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Bilateral oophorectomy and premature menopause

  • Susan L. Hendrix
    Correspondence
    Requests for reprints should be addressed to Susan L. Hendrix, DO, Department of Obstetrics and Gynecology, Wayne State University/Hutzel Women’s Hospital, Detroit, Michigan 48201.
    Affiliations
    Department of Obstetrics and Gynecology, Wayne State University School of Medicine/Hutzel Women’s Hospital, Detroit, Michigan, USA
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      The ovary is a complex metabolic organ. The follicles produce both androgens and estrogens, whereas the stromal tissue synthesizes androgens only. When menopause occurs, both androgen and estrogen levels decrease. The postmenopausal ovary remains a source of endogenous androgens that are converted to estrogen. The consequences of premature removal of the ovaries are not well known. The risks and benefits of menopausal hormone therapy (HT) in women with premature menopause have not been studied. Women who have had surgical menopause experience more severe symptoms and will need to stop estrogen therapy at some point in their lives. Intense symptoms such as hot flashes, night sweats, and insomnia will redevelop, so women should be given informed consent about the need for long-term use of HT and the greater difficulty in discontinuing therapy.

      Keywords

      Premature menopause results from bilateral oophorectomy or premature ovarian failure. Bilateral oophorectomy and premature ovarian failure are similar in that they are both hypoestrogenic conditions that increase a woman’s risk for osteoporotic fracture and coronary heart disease (CHD). However, they are different in that with premature ovarian failure, the menopausal transition is similar to natural menopause; there is a gradual decline in sex hormone levels, and women often experience intermittent menopausal symptoms and irregular uterine bleeding for many years before the onset of amenorrhea. In contrast, surgical castration results in acute hypoestrogenism and hypoandrogenism, most commonly resulting in acute symptomatology. Estrogen requirements for symptom control in women with bilateral oophorectomy may be higher than in the woman with premature ovarian failure, and the inability to discontinue estrogen also may be greater in the woman who has undergone oophorectomy because of the severe symptomatology.
      The usual and common indications for bilateral oophorectomy include ovarian, endometrial, or fallopian tube cancers; severe endometriosis; bilateral tubo-ovarian abscess (ruptured or chronic); familial breast–ovarian cancer syndrome; and severe premenstrual syndrome. Routine prophylactic oophorectomy also causes premature menopause in premenopausal women. Surgical menopause occurs when the ovaries are removed, usually as part of a total hysterectomy. Natural menopause occurs gradually around the age of 51 years. Surgical menopause happens immediately upon removal of the ovaries if a woman has not yet experienced natural menopause. Premature ovarian failure is the development of amenorrhea with concomitant sex hormone deficiency and elevated serum gonadotropin levels before the age of 40 years. It can be spontaneous or induced by chemotherapy, radiation therapy, or oophorectomy.
      With natural menopause and premature ovarian failure, the ovaries continue to produce significant amounts of testosterone and androstenedione for many years after menopause, and these androgens are converted to estrogen peripherally.
      • Judd H.L.
      • Judd G.E.
      • Lucas W.E.
      • Yen S.S.
      Endocrine function of the postmenopausal ovary concentration of androgens and estrogens in ovarian and peripheral vein blood.
      With bilateral oophorectomy, this is absent. With hysterectomy, the ovaries are not automatically removed; however, hysterectomy alone is associated with earlier menopause. The mean age of ovarian failure in women who have had hysterectomy is reported to be 45.4 ± 4.0 years—significantly lower than the mean age of 49.5 ± 4.04 years in women without hysterectomy (P <0.001).
      • Siddle N.
      • Sarrel P.
      • Whitehead M.
      The effect of hysterectomy on the age at ovarian failure identification of a subgroup of women with premature loss of ovarian function and literature review.
      Generally 50% to 60% of hysterectomy procedures involve oophorectomy.
      Historically, younger women undergoing bilateral oophorectomy and women with premature ovarian failure have been treated similarly to women aged >50 years who are experiencing the menopausal transition. However, premature menopause is not equivalent to natural menopause occurring at the average age of 51 years.

      Prophylactic oophorectomy

      Approximately 600,000 hysterectomies are performed each year in the United States.
      • Lepine L.A.
      • Hillis S.D.
      • Marchbanks P.A.
      • et al.
      Hysterectomy surveillance—United States, 1980–1993.
      • Dicker R.C.
      • Scally M.J.
      • Greenspan J.R.
      • et al.
      Hysterectomy among women of reproductive age.
      Because of the simplicity of the procedure, routine prophylactic oophorectomy to remove both ovaries is often performed concomitantly with hysterectomy in women aged >40 years. The theoretical benefits of prophylactic oophorectomy include the prevention of ovarian cancer and fewer reoperations for ovarian pathology, conditions that occur in 4% to 5% of women who have had a previous hysterectomy.
      • Christ J.E.
      • Lotze E.C.
      The residual ovary syndrome.
      • Grogan R.H.
      • Duncan C.J.
      Ovarian salvage in routine abdominal hysterectomy.
      Despite ovarian ultrasound, the CA-125 antigen test, and other tumor marker and genetic tests in development, nothing has proved to be sensitive or specific enough to detect the early presence of cancer. This is important because 70% of the patients with ovarian cancer present after it has spread beyond the ovary.
      Ovarian cancer is the fourth most common cause of cancer death and the most common cause of gynecologic cancer death in women, with an estimated 23,300 new diagnoses and 13,900 deaths related to ovarian cancer each year.
      • Plockinger B.
      • Kolbl H.
      Development of ovarian pathology after hysterectomy without oophorectomy.
      Women in the United States have a lifetime risk for ovarian cancer of 1 in 70, and approximately 4% to 14% of these women have had preceding hysterectomies in which the ovaries were preserved.

      Jemal A, Thomas A, Murray T, Thun M. Cancer statistics, 2002 [published corrections appear in CA Cancer J Clin. 2002;52:119 and CA Cancer J Clin. 2002;52:181–182]. CA Cancer J Clin. 2002;52:23–47.

      Oophorectomy does not eliminate the risk of ovarian cancer—women can develop peritoneal carcinoma, which acts like ovarian cancer—but reports of post-oophorectomy cases of ovarian cancer are rare.
      • Sightler S.E.
      • Boike G.M.
      • Estape R.E.
      • Averette H.E.
      Ovarian cancer in women with prior hysterectomy a 14-year experience at the University of Miami.
      It has been suggested that, in the United States, approximately 1,000 cases of ovarian cancer can be prevented if prophylactic oophorectomy is practiced in all women >40 years of age who undergo hysterectomy.
      • Piver M.S.
      • Jishi M.F.
      • Tsukada Y.
      • Nava G.
      Primary peritoneal carcinoma after prophylactic oophorectomy in women with a family history of ovarian cancer.
      This assumes an annual incidence of 24,000 new ovarian cancer cases and does not take into account the incidence of peritoneal carcinoma. The dilemma for the patient and the clinician is whether the estimated number of cancer cases prevented (approximately 1,000) is worth the number of oophorectomies performed (approximately 300,000).
      Because of the limitation of current screening modalities for early detection of ovarian cancer, prophylactic oophorectomy is a consideration in women with a hereditary disposition for this high-mortality disease. These women may have an up to 50% lifetime risk of ovarian cancer, and prophylactic oophorectomy is indicated after childbearing or the age of 35 to 40 years at the latest. Most women with a positive family history of ovarian cancer do not have a recognized hereditary cancer syndrome. Women with 1 or 2 affected relatives do have an increased risk of ovarian cancer, from a baseline risk of 1.6% to a lifetime risk of 5% to 7%. However, this risk is not great enough to warrant recommendation of prophylactic oophorectomy for a large number of women. The familial cancer syndromes include breast–ovarian cancer syndrome; the Lynch II syndrome, involving cancers of the colon, breast, endometrium, and ovary with hereditary nonpolyposis colorectal carcinoma syndrome; and site-specific ovarian cancer syndrome.

      Premature ovarian failure

      Premature ovarian failure occurs in about 1% of women. Causes are genetic, autoimmune, or idiopathic. Original estimates were based on a small study using Mayo Clinic data that evaluated medical records and required documentation of elevated follicle-stimulating hormone to define ovarian failure.
      • Averette H.E.
      • Nguyen H.N.
      The role of prophylactic oophorectomy in cancer prevention.
      More recently, the Study of Women Across the Nation (SWAN) reported that 1.1% (126 of 11,652) of their cohort reported natural menopause occurring before age 40 years.
      • Coulam C.
      • Adamson S.
      • Annegers J.
      Incidence of premature ovarian failure.
      SWAN is a study of the menopausal transition in US women between 40 and 55 years of age at enrollment. Results differed by race/ethnicity, with 1.0% (61 of 11,652) of Caucasian, 1.4% (41 of 11,652) of African Americans, 1.4% (21 of 11,652) of Latinas, 0.5% (3 of 11,652) of Chinese, and 0.1% (1 of 11,652) of Japanese experiencing premature ovarian failure. Although 1% may appear to be a small number, this translates into >700,000 women in the United States who have experienced premature ovarian failure. Approximately 120,000 women are currently aged <40 years and have experienced premature ovarian failure. These are the women who are asking the questions, “Is this a condition that needs treatment?” and “Is this something for which I need to be evaluated or treated?” The remaining 600,000 subjects are women in their 40s, 50s, or 60s who had experienced premature ovarian failure and are now living with the consequences of long-term risks associated with the condition, either with treatment or without treatment.

      Physiologic differences

      Levels of the steroid hormones estradiol, testosterone, and progesterone are different in natural versus surgical menopause. With bilateral oophorectomy, the hormone levels are lower and the decline is abrupt as opposed to gradual. The data in Table 1 show that the postmenopausal ovary maintains some functionality to secrete estradiol.
      • Judd H.L.
      • Judd G.E.
      • Lucas W.E.
      • Yen S.S.
      Endocrine function of the postmenopausal ovary concentration of androgens and estrogens in ovarian and peripheral vein blood.
      The actual endocrine effect on the postmenopausal ovary may be related to its contribution of androgens to the plasma pool of estrogens through extragonadal conversion.
      Table 1Levels of steriod hormones in natural versus surgical menopause
      Mean Steroid Luteal Phase Levels in Women (pg/mL)
      Reproductive AgeNatural MenopauseSurgical Menopause
      Estradiol15010–1510
      Testosterone400290110
      Progesterone12,000–20,000<100<100
      Reprinted from J Clin Endocrinol Metab.
      • Judd H.L.
      • Judd G.E.
      • Lucas W.E.
      • Yen S.S.
      Endocrine function of the postmenopausal ovary concentration of androgens and estrogens in ovarian and peripheral vein blood.

      Symptoms

      The menopausal symptoms experienced differ for naturally and surgically menopausal women. Several studies suggest that symptom episodes are apt to be worse when women have undergone surgical menopause, necessitating treatment with menopausal hormone therapy (HT) for symptom relief.
      • Luborsky J.L.
      • Meyer P.
      • Sowers M.F.
      • Gold E.B.
      • Santoro N.
      Premature menopause in a multi-ethnic population study of the menopause transition.
      • McKinlay J.B.
      • McKinlay S.M.
      • Brambilla D.J.
      Health status and utilization behavior associated with menopause.
      In premenopausal women undergoing oophorectomy, the mean reduction in serum testosterone is 50% and the mean reduction in serum estradiol concentration is 80%.
      • Thompson B.
      • Hart S.A.
      • Durno D.
      Menopausal age and symptomatology in a general practice.
      An abrupt decline in estradiol is associated with more frequent and severe symptoms. These include hot flashes,
      • Guzick D.S.
      • Hoeger K.
      Sex, hormones, and hysterectomies.
      sexual dysfunction,
      • Oldenhave A.
      • Jaszmann L.J.
      • Everaerd W.T.
      • Haspels A.A.
      Hysterectomized women with ovarian conservation report more severe climacteric complaints than do normal climacteric women of similar age.
      depression,
      • Sherwin B.B.
      • Gelfand M.M.
      The role of androgen in the maintenance of sexual functioning in oophorectomized women.
      • Dennerstein L.
      • Guthrie J.R.
      • Clark M.
      • Lehert P.
      • Henderson V.W.
      A population-based study of depressed mood in middle-aged, Australian-born women.
      migraine headaches,
      • Roos N.P.
      Hysterectomies in one Canadian province a new look at risks and benefits.
      vaginal dryness,
      • Oldenhave A.
      • Jaszmann L.J.
      • Everaerd W.T.
      • Haspels A.A.
      Hysterectomized women with ovarian conservation report more severe climacteric complaints than do normal climacteric women of similar age.
      and cardiac symptoms.
      • Riedel H.H.
      • Lehmann-Willenbrock E.
      • Semm K.
      Ovarian failure phenomena after hysterectomy.
      In 1 study, severe hot flashes were experienced by approximately 90% of women who had a previous hysterectomy, compared with 50% of naturally menopausal women.
      • Oldenhave A.
      • Jaszmann L.J.
      • Everaerd W.T.
      • Haspels A.A.
      Hysterectomized women with ovarian conservation report more severe climacteric complaints than do normal climacteric women of similar age.
      The definition of a severe hot flash was an episode that affected a woman’s capacity to function. The lack of ovarian reserve means that many women with bilateral oophorectomy have difficulty stopping HT use at any age because of the return of severe symptoms.

      Are risk factors different for women undergoing premature menopause?

      Premature menopause from all causes is associated with earlier onset of osteoporosis and CHD.
      • Roos N.P.
      Hysterectomies in one Canadian province a new look at risks and benefits.
      • Centerwall B.S.
      Premenopausal hysterectomy and cardiovascular disease.
      • Derby C.A.
      Cardiovascular pathophysiology.
      Recent findings suggest women with bilateral oophorectomy have elevated subclinical atherosclerosis compared with women of similar age who had natural menopause.
      • Bairey Merz C.N.
      • Johnson B.D.
      • Sharaf B.L.
      • et al.
      WISE Study Group
      Hypoestrogenemia of hypothalamic origin and coronary artery disease in premenopausal women a report from the NHLBI-sponsored WISE Study.
      One study reported that, compared with women who had a natural menopause, women with bilateral oophorectomy had an increased risk for suicidal depression (relative risk, 2.4).
      • Sherwin B.B.
      • Gelfand M.M.
      The role of androgen in the maintenance of sexual functioning in oophorectomized women.
      However, women reporting an earlier menopause are reported to have a reduced risk for breast cancer.
      • Kritz-Silverstein D.
      • Barrett-Connor E.
      Early menopause, number of reproductive years and bone mineral density in postmenopausal women.

      Characteristics by hysterectomy status

      The Women’s Health Initiative (WHI) compared baseline characteristics of the women participating in the 2 hormone trials—the WHI E-alone trial, in which subjects received only estrogen, and the WHI E + P trial, in which subjects received estrogen and progestin—in order to better define the differences in the 2 populations.
      • Mack W.J.
      • Slater C.C.
      • Xiang M.
      • Shoupe D.
      • Lobo R.A.
      • Hodis H.N.
      Elevated subclinical atherosclerosis associated with oophorectomy is related to time since menopause rather than type of menopause.
      Randomization stratification was by hysterectomy status. The 2 cohorts differed with respect to many baseline characteristics. However, because most studies do not provide characteristics or results by hysterectomy status, it is difficult to discern whether the differences seen in WHI reflect those of the general population. Nonetheless, the information reported helps further our understanding of differences between these 2 populations that may influence treatment decisions.
      Women who had undergone previous hysterectomy with or without oophorectomy were at higher risk for cardiovascular disease (myocardial infarction, coronary artery bypass graft/percutaneous transluminal coronary angioplasty, and stroke); had higher systolic and diastolic blood pressure, with more individuals being treated for hypertension; and were more obese and less active. Approximately 75% of the women with an intact uterus and 50% of the women with hysterectomy had never used postmenopausal HT, suggesting that the need for hormone use was greater in the women with a hysterectomy. The total duration of HT use was greater in women without a uterus, in whom the rate of HT use for >10 years was 27.3% (1,444 of 10,739) compared with 11.6% (514 of 16,608) in women with a uterus.

      Discussion

      The ovary is a complex metabolic organ. The follicles produce both androgens and estrogens, whereas the stromal tissue synthesizes androgens only. During menopause, when follicles decrease, both androgen and estrogen levels decrease as well. However, the postmenopausal ovary remains a source of endogenous androgens that are converted to estrogen. The role of those endogenous androgens and the consequences of their premature removal through oophorectomy may be significant, but research has not yet shed much light on this issue.
      Once the ovaries are removed or fail to produce endogenous sex steroids, exogenous estrogens are almost always needed for symptom relief. The risks and benefits of these agents in women with premature menopause have not been studied. In these women HT is used as true replacement therapy, just as thyroid hormone is used as the replacement therapy for thyroid deficiency. The only guidance available on the balance of benefits and risks are from the 2 randomized trials of HT in menopausal women from the WHI. The WHI E + P trial showed that the risks of HT (increased breast cancer, heart attacks, strokes, and blood clots in the lungs and legs) outweigh the benefits (fewer hip fractures and colon cancers).
      • Karagas M.R.
      • Kelsey J.
      • McGuire V.
      Cancers of the female reproductive system.
      The WHI E-alone trial indicated that use of conjugated equine estrogens alone increases the risk of stroke, decreases the risk of hip fracture, and does not affect CHD incidence, with no overall benefit in postmenopausal women with prior hysterectomy.
      • Stefanick M.L.
      • Cochrane B.B.
      • Hsia J.
      • Barad D.H.
      • Liu J.H.
      • Johnson S.R.
      The Women’s Health Initiative postmenopausal hormone trials overview and baseline characteristics of participants.
      However, data from the WHI should not be extrapolated to women with premature menopause in whom HT generally is initiated at a much younger age.
      Women who have had surgical menopause experience more severe symptoms and will be faced with the decision to stop estrogen therapy at some time in their lives. When they do try to discontinue therapy, many of these women will redevelop intense symptoms such as hot flashes, night sweats, and insomnia. Therefore, before ovarian removal, they must be informed about the need for long-term HT use and the greater difficulty in discontinuing therapy. We do not know what percentage of women redevelop symptoms after stopping long-term HT or how best to stop therapy (i.e., immediate or taper).

      Summary

      Women undergoing premature menopause either because of bilateral oophorectomy or premature ovarian failure are faced with consequences of long-term hormone exposure that are unknown in the population younger than the average age of natural menopause. It remains to be determined at what age HT should be stopped in women with premature menopause. However, results from the WHI suggest that continuing HT beyond the approximate natural age of menopause may not be beneficial and in some women might cause harm.
      Future research on menopausal symptoms in women undergoing premature menopause should focus on addressing the following critical gaps in our knowledge of this topic:
      • 1
        Is premature menopause a deficiency disease requiring physiologic replacement?
      • 2
        Should women with idiopathic premature ovarian failure or bilateral oophorectomy be treated with exogenous estrogen with or without progestin?
      • 3
        What form of HT is most appropriate: combination oral contraceptives, continuous menopausal HT, or sequential therapy?
      • 4
        Is physiologic estradiol replacement safer than synthetic forms of HT?
      • 5
        For how long should hormonal treatment be administered?
      • 6
        How safe is HT in women with premature versus natural menopause at average age 51 years?
      • 7
        What is the physiologic mechanism of premature ovarian failure?
      Long-term follow-up also is needed until women are ≥10 years postmenopausal, so that longer-term effects, including the natural history of untreated symptoms, can be studied.
      • Rossouw J.E.
      • Anderson G.L.
      • Prentice R.L.
      • et al.
      Writing Group for the Women’s Health Initiative
      Risks and benefits of estrogen plus progestin in healthy postmenopausal women principal results from the Women’s Health Initiative randomized controlled trial.
      • Anderson G.L.
      • Limacher M.
      • Assaf A.R.
      Women’s Health Initiative Steering Committee
      Effects of conjugated equine estrogen in postmenopausal women with hysterectomy the Women’s Health Initiative randomized controlled trial.

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