the loss of desire is inversely correlatedwith age. The data indicate that age at meno-pause is a critical factor: younger women under-going a surgical PM have a significantly highervulnerability to HSDD in comparison witholder women with either natural or surgicalmenopause.

Etiology of premature menopause & associated health vulnerabilitiesHeterogeneity is the hallmark of PM etiology. Itcan be idiopathic or can include genetic causes and autoimmune factors, or be associated with chronic diseases, such as primary biliary cirrhosis. PM canalso have iatrogenic causes, namely benign or malignant disease (Box 1).

Box 1. Etiology of premature menopause.

Premature ovarian failure

  • Idiopathic
  • Genetic: Turner's syndrome, fragile X syndrome, mosaicism, deletion/inversion, galactosemia
  • Autoimmune: lupus erythematosus, rheumatoid arthritis
  • Associated with chronic disease: chronic renal insufficiency, primary biliary cirrhosis

Iatrogenic: benign conditions

  • Endometriosis
  • Bilateral disgerminoma or cystoadenoma
  • Ovarian hyperstimulation in infertility
  • Oophorectomy concomitant to hysterectomy

Iatrogenic: women at risk of ovarian cancer

  • Breast cancer-associated genes (BRCA1 and/or BRCA2)

Iatrogenic: established malignant conditions

  • Bilateral oophorectomy
  • Chemotherapy
  • Pelvic radiotherapy
  • Total body irradiation

The effect of PM on health and sexuality var-ies accordingly. It may be limited in womenaffected by POF who already have a family andwho are receiving optimal HT. It may be dra-matic when the consequences of PM are super-imposed onto a serious medical condition, suchas chronic autoimmune disease or cancer, moreso if the latter is hormone dependent andcontraindicates HT.

Therefore, the diagnosis and treatment of sex-ual dysfunctions associated with PM require aninterdisciplinary medical and psychosexualapproach. If unaddressed, the many sexual fearsand complaints of women with PM can contrib-ute to feelings of helplessness and hopelessness, adding to the distress associated with PM.

According to the etiology, both symptoms ofmenopause and sexual problems may haveappeared before the clinical diagnosis of PM. Key factors to be considered in the clinicalpractice may be summarized as follows:

  • In POF, premenopausal symptoms – polymen-orrhea and/or menstrual variability, worseningof premenstrual symptoms, hot flushes or nightsweats, night tachycardia, insomnia, moodimbalance, irritability, arthralgias – usually not recognized as signs of imminent menopause, may have already challenged the woman's equi-librium, self-confidence and sense of control. Clinicians should alert themselves to thisdiagnostic possibility, independently of thewoman's fertile age, as an early diagnosis is thefirst step to minimizing PM consequences onboth general and sexual health
  • Turner's syndrome requires a timely diagnosisin order to start treatment in the early peri-pubertal years and minimize the impact of themissed production of sexual hormones ongrowth
  • Fragile X syndrome and other genetic condi-tions may be associated with a variable degreeof mental retardation, which may delay thediagnosis of PM and affect its consequences ongeneral health and sexuality
  • In galactosemia, an inherited inborn error ofthe major galactose assimilation pathway, long-term complications, such as cognitiveand motor abnormalities and hyperdonado-tropic hypogonadism in female patients, arestill unavoidable. Clinical management ofovarian failure relies on hormonal treatment
  • In autoimmune conditions, such as systemiclupus erythematosus (SLE), the impacton sexuality depends on the age of onset, rateof progression, severity of disease, duration oftreatment with cortisone and immuno-suppressants, and their impact on generalhealth, body shape and body image. In SLEpatients treated with cyclophosphamide, 60%suffered from POF and hypergonadotropicamenorrhea. In SLE-affected women, PMmay be the latest trauma of a challengingdisease or a devastating new problem in anotherwise controlled situation
  • Endometriosis may compound prior sex-ual dysfunction due to deep dyspareunia and/or chronic pelvic pain and low sexualconfidence associated with impaired fertility. Relationship issues related both to sexual diffi-culties and infertility further increase thevulnerability for problematic sexuality
  • Iatrogenic PM associated with cancer treat-ments may be the most challenging form ofPM. Key variables include: type of cancer, stage and prognosis; age at diagnosis; the surgery involved;conservative versus radical treatment;adjuvant chemo - and/or radio-therapy andassociated side effects; and pres-ence and severity of recurrences. The impact of bone marrow transplantation, either allo-genic or autologous, on overall health is a fur-ther complicating issue. Depending onetiology, menopausal symptoms appearshortly after surgical PM, while there may be avariable lag time between medical oncologicaltreatment and onset of PM. This istrue for PM subsequent to chemotherapy orradiation and varies according to differentdrug regimens, radiation doses and thewoman's age.

It follows that PM has a different impactaccording to whether it is 'isolated' in an otherwisehealthy woman, or associated with other genetic oracquired medical and psychological problems.

Factors modulating sexual issues associated with premature menopause

Etiology of PM is the single most powerful bio-logical factor affecting the psychosexual out-come. Age at PM and stage in life cycle, factorspersonal to the woman, and contextual factors –both relational and sociocultural – that interactand partly overlap, further contribute to modu-late the final impact of PM on the individualwoman and couple (Box 2).

Box 2. Factors affecting sexual outcome after premature menopause.

Biological factors

  • Age at PM
  • Etiology of PM
  • Premature ovarian failure versus PM associated with chronic disease
  • Iatrogenic: benign versus malignant causes
  • Debility from associated medical conditions
  • Reactive depression
  • Severity of the residual chronic pelvic pain and deep dyspareunia in endometriosis
  • Type of cancer, stage and prognosis, conservative versus radical surgery
  • Adjuvant chemo/radiotherapy/bone marrow transplant
  • Hormone therapy: feasibility, type and length
  • Fertility protection

Psychosexual factors

  • Psychosexual stage at PM: the younger the woman the higher the impact
  • Fulfilment of life goals prior to diagnosis
  • Coping strategies
  • Previous erotic self-perception, sexual self-confidence
  • Premenopausal sexual experiences and quality
  • Premorbid personality and psychiatric status
  • Social/professional role

Contextual factors

  • Family dynamics (attachment vs autonomy in peripubertal children and adolescents)
  • Couple dynamics and marital status
  • Partner-related issues: his acceptance of PM-induced infertility
  • Support network (family, friends, colleagues and self-help groups)
  • Quality of medical and psychosexual care
  • Ethnicity and sociocultural issues
PM: Premature menopause

Etiology of premature menopause & psychosexual issues in adolescents

In a lifespan perspective, the earlier the PM, themore complex the impact on all dimensions ofsexuality. Sexual identity is particularly vulnera-ble when PM disrupts the process of psycho-sexual maturity, both in women withPOF, especially those with Turner's syndrome, and in iatrogenic conditions, such as child-hood and adolescent cancers. In thesecases, the psychosexual impact of the primarydisease is added to the consequences of PM. Che-motherapy and/or radiotherapy, particularly inhematological cancers, may irreversibly damagethe ovaries. Pubertal changes may not occurunless timely HT is started. Attach-ment needs may be very disturbed in childrenand adolescents, due to repeated hospitalization, separation from parents, friends, school and play-time, invasive and painful tests and treatments, long hours of loneliness, anxiety, fear regardingthe future and possibly the absolute isolationrequired in bone marrow transplantation. The average time involved in treatment and closefollow-up in hematological cancers is 3 years: thiscritical suspension from normal life and the shiftto emergency survival may disrupt the basic process of psychosexual maturity. Achieve-ment of autonomy is delayed, compromising selfconfidence and the timing of normative psycho-sexual events, with variably increasing age at firstkiss, first dating, first masturbation, first foreplayand sexual intimacy. The impact of cancer at ayoung age on self-perception, plus the need forinvasive treatments, may further affect bodyimage, and self-confidence and intimacy issues –both physically and emotionally. Differentcoping strategies at the time of cancer treatmentmay shape future relationships, including sexualrelationsh ips.

Research focusing on sexuality in youngwomen surviving leukemia involving 31 survivors(mean age 20.1 years) and 50 healthy controls, confirms this complex psychosexual vulnerability. Women in this study were similar when con-sidering age at initiation of dating and sexualactivity, frequency of sexual intercourse, and opin-ions on sexual behavior, but significantly differentin specific domains:

  • Less feminine in sexual identity and moreinfantile (p < 0.002)

  • More restrictive, passive and submissiveimages of sexuality (p < 0.001)

  • Lower confidence with masturbation(p < 0.001)

  • Less experience of sexual intercourse(p < 0.03)

  • Less initiative in sexual intercourse(p < 0.003)

  • Minor ability to express personal sexualdesires to the partner (p < 0.001)

  • Less enjoyment of sexual intercourse p < 0.01)

  • Successful psychosexual development is a pre-requisite for a satisfactory sexual function

  • Psychosexual consequences of childhood/ado-lescent cancers may overlap the consequencesof iatrogenic menopause

  • The scenario is complex and needs to beaddressed with a combined medical andpsychosexual approach

Age at premature menopause, stage in lifecycle & fertility

Approximately 1/1000 adults is a cancer survi-vor, and most are of reproductive age. Radia-tion therapy may irreversibly damage fertility. The degree and persistence of damage dependson three factors: dose of radiation; intensity ofthe irradiation field; and the patient's age. The two most important factors affecting fertility fol-lowing cancer chemotherapy are a woman's ageand the agent used. Fertility is a critical issueaffecting sexual adjustment; the younger thewoman the higher her vulnerability to personaland couple's consequences of iatrogenic POF.

The loss of cycling periods deprives the youngwoman of a biological clock, of biorhythms thatmake her feel part of the community of fertilewomen, with their sharing of dreams andprojects regarding present and future family andchildren.

Already having children or not at the time ofPM is a critical factor modulating the overallpsychosexual outcome. While some women, especially those with higher education and career focus, are seen to be making a choice to delaypermanent relationships and children, PMremoves such options, often at a very earlystage. The loss of reproductive potentialmay specifically impair the motivation to initiateor accept intercourse in women highly distressedby their loss of fertility. 'It's worthless now', isfrequently a dominant theme.

Reproductive function is a particularly vulnera-ble dimension of sexual self-image in young PM women. After PM, biological maternitybecomes impossible, unless ovodonation is feasi-ble, accepted and legally available. Sexual repro-duction requires three types of differentiation: gonadal, for the production of gametes; genital, for the conveyance of gametes to the point of fer-tilization; and behavioral, for the urge to behavesexually. PM may variably impair all three:gametes are depleted; estrogen loss leads togenital atrophy; estrogen and androgen lossmay impair sexual pleasure, response anddesire. PM-related biological andpsychosexual factors do variably interact in theindividual woman, with infertility becoming theparadigm of all the losses the woman has to copewith. Prevention of infertility, when feasible, is acritical part of the medical approach (see sectionon protection of fertility).

Woman-related factors. These include biological, psychosexual andsociocultural factors.

Biological factors

PM may affect body image. Physical and psycho-sexual consequences of both the specific condi-tion causing PM and PM itself may impair bodyimage with a complex mechanism, more so whenthe etiology, for example, hormone-dependentcancer, contraindicates HT. Skin and hair textureand her scent (pheromone secretion is hormon-ally modulated) may all change. The skinis a key sexual organ: subtle changes ofincreased wrinkles, mucosal and skin drynessand loss of elasticity, hair loss and nail fragilitydiminish the young woman's sense of attractive-ness. Some speak of their sense of 'sexualinvisibility' and difficulties of dating. Change ofbody shape and tendency to gain weight isof special concern to women who care mostregarding their fitness. Many complain that theyneed much more exercise to maintain the samemuscle tone and strength – a more demandinggoal when fatigued.

Psychosexual factors

The coping attitudes a woman has, her personal-ity, mental wellbeing and quality of sexualitybefore PM, may further modulate the psycho-sexual outcome after PM. Denial, anger, an over-whelming sense of loss and/or a catastrophizingapproach increase the severity of consequent sex-ual dysfunctions. The quality of pre-menopausal sexual experiences is an independentpredictor, in PM as well as in normal menopause. Premorbid personality and psychiatric status fur-ther modulate coping strategies, affecting thefinal outcome. Affective disorders, depressionand anxiety, frequently secondary to the diagnosisof PM and the underlying medical condition, especially if chronic pain is involved, may furthermodulate the sexual outcome.

Eroticism may be impaired by both thereduced sense of femininity and sensuality andthe specific sexual dysfunctions. Loss of sex-ual desire, mental and gen-ital arousal impairment, orgasmicdifficulties, dyspareunia and physical sexual dissatisfaction may all affecterotic self-perception and sexual self-confidence.

Sociocultural factors

The level of education a woman has reachedbefore PM, a satisfying professional/social role– another dimension of female sexual identitythat is increasingly important in high-incomesocieties – and her socioeconomic status mayfurther modulate the impact of PM. The net-work of supportive relationships, personalincome and likelihood of accessing good medi-cal and psychosexual support may all be rele-vant. A solid social role may minimizethe impact of PM and its associated conditionsas it offers other life-goals than maternity. Indeed, the subsets of women more vulnerableto the consequences of PM, as seen in youngbreast cancer patients with PM, includethose who are younger, single and in conflict-ing relationships, and those with a lowsocio–economic status and/or unemployed. However, even social role and professional abil-ity may be biologically impaired by the impactof chemotherapy on the brain. Cognitiveimpairment following chemotherapy includedreduced attention, mental flexibility, speed ofinformation processing, visual memory andmotor function. The impairment was appar-ently unaffected by anxiety, depression, fatigueand time since treatment, and not related tothe self-reported complaints of cognitive dysfunction. The combination of chemo-therapy and loss of sexual hormones oncognition needs to be investigated.

Contextual factors

Partner-related factors

The partner's reaction to the associated infertil-ity, his/her personal and sexual health, the qual-ity of intimacy and of the relationship before andafter PM further modulate the individual andcouple's coping attitudes, the need for help andthe clinical outcome.

PM, particularly when associated with a can-cer diagnosis, can be a tremendous strain on thecouple's relationship and on the family. Youngerwomen experience more emotional distress com-pared with older women. Younger husbandsreport more problems carrying out domesticroles (p < 0.001) and more vulnerability to lifestressors (p < 0.01) in comparison with olderhusbands. PM may lead to male sexual dys-function. Vaginal dryness makes penetra-tion unpleasant or difficult, precipitatingerectile dysfunction or great delay in reachingejaculation, especially if the man believes the lackof lubrication to imply rejection. His partner'slack of sexual excitement may also lead to situa-tional erectile dysfunction. Men who cannotaccept the loss of reproductive potential may endthe relationship. Multiple psychosexual losses, on personal goals achievement, love and relation-ship commitment, may further worsen theimpact of PM on women's sexual wellbeing.


The ethnic background of the affected womanmay also be important. A cohort of 10, 425 survivors of cancer, diagnosed between1970 and 1986 and treated in childhood or ado-lescence (<20 years), of whom 46.3% werefemale, were followed at 25 oncology centers inthe USA and Canada, participating in the Child-hood Cancer Survivor Study. Self-reporteddata on marriage, living as married and divorcewere compared with the US population accord-ing to age-specific cohorts. Overall, 32% of sur-vivors were married or common-law (much lessthan the US population); 6% divorced or sepa-rated (women less and men more than the USpopulation); 0.07% widowed (less than the USpopulation); 62% never married (significantlymore than the US population in each cohort). Black survivors were more likely to have married, although they were more likely to divorce/sepa-rate once married compared with white or Hispanic survivors. Younger black survivors werealso more likely to divorce than black peoplewithout cancer. Ethnicity may prove to be animportant variable modulating adaptation tocancer, chronic disease, loss of fertility and PM.

Pathophysiology of sexual dysfunction after premature menopause

Reduced androgen production

In women, the serum levels of testosterone andproandrogens exceed that of estradiol, even dur-ing peak reproductive years, by several-fold toseveral thousand-fold. This often-over-looked biological fact highlights the importanceof androgens for a woman's wellbeing. In women, approximately half of circulating testosterone issecreted directly by the ovarian stroma and adre-nal zona fasciculata in roughly equal quantities;the other half is derived from conversion of theproandrogen androstenedione, which is secretedby the same tissues. The proandrogen dehydro-epiandrosterone sulfate (DHEAS) is producedentirely in the adrenal zona reticularis; conversionof DHEAS accounts for approximately 30% ofcirculating dehydroepiandrosterone (DHEA), with the remaining DHEA secreted by the adre-nal zona reticularis and the ovarian theca. Incontrast with the relatively sharp decline in circu-lating estrogens during natural menopause, androgen levels tend to peak when women are intheir twenties and drop gradually with age; typi-cal serum levels of testosterone and androstenedi-one at age 40 years are approximately half thoseat age 20 years, and at age 60 years are furtherreduced.

Ovarian androgen production ceases with sur-gical PM and is often minimal after radiation - orchemotherapy-induced PM. Despite having ova-ries in situ, such therapies may irreversiblydestroy not only follicles, but also the Leydigcells that are responsible for ovarian androgenproduction, leading to characteristic symptomsof androgen deficiency. These women constitutean often-unrecognized subgroup of iatrogenicmenopause patients.

The situation in POF is variable. Recent worksuggests reduced production of both ovarian andadrenal androgens in some women with POF, especially those with organ-specific antibodies.

Androgen loss undermines the neurobiologyof sexual drive and central/subjective sexualarousal, given androgen's biological 'initiating'role on the seeking–appetitive pathway in thebrain. Complaints of lack of energy, decreased muscle strength and tone, and reduced assertiveness may be due to androgenloss. Thus, androgen loss may play a rolein changes in body shape and body image. Itmay also contribute to genital arousal disordergiven androgen's enhancement of nitric oxideactivity in cavernosal tissues.

The impact of testosterone loss on sexualdesire and overall sexual wellbeing of womenafter natural and surgical menopause has beenrecently reviewed in Wo me n' s He al t h by Alex-ander and colleagues, with a solid body of evi-dence to support its role in improving women'ssexuality and psychological wellbeing. Thepositive impact of testosterone on all domains ofsexual function has also been reviewed in the lastCochrane review. However, a more cautiousapproach to the diagnosis of 'androgen defi-ciency' has been recently published by Wiermanand colleagues.

Reduced estrogen activity

For some women with POF, ovarian androgenproduction continues, allowing estrogen synthe-sis from adrenal and ovarian sources, particularlywhen the woman has an elevated body massindex. When ovarian androgen activity is absent, estrogen production will be limited to estronederived from conversion of adrenal androgens.

Loss of estrogens may lead to genital arousaldisorder, contributing to vaginal dryness and dys-pareunia. There is high clinicalcomorbidity of urinary tract symptoms, genitalarousal disorder and sexual pain disorders. Of note, urinary tract symptoms were associatedwith arousal disorders and sexual pain disorders(relative risk [RR]: 4.02 and 7.61, respectively), according to an epide-miological survey by Laumann and colleagues. This has a plausible pathophysiological back-ground given the role of progressive urogenitalatrophy, reduced vascular congestion aroundthe vagina and the urethra, where an extensionof the equivalent to the male corpus spongiosumhas been histologically demonstrated, andreflex hypertonicity of the pelvic floor. Sexualsymptoms associated with estrogenic loss includevaginal dryness, dyspareunia (both superficial anddeeper) and sexual avoidance due to pain and/orpostcoital cystitis. The marked clinical asso-ciation of sexual pain disorders with urogenitaldysfunction requires further research. Particularlywhen PM overlaps with cancer treatments forbreast or gynecologic cancers, genital arousal disor-der and dyspareunia tend to worsen over time, making early intervention urgent.

It is possible that estrogen loss may be involvedin the reduced arousability and desire from PM. Although traditionally androgen rather thanestrogen has been considered to be the relevantsex hormone, both hormones maycontribute to optimal desire and mental and gen-ital arousability. Loss of sexual hormones maysynergize in causing FSD after PM.

Medical comorbidities associated with premature menopause

The psychosexual consequences secondary to sex-ual hormone loss may be further worsened by con-comitant medical comorbidities associated with orconsequent to the different etiologies of PM. Asthenia and depression may contribute to loss ofdesire and difficulties in mental arousability. Radi-cal surgery and pelvic radiotherapy may cause vag-inal shortening and vascular damage, and impairthe genital arousal response, leading to vaginaldryness, introital and deep dyspareunia and orgas-mic difficulties. Associated bladder problemsmay further complicate the clinical picture. Clini-cians should be aware that a comprehensive medi-cal evaluation of women affected by PM, andappropriate management of their menopausalsymptoms, is a prerequisite for both optimalhealth outcomes and psychosexual management. Unfortunately, this comprehensive approach isstill too often neglected, even in recent years, particularly in cancer survivors.

Diagnosis of female sexual disorders associated with premature menopause

FSD may be antecedent to PM, concomitant toPM, and/or specifically caused and/or main-tained by PM. Early diagnosis of PM is key:alerting symptoms, even in adolescents, includecycle irregularities, such as polymenorrheaand/or skipping periods not due to other obvi-ous causes, worsening of the premenstrualsyndrome, transient and recurrent hot flushesand sweats, night tachycardia and/or sleep disor-ders (more frequent in the menstrual phase, when estrogens are at the lowest level) and/orsexual complaints. The etiology of PM, accom-panying symptoms (cycle-related, menopausaland/or sexual), time since PM diagnosis, ongo-ing treatments (for the disease causing PM, ifany, or HT) and her current health may alldeeply modulate the physical and psychosexualscenario that the woman is experiencing.

A comprehensive diagnosis of sexualdysfunctions associated with PM should there-fore investigate both the health context and outcome related to PM and the specificpsychosexual complaint, focusing on thefollowing factors.

Etiology of the female sexual disorderPM may act as a specific biological precipitatingfactor in a context of a variable individual and/orcouple psychosexual vulnerability. Coherently with the pathophysiology of PM, thehealthcare provider should evaluate:

  • Biological factors, such as age at PM andmodality of loss of sexual hormones (suddenin surgical menopause vs gradual in POF ofvarious etiologies). Menstrual irregularitiesand/or menopausal symptoms should alert theclinician to an impending PM, independentlyof the woman's age: the earlier the diagnosis, the higher the possibility of more effectiveinterventions to protect fertility and sexualfunction. Potential contributingfactors, such as pelvic floor disorders, urologi-cal issues (e.g., recurrent cystitis or urinaryincontinence), neurological conditions (par-ticularly pain-related), depression and anxiety(either pre-existing, associated with or causedby PM), should be assessed. All themedical conditions that may directly or indi-rectly affect sexuality, through their multi-systemic impact and/or the consequences ofpharmacologic, surgical and/or radio-therapeutic treatment, should be consideredin the differential diagnosis of potential con-tributors to FSD. If the woman is alreadyreceiving HT after PM and complains of per-sisting FSD, diagnosis should consider if andwhy HT could be inadequate, to offer a betterHT tailoring. Clinicians should reconsiderother contributors, biological, psychosexual orcontext-dependent, not previously evaluatedor more recently appeared.
  • Psychosexual factors: diagnosis should includepredisposing psychosexual factors (such as pro-longed attachment dynamic and/or sexualidentity issues secondary to childhood or ado-lescent cancers); body image con-cerns, more frequent in women treated forbreast or gynecologic cancer orreceiving long-lasting corticosteroids for SLE;loss of self-esteem and self-confidence, whichmay also modulate the level of trust in the rela-tionship, the intensity of the commitment andthe confidence in loving and long-standingattitudes toward affective and erotic intimacyafter the disrupting effect of PM; and previous maternity or desire for having chil-dren. Diagnostic attention should carefullyrecord the leading sexual symptoms thewoman is reporting and the associated FSD.
  • Contextual factors: diagnosis should considerif the woman is single or in a significant rela-tionship, current interpersonal difficulties, partner's general health issues and/orsexual dysfunctions, his concerns regardingfuture fertility, and sexual, emotional and/orsociocultural contexts.

It is important to determine whether the dis-order is generalized (with every partner and inevery situation) or situational (specifically pre-cipitated or worsened by partner-related orcontextual factors, which should be specified): the former is more likely rooted in thebiological etiology of PM and related FSD, while the latter is more likely to involve psycho-dynamic/relational factors. For example, loss ofdesire consequent to POF and associated infer-tility may be precipitated by the partner's inac-ceptance to remain childless, but may berelieved in a relationship with a partner whoalready has children.

It should be noted whether the disorder hasbeen lifelong (from the very first sexual experi-ence) or acquired after PM, after months or yearsof satisfying sexual interaction.

In addition, it should be recorded whether thelevel of distress consequent to PM and its etiol-ogy, and FSD, and its impact on personal life isan important factor. Sexual distress should bedistinguished from nonsexual distress and fromdepression. The degree of reported dis-tress may have implications for prognosis and forthe woman's motivation for therapy.

The woman's perception of the relative weightof different factors contributing to her currentcomplaint should be noted, as well as her (andher partner's) motivation to comply with treat-ment recommendations. In a stable rela-tionship, counseling for both partners couldhelp the couple understand the compoundingeffects of:

  • The woman's impaired physical response fromandrogen deficiency and reduced sexual self-image from the prematurity of the menopause– both of which reduce her sexual arousability
  • Lack of reward from sexual experiences, resulting in little motivation to repeat them
  • Decreased emotional intimacy due to negativesexual outcomes

On the positive side, couples should beinformed of the possibility of regaining a satis-factory sexual intimacy if appropriate HT, when indicated, and psychosexual support areintegrated in the therapeutic approach.

Physical examination

Given the importance of the biological disruptionassociated with PM, the diagnosis of FSD shouldbe made in the context of a rigorous medicalassessment. Accurate physical exami-nation of the woman, particularly her externalgenitalia, vagina – including end vaginal pH –and pelvic floor should be carried out, with specialattention paid to recording the 'pain map' for dyspareunia. Iatrogenic consequences of sur-gery and/or pelvic radiotherapy (cosmetic andfunct ional) should be recorded. Assessment ofvaginal tropism and pH is preliminary to topicalestrogenic therapy, when oncologically appropri-ate, to normalize both the vaginal ecosystem, thusreducing the vulnerability to recurrent vaginitisand cystitis, and vaginal lubrication. The physical examination mayalso contribute to the assessment of acquireddesire disorders, given that they are frequentlysecondary to sexual pain disorders.

Clinical approach to psychosexual consequences of premature menopause

Psychosexual impact of premature menopause in adolescents

Psychosexual support should be offered to ado-lescents who face POF, either spontaneous oriatrogenic. Well-tailored HT, whenoncologically appropriate, should be recom-mended. Bioidentical hormones (i.e., estradioland natural progesterone) may be appropriate asthey 'mimic' the normal cycle. However, manyyoung women prefer the estroprogestinic contra-ceptive choice (pill, patch or vaginal ring) to feel'normal' like their fertile friends.

Prevention of infertility in women facing impending premature ovarian failure

Fertility normally peaks in the early twenties. Results from studies on women treated withdonor sperm demonstrate that the monthlyprobability of conception leading to a live birthremains optimal until age 31 years, and decreasesprogressively thereafter. However, at age38 years, the monthly probability of conceptionhas already dropped to a quarter of that inwomen aged below 30 years. This probabilityof conception is likely to be significantly further reduced in women facing an earlier menopausaltransition, and this should be clearly discussedwith the woman/couple when diagnosingimpending PM. However, fertility is not defi-nitely excluded in POF and cases of spontaneouspregnancies having been reported 2 years after aconfirmed diagnosis of PM.

Protection of fertility in these women is there-fore a key issue. It may be indicated in young, single women facing a diagnosis of spontaneousPOF, or in young couples who cannot committo/afford a pregnancy in that period of life and yetwould like to maintain an open door for thefuture. It may reduce the emotional and psycho-sexual impact of ongoing cancer treatment andhelp to maintain hope in a better future. However, an honest disclosure of current limits of all thesetechniques should be clearly acknowledged incounseling with patients.

Protection of fertility can be surgical, with trans-position of the ovaries away from the radiationfield to protect them from the toxic effect of radio-therapy; pharmacologic (with oral contraceptivepills, medroxyprogesterone acetate, gonadotropin-releasing hormone agonists [GnRH-a]); and/orinvolve assisted reproductive technologies.

Three lines of research are currently raising newhopes in the pursuit of ovarian and fertility protec-tion in young women: cryopreservation, temporaryovarian suppression and oocyte protection.


Cryopreservation is an option in women withimpending POF, either spontaneous (when fam-ily history suggests a high risk of it) or in womenwho have to undergo chemo - and/or radio-ther-apy for cancer. Oocyte cryopreservation canbe considered for single adult women whounderstand that pregnancy rates are low withthis experimental strategy. However, thisapproach, similar to embryo freezing, needsseveral weeks of ovarian stimulation.

Women of reproductive age and their part-ners can undergo a cycle of IVF to cryopreservetheir embryos before chemotherapy. Unfortunately, most cancer patients do not havesufficient time to complete the necessary ovarianstimulation for IVF, a choice that may also berisky in patients with hormone-dependent can-cers. This option is also not acceptable for singlewomen who do not want to use donor sperm fortheir children.

An experimental ovarian cryopreservation andautotransplantation technique has been devel-oped. Cryopreserved ovarian tissue, obtained from a 30-year-old woman with breast cancerbefore chemotherapy-induced menopause, wassuccessfully subcutaneously transplanted 6 yearslater. Ovarian function resumed and 20oocytes were retrieved. Of the eight oocytes suit-able for IVF experiments, one fertilized normallyand developed into a four-cell embryo. How-ever, hematological and solid tumors that mayspread to the ovary are contraindications to anyconsideration of grafting.

Temporary ovarian suppression

Experimental temporary ovarian suppressionversus chemotherapy for adjuvant therapy inbreast cancer has recently been evaluated. Theefficacy and tolerability of goserelin (3.6 mgevery 28 days for 2 years; n = 817) versus cyclo-phosphamide, methotrexate and fluorouracil(CMF) chemotherapy (six 28-day cycles;n = 823) for adjuvant therapy in premenopausalpatients with node-positive breast cancer wastested. Analysis was performed when684 events had been achieved and the medianfollow-up was 6 years. A significant interactionbetween treatment and estrogen status wasfound (p = 0016). In estrogen receptor (ER)-positive patients (approximately 74%), but notin ER-negative patients, goserelin was equivalentto CMF for disease-free survival (hazard ratio[HR]: 1.01; 95% confidence interval[CI]: 0.84–1.20). Amenorrhea occurred in morethan 95% of patients by 6 months versus 58.6%of CMF patients. Menses returned in most gos-erelin patients after therapy had finished, whereas amenorrhea was generally permanent inCMF patients (22.6 vs 76.9% amenorrheic at3 years).

Despite these and other positive reports, thelong-term effects and benefits of cotreatment withGnRH-a are still unclear. This treatment shouldtherefore be offered as an investigational protocol, with institutional board review, and appropriateinformed consent, to young women (and couples)of ch ildbearing age with ER-positive breast cancerwho would like to consider maternity aftercompletion of breast cancer therapy.

Oocyte protection

The mechanism mediating the undesirable ova-rian toxicity of cancer therapies has only recentlybeen explored. Some important, although verypreliminary, insights into the role of ceramideand sphingosine-1-phosphate as a mediator andsuppressor, respectively, of cancer therapy-induced oocyte apoptosis have emerged over the past few years. A better understanding of howradiation and chemotherapy destroy this irre-placeable population of ovarian cells may allowfuture development of novel lipid-based strategiesto prevent infertility and PM. However, thisapproach is currently only experimental.

Management of sexual dysfunction associated with premature menopause

The most important sexual issues are related to:

  • Age and psychological impact of the diagnosisof PM per se
  • Effects of estrogen and androgen loss
  • Severity of menopausal symptoms
  • Loss of fertility and its meaning to both partners

Early diagnosis of PM is key to effective man-agement. HT is the hormonal etiologicalanswer, when no contraindications exist. HT-positive effects on both menopausal symp-toms and acquired FSD after PM may be suffi-cient to normalize sexuality in women withspontaneous POF or after surgical menopause. HT is also a pre-requisite for the specific treatment of other con-tributors to sexual dysfunctions after PM. Management of FSD is more difficult in femalesurvivors of breast cancer or genital adeno-carcinoma. Current contraindications toHT in such patients complicate the treatmentof both the menopausal symptoms and con-comitant sexual disorders. Optimal manage-ment of sexual dysfunction associated withmenopause has been recently well discussed. Here the focus is on special issues arising fromthe prematurity.

Sexual interest/desire disorders

PM may exacerbate lifelong or acquired hypo-active desire/interest disorder, usually comorbidwith subjective arousal disorder. Both may benefitfrom medical and psychosexual approaches.

Medical approach


Androgen treatment, although still consideredinvestigational in many countries, including theUSA, may be indicated when the neurobiology ofsexual desire is impaired by the androgen loss typ-ical of surgical menopause. RCTs indicate the positive effect of androgens, namely testosterone, on different domains offemale sexual function. The useof androgens locally for vulvar dystrophy and cli-toral insensitivity is often overlooked, but is a veryefficacious treatment for genital sexual dysfunc-tion. A recently published RCT was conducted insurgically menopausal women (aged 24–70) whodeveloped stressful hypoactive sexual desire disor-der. Treatment with 300 µg/day testosteronepatches in women receiving estrogen therapyincreased sexual desire and frequency of satisfyingsexual activity and were well tolerated. Sec-ondary outcomes indicate a significant improve-ment of arousal and orgasm, self-image and self-esteem, and a significant reduction in anxiety andconcerns. The testosterone patch treatment wasapproved by the European Agency for the Evalua-tion of Medicinal Products in July 2006. Moststudies to date have involved women with surgicalmenopause for benign disease. Androgen treat-ment attempting to achieve high physiologicalandrogen levels rather than markedly supraphysi-ological levels is now beginning. Awareness thatandrogens may be important for sexual arousabil-ity and response, as well as possibly increasing sex-ual thinking and desire, is another importantadvance. Caution remains regarding hor-mone-dependent cancers, with different opinionsamong experts. Hormonal therapy with estra-diol and norethisterone has shown a signifi-cant improvement in muscle strength, tone andperformance in a controlled study in post-menopausal women. This finding is of specialinterest for women complaining of PM associatedwith low sexual drive and somatic symptoms, such as reduced muscle competence, who are con-cerned regarding their fitness and physical shape. Tibolone, available in Europe but not in the USA, via its androgenic metabolite and its ability to sig-nificantly reduce sex-hormone binding globulin, has been shown to increase sexual desire/interestand subjective sexual arousal. Long-term safetydata for the use of androgens or tibolone regard-ing cardiovascular or metabolic outcomes are lack-ing. Careful ongoing follow-up is necessary, inaddition to explaining that androgen therapy forsexual dysfunction is still deemed investigationalin many countries, even for women with knownsudden reduced production.


There are no approved nonhormonal pharmaco-logical treatments for low arousability or low desire, but a recent placebo-controlled study of bupropionfor nondepressed women with low desire showedincreased sexual arousability and response in thosereceivin g active drug. However, changes in 'sex-ual desire', defined as sexual thoughts and fantasies, were not significantly different from placebo.

Psychosexual approach

Individual psychosexual or behavioral ther-apy should be considered, especially whenpsychosexual immaturity, attachment issues, sex-ual inhibitions, poor erotic skills, poor bodyimage, low self-confidence or previous abuse areinvolved. Any comorbid depression and anxietyshould be addressed with a combined pharmaco-logical and psychotherapeutic approach. Associated sexual dysfunction in the partnercontributing to the woman's low desire must alsobe addressed. Similarly, nonsexual couple issues, such as conflicts, poor erotic skills or communi-cation inadequacies, need to be addressed firstwith couple psychotherapy.

Arousal disorders

Subjective and combined arousal disorders, eitherlifelong or acquired, usually comorbid with sex-ual desire disorders, should be treated as men-tioned above. Combination of medicaland psychosexual therapy is most beneficial.


Vaginal dryness is the most frequently reportedsymptom of genital arousal disorders. It can be treated at least with localestrogen. The Million Women Study, within the limits of an observational study, is reas-suring regarding breast cancer risk when t opicalvaginal treatments are prescribed, the RR being0.67 for any type of vaginal estrogen. Itssafety in breast cancer patients was recently con-firmed in the cohort study of Dew andcolleagues. In terms of compliance, one head-to-head study suggested vaginal treatment withtablets of 17-.-estradiol is preferred to topicalconjugated equine estrogens. Vaginal estro-genic treatment is key when the genital arousaldisorder causes and/or is associated with dyspareu-nia, postcoital cystitis, urogenitalatrophy or urinary incontinence. Earlytreatment, during pelvic or vaginal radiotherapy, may minimize the impact of radiotherapy on vag-inal tissue.

While women with prior breast cancer, SLE orother known contraindications to exogenousestrogen are prescribed local vaginal estrogen only, the question of systemic estrogen for otherwomen after PM, over and beyond short-termmanagement of menopausal symptoms, remainsopen. Guidelines from the American College ofObstetrics and Gynecology and the CanadianSociety of Obstetrics and Gynecology endorse thecareful prescription of systemic estrogen treatment(ET) for some of these women for ongoing sexualproblems. Recommendations from the EuropeanMenopause and Andropause Society, the Inter-national Society of Menopause and the NorthAmerican Menopause Society include PM beingtreated with HT until the age of natural meno-pause (51 years of age), unless a specific contrain-dication is diagnosed. In iatrogenic PMcaused by benign conditions, such as endo-metriosis when the uterus is preserved, individu-ally tailored continuous combined estrogen plusprogesterone is the first choice. Caution regardingsystemic HT in breast cancer patients continuesafter the publication of the Hormonal replace-ment therapy After Breast cancer diagnosis – Is iTSafe. (HABITS) study, which reduces theoptimism from previous studies. Although RCTsof tibolone have shown a positive effect of thedrug on both subjective and genital arousal, these studies have not focused on women diag-nosed with sexual dysfunction. The randomized, prospective, controlled Livial International Studyin sexual Arousal disorders (LISA) trial of tibolonein women with breast cancer has been completed. Data should be available in 2007–2008.

Radical hysterectomy accompanying bilateralsalpingo-oophorectomy in the young woman mayor may not damage the autonomic nerve fiberssubserving vaginal and vulval engorgement. Sur-geries minimizing damage to autonomic fibers inthe uterosacral and cardinal ligaments may mini-mally impair the urogenic vasodilation. It ispossible that phosphodiesterase inhibitors mayprove to be beneficial for women with autonomicnerve damage. Early rehabilitation, with topicalestrogen (except in women having had an adeno-carcinoma) soon after surgery, pelvic floor stretch-ing and vaginal moulds to maintain vaginalelasticity, optimal length and 'h abitability', is to berecommended to guarantee the possibility ofsatisfying intercourse.


Counseling to address the complex psychosexualissues that may inhibit mental arousal andworsen the desire disorder is a key part of thetreatment. Couple support, in stable cou-ples, may also help to address the partner's issues, such as an acquired functional erectile deficit, when vaginal dryness may precipitate it.

Orgasmic disorders

Comorbidity of FSD is frequent; more so in PMwomen, especially after surgical menopause, asthe loss of testosterone may impair both the central and peripheral mechanisms leading toorgasm. Orgasmic difficulties after PM mayalso be treated with a combined medical andpsychosexual approach.


True orgasmic disorder acquired subsequent toPM may benefit from HT. Failure to orgasm maybe the result of unsatisfactory stimulation ofestrogen-depleted vulval and/or vaginal tissues, with pain and soreness distracting from sexualsensations. Topical or systemic estrogen mayrestore orgasmic potential. However, not uncom-monly, there is difficulty in reaching orgasmdespite ET and any orgasm is muted. As previ-ously mentioned, androgen's ability to restoreorgasmic response is now under more intenseinvestigation, with an increasing body of evi-dence supporting a positive restorative role of tes-tosterone. Pelvic floor rehabilitationis indicated when hypotonia is diagnosed as con-tributing to reduced orgasmic sensations. Comorbid urge or stress incontinence with fearof leakage with orgasm should be appropriatelyaddressed.


Lifelong 'isolated' orgasmic disorders may benefitfrom a behavioral educational treatment, encour-aging self-knowledge and eroticism with theexperience of higher arousal sensations, possiblywith use of vibrators. However, more often, lack of orgasm is associated with poor arousal, the latter being the focus of treatment.

Lack of orgasm may result from intrapersonalpsychological issues related to the PM or to itsetiology. Fear of premature aging and loss of sex-ual attractiveness is a common theme. Emo-tional distancing between the partners from theoutcome and meaning of PM may similarly con-tribute. Psychological help for the couple or thewoman may be needed in addition to a medicalapproach.

Sexual pain disorders

Pain is (almost) never psychogenic. Sexual pain isno exception. Attention to biological etiolo-gies of dyspareunia is mandatory also in PMpatients, when loss of sexual hormones may becomplicated by factors more related to a specificPM etiology, such as vaginal shortening after radi-cal surgery for cervical cancer and/or vaginal nar-rowing after pelvic or vaginal radiotherapy. Again, the clinical approach shouldconsider the two, usually interacting, components.


Dyspareunia may have a prominent endocrineetiology, secondary to sexual hormone loss, inwomen undergoing spontaneous POF or aftersurgical menopause for benign conditions. Restoring the hormonal balance through appro-priate HT may be sufficient for the woman toenjoy a normalization of her sexual response anda pleasurable intercourse. Dys-pareunia may be variably complicated by differ-ent iatrogenic factors, when PM is secondary tomedical treatment of cancer. Urogenitalatrophy may cause painful vaginal entry, a fric-tion type of dyspareunia associated withreduced lubrication, reflexive pelvic muscletightening or embarrassment from repeated vag-inal or urinary tract infections. Pelvic radi-ation may cause painful or impossible vaginalentry. It may also cause distress from the part-ner's complaint of minimal depth of penetrationdue to vaginal foreshortening.

The stress of PM may be associated with exacer-bation or onset of localized vulvar dysesthesia (for-merly known as vulvar vestibulitis syndrome). There may be pre-existing chronic deep dyspareu-nia from the underlying disease, for example, endometriosis. Whatever the nature of the initialmedical problems, the mechanisms of chronicpain, with its associated central and peripheralsensitization, may be similar.

Reflexive pelvic muscle tightening ('hyperactiv-ity of the elevator ani') may benefit from self-mas-sage and stretching, electromyographicbiofeedback and/or physiotherapy. If vulvo-dynia is present, comprehensive treatment shouldinclude pain modulation with predominantlycentrally acting drugs, such as pregabalin, gaba-pentin or amitryptiline, which seems to workboth at central and peripheral levels, and periph-erally acting anthalgic techniques, such as elec-troanalgesia and/or the ganglion impar block. Reducing the complex biological components ofpain is preliminary to the psychosexual support.


Ongoing sexual symptoms, such as dyspareunia, can contribute to the avoidance of all physicalintimacy. Affectionate sharing may partiallyreplace former erotic experiences such that over-all emotional satisfaction remains high. However, the price of survival – the progressiveloss of the erotic life and physical satisfaction –can be high, especially in young women (andcouples) where PM is secondary to iatrogenictreatment for malignant conditions.

Management needs to be both general andspecific. Generally the couple can be encouragedto capitalize on nonpenetrative sex – expanding, possibly for the first time, the full range of sexualexpression over and beyond intercourse. Abrief explanation of the nature of chronic painand its detrimental effect on the rest of thewoman's sexual response cycle should be given toboth partners. Specific therapies includebehavioral therapy, especially when there is pho-bic avoidance, vaginal inserts, progressive reha-bilitation of the pelvic floor and, if necessary, pharmacological treatment for any intensephobic avoidance.

Multidisciplinary teams

Sexual dysfunctions associated with PM need amultidisciplinary approach, given the hetero-geneity of etiological factors and the variety ofco-morbidity, both in the medical and psycho-sexual domain. One individual clinician couldbecome skilled in all areas but often appropriatereferral is required (Box 3).

Box 3. Referral resources.
  • Gynecologist: when premature menopause (PM) requires a well tailored hormone treatment (HT) and/or diagnosis of pelvic comorbidities.
  • Gynecologist with special interest in sexual dysfunction: when sexual dysfunction requires specialized evaluation and/or treatment.
  • Reproductive endocrinologist: when fertility protection and/or fertility assisted technology is an issue.
  • Urologist: when the partner has erectile or ejaculatory dysfunction that is assessed to require medical intervention.
  • Internist or family physician with special interest in sexual medicine: for sexual dysfunctions in either partner and/or metabolic comorbidities (e.g., diabetes).
  • Oncologist: when HT is considered for cancer survivors; and/or recurrences are present.
  • Psychiatrist: when depression and anxiety are precipitated by PM.
  • Sex therapist: to address the need for different and more intense sexual stimulation in view of the altered hormonal status, situational erectile dysfunction, either partner's orgasmic difficulties, as well as loss of sexual motivation in either partner.
  • Couple therapist: when relationship issues are a primary contributor to the sexual dysfunction.
  • Individual psychotherapist: when personal psychodynamic issues are inhibiting sexual function.
  • Physical therapist: when hyper- or hypo-tonicity of pelvic flooris contributory.

The gynecologist is usually the first physicianto be asked for help for FSD after PM. His/herrole is key to prescribe a well-tailored HT, whenno contraindications exist, and to address FSDitself, if he/she has special interest in sexualdysfunction. This approach can be carried out byan internist or family physician with a specialinterest in sexual medicine, for sexual dysfunc-tions in either partner. The oncologist is a neces-sary decision-making partner when HT isconsidered for cancer survivors. The urologist isanother referral resource, when the partner haserectile or ejaculatory dysfunction that is assessedto require medical intervention. The psychiatrist'shelp is indicated when depression and anxiety areprecipitated by PM and do not normalize afterHT. Given the increasing awareness of pelvic floordysfunctions as predisposing, precipitating and/ormaintaining factors in the etiology of FSD, beforeand after PM, the physical therapist is a key figureof the multidisciplinary FSD team, specificallywhen hyper - or hypo-tonicity of pelvic floor iscontributory.

Physicians may need to specifically refer topsychotherapists with different specializations:to a sex therapist, to address the need for differ-ent and more intense sexual stimulation in viewof the altered hormonal status, situational erec-tile dysfunction, either partner's orgasmic diffi-culties and loss of sexual motivation in eitherpartner; to a couple therapist, when relationshipissues are a primary contributor to the sexualdysfunction; to an individual psychotherapist, when personal psychodynamic issues areinhibiting sexual function.

Before referral, the clinician should establishthat the woman has one or more treatable sexualdysfunctions and has tried a first-line hormonalapproach if indicated. Medical, lifestyle and rela-tionship issues need to be addressed before specificsexual referral. The sexual symptoms as describedby the patient can be summarized in the referralletter, along with the provisional diagnoses. Othermedical problems, medications, past relevantmedical and surgical interventions, and importantpsychological and relationship issues should beincluded. The clinician should also detail manage-ment to date, plus outcome. It is helpful to endwith expectations (e.g., treat, advise, educate andoperate) of the specialist and of the patient. Suchtransfer of information gives the patient/couplethe feeling of coordinated care, and confirms thelegitimacy of their sexual complaints and thehealthcare providers' commitment to addressthem with an integrated approach.


PM is a heterogeneous condition comprisingwidely different etiologies. Early assessment of theindividual's risk of developing POF, development of a strategic management plan, and timely com-mencement of infertility and hormone deficiencytreatment, together with counseling, in an inte-grated management plan should improve both theshort- and long-term health of those with POF.

The impact of PM on women's sexuality ismodulated by its etiology, the lifecycle stage, fac-tors personal to the woman, as well as thoserelated to relationship, family and society. Age isa critical factor: the earlier the PM, the higherthe likelihood of complex impairment of manyaspects of sexuality. PM may be associated withdelay in reaching psychosexual maturity, impair-ment of the sense of sexual identity, onset orexacerbation of sexual dysfunction, and emo-tional distancing of partners. When appropriateHT is prescribed, and the woman and her part-ner have worked through the real and symboliclosses of PM, the sexual outcome is generallypositive. Sexual adjustment can be increasinglydifficult when women are younger, single or introubled relationships, when childlessness is amajor loss, when the partner cannot accept achildless future, and when the socioeconomicstatus is low. Improvement of the sexual out-come requires a comprehensive assessment of thepredisposing, precipitating and maintaining fac-tors using a combined medical and psychosexualapproach. Appropriate counseling, medical andpsychosexual, is a critical component of the rela-tionship between the woman and her healthcareprovider(s) on such a sensitive issue. In the caseof a stable relationship, listening to and counsel-ing the couple may be critical, more so wheninfertility is a core issue and/or specific sexualdisorders are complained of.

Future perspective

The incidence of POF is increasing, largely due toimproved survival rates of cancer patients treatedwith radiation and chemotherapy. The two majordeterminants of ovarian damage following cancertherapy are the woman's age and the class of che-motherapeutic agents used. As delayed diagnosisand management of POF leads to suboptimaloutcomes, anticipation and early detection of thiscondition in high-risk women by means of ova-rian function testing, followed by early institutionof appropriate management, should become aroutine part of cancer patients' follow-up, toincrease their quality of life and sexual life. Choiceof strategies should vary depending on the age ofonset, associated symptoms and fertility aspira-tions of the individual, and should change withthe patient's advancing age.

A strong educational effort is needed, bothamong healthcare providers and women, toincrease their awareness of PM and the need forearly diagnosis and treatment.

Counseling on sexual issues after spontaneous oriatrogenic POF should be increasingly offered inevery menopausal clinic and in oncology centers.

Given the current controversy on the 'real'androgen deficiency, further research onthe specific role of PM in the etiology of sexualdysfunction and safety data for long-term estro-gen and androgen therapy in young women withPM are needed.

The most promising area of PM researchinvolves fertility preservation: prevention ofgonadal toxicity in all conditions requiringchemotherapy (either malignant or benign, suchas SLE) is rapidly improving and future studieswill design different treatment options.

Development of better freezing, thawingand maturation techniques is expected toimprove pregnancy rates following oocytescryopreservation in PM patients.

Gynecologists, reproductive endocrinologists, oncologists and family physicians shouldbecome increasingly familiar with the optionsavailable to preserve fertility in young cancersurvivors. Options should be discussed beforestarting treatment.

Definition of premature menopause & key features

  • Premature menopause (PM) refers to menopause occurring at or before the age of 40 years.
  • PM may be spontaneous, which is referred to as premature ovarian failure (POF).
  • PM may be iatrogenic: secondary to surgical removal of both ovaries (bilateral oophorectomy), or to the irreversible ovarian damage caused by chemotherapy or radiotherapy.
  • Surgical menopause suddenly deprives the woman of the total ovarian hormone production.
  • POF, either spontaneous or iatrogenic, has a gradual, insidious evolution over 2 or more years.
  • Occasional ovulation is possible for 2–3 years after POF diagnosis, defined as follicle-stimulating hormone elevation above 40 International Units (IU)/l in two consecutive samples, 1-month apart.
  • A variable ovarian testosterone production is maintained after POF.
  • The POF acronym currently encompasses all modalities of ovarian exhaustion when the ovaries remain in situ.

Prevalence of premature menopause

  • Spontaneous POF affects, on average, 1% of women aged under 40 years, although percentages as high as 7.1% have been reported.
  • Iatrogenic menopause, caused by benign and malignant conditions, affects 3.4–4.5% of women aged under 40 years.

Prevalence of female sexual disorders after premature menopause

  • The prevalence of low desire for younger surgically menopausal women is significantly higher (32%) than that found for premenopausal women of the same age (19%).
  • The probability of hypoactive sexual desire disorder increases with age, while the distress associated with the loss of desire is inversely correlated with age.

Etiology of premature menopause & health vulnerabilities

  • Heterogeneity is the hallmark of the PM etiology.
  • Etiology can be genetic, autoimmune, associated with chronic diseases or iatrogenic in the context of benign or malignant disease.
  • PM should be considered in the differential diagnosis when, independent of the fertile age of the woman, premenopausal symptoms are complained of.

Factors modulating sexual issues associated with premature menopause

  • Etiology of PM is the single most powerful biological factor affecting the psychosexual outcome.
  • Age at PM is critical: the earlier the PM, the more complex the impact on all dimensions of sexuality.
  • Stage in life cycle may contribute to FSD, fertility being a major issue in childless women and couples.
  • The woman’s coping attitude, personality, mental wellbeing and quality of sexuality before PM may all affect the sexual outcome after PM.
  • Education, socioeconomic status, professional role and access to qualified medical care affect PM and FSD outcome.
  • The partner’s reaction to the associated infertility, his/her personal and sexual health, the quality of intimacy and of the relationship before and after PM further modulate the individual and couple’s coping attitudes.
  • Contextual factors – both relational and sociocultural, such as ethnicity – further contribute.

Pathophysiology of sexual dysfunction after premature menopause

  • Estrogens and androgens modulate the neurobiology of sexual desire and mental arousal, and the neurovascular cascade of events leading to genital arousal, lubrication and orgasm.
  • Estrogen is thought to be a modulator of sexual response, and a permitting factor for the vasoactive intestinal polypeptide, which translates desire and central arousal into vaginal congestion and lubrication.
  • Testosterone is thought to have an initiating role in desire and central arousal, acting on the dopaminergic appetitive pathway, and a modulator role in the peripheral response as a permitting factor for nitric oxide, the key mediator of clitoral and cavernosal body congestion.
  • Estrogen and androgen loss combine to reduce desire and central and peripheral arousal, with vaginal dryness, and cause/worsen orgasmic difficulties and dyspareunia, causing loss of self-confidence and self-esteem, and increase in anxiety and concerns.
  • Comorbidity of FSD is frequent.
  • Concomitant medical comorbidities associated with or consequent to different etiologies of PM may contribute to FSD.

Diagnosis of premature menopause

  • Impending PM is hypothesized when menopausal symptoms appear in women younger than age 40 years, leading to POF.
  • Definite diagnosis is based on follicle-stimulating hormone levels above 40 IU/l in two consecutive samples, 1-month apart.
  • Ecography may show small ovaries for the age, with no residual oocytes.
  • PM is implicit when bilateral oophorectomy is performed in women younger than age 40 years.

Diagnosis of female sexual disorders after premature menopause

  • FSD may be antecedent to PM, concomitant to PM, and/or specifically caused and/or maintained by PM.
  • Early diagnosis is key to minimize health and sexual consequences.
  • Biological, psychosexual and contextual factors, including having a partner and his/her attitude, may modulate the scenario of the individual FSD experience.
  • Diagnosis should consider etiology of FSD, the disorder being generalized or situational, lifelong or acquired, and the level of distress it causes.
  • In stable relationships, counseling for both partners is a crucial part of the diagnosis and management.
  • Accurate physical examination is mandatory, given the importance of biological disruptions associated with PM, with focus on tropism of external genitalia, vagina and vaginal pH, pelvic floor tonicity and ‘pain map’, in the case of dyspareunia.

Treatment of premature menopause

  • Tailored HT is the treatment of choice in POF (when noncontraindicated, i.e., in survivors of breast cancer or genital adenocarcinoma, or after thromboembolic disease and acute hepatitis).
  • Systemic estrogen therapy (ET) is the choice in women who underwent hysterectomy besides oophorectomy.
  • Topical vaginal ET may address vaginal atrophy and bladder symptoms when system ET is not suitable or not considered.
  • Recommendations from the European Menopause and Andropause Society, the International Society of Menopause and the North American Menopause Society include PM being treated with HT until the age of natural menopausal (51 years) unless a specific contraindication is diagnosed.

Management of female sexual disorders associated with premature ovarian failure

  • The most important sexual issues are related to: age and psychological impact of the diagnosis of PM per se; effects of estrogen and androgen loss; severity of menopausal symptoms; and loss of fertility and its meaning to both partners.

Management of desire disorders

  • Randomized, controlled trials (RCTs) indicate the positive effect of testosterone in estrogen-replenished women after surgical menopause, when etiology appears to be hormone dependent.
  • RCT treatment with 300 µg/day testosterone patches in estrogen-replenished women increased sexual desire and frequency of satisfying sexual activity, and was well tolerated.
  • Secondary outcomes indicate a significant improvement of arousal and orgasm, of self-image and self-esteem, and a significant reduction in anxiety and concerns.
  • The testosterone patch treatment was approved by the European Agency for the Evaluation of Medicinal Products in July 2006.
  • T ibolone and HT with estradiol and norethisterone are other options to improve sexual desire.
  • Bupropion is a nonhormonal drug that may improve sexual desire.
  • Psychosexual support includes individual behavioral therapy; psychotherapy to cope with the many losses PM and its etiology have caused; and couple’s therapy to address nonsexual couple issues, such as conflicts, poor erotic skills or communication inadequacies.

Management of arousal disorders

  • Subjective and combined arousal disorders, either lifelong or acquired, usually comorbid with sexual desire disorders, should be treated as mentioned above.
  • Vaginal dryness, leading complaint of genital arousal disorders, can be treated with vaginal estrogens.
  • Safety of vaginal estrogen therapy has been documented in RCT and in observational studies such as the Million Women Study, the relative risk of breast cancer being of 0.67 for whatever type of vaginal estrogen used.
  • Vaginal estrogenic treatment is key when the genital arousal disorder causes and/or is associated with dyspareunia, postcoital cystitis, urogenital atrophy or urinary incontinence.
  • Psychosexual counseling is synergic in desire and arousal disorders.

Management of orgasmic disorders

  • True orgasmic disorder acquired subsequent to PM may benefit from HT.
  • Increasing evidence supports a positive role of testosterone in restoring orgasmic potential.
  • Pelvic floor rehabilitation is indicated when hypotonia is diagnosed as contributing to reduced orgasmic sensations.
  • Comorbid urge or stress incontinence with fear of leakage with orgasm is to be appropriately addressed.
  • When lack of orgasm is associated with poor arousal, the latter is the focus of psychosexual treatment.

Management of sexual pain disorders such as dyspareunia

  • Pain is (almost) never psychogenic. Sexual pain is no exception.
  • Friction introital dyspareunia, secondary to vaginal dryness, may benefit from vaginal ET.
  • Reflexive pelvic muscle tightening (‘hyperactivity of the elevator ani’, secondary to pain) may benefit from self-massage and stretching, electromyographic biofeedback and/or physiotherapy.
  • If vulvodynia is present, treatment should include pain modulation with drugs, such as pregabalin, gabapentin and/or amitryptiline, and peripherally acting anthalgic techniques, such as electroanalgesia and/or the ganglion impar block.
  • Psychosexual therapy includes behavioral therapy, vaginal inserts/moulds, progressive rehabilitation of the pelvic floor and, if necessary, pharmacological treatment for any intense phobic avoidance.


  • PM, and FSD reporting after PM, is increasing.
  • FSD increases with age. However, the distress associated to FSD is inversely correlated with age. Women with PM are at higher risk for distressing sexual disorders.
  • Positive outcomes of a RCT of 300 µg testosterone patches in treating desire disorders (and associated FSD) in surgically menopausal women will fuel new interest in addressing FSD in PM women.
  • Awareness of the impact of PM on general and sexual health will increase in the next few years.
  • More studies are needed to improve fertility protection in women undergoing POF and to assess long-term safety of HT.

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