20 July, 2015 

Most women experience menopause between the ages of 45 and 55 years. However, 5% of women will go through menopause early, between the ages of 40 and 45 years, and 1% of women become menopausal prematurely, before the age of 40 years [1]. The causes of premature or early menopause are multiple and range from the most common, bilateral oophorectomy, to more rare causes such as genetic, autoimmune, or infectious etiologies. There are multiple adverse long-term health consequences associated with premature or early menopause, including increased risk of dementia, parkinsonism, glaucoma, depression, anxiety, osteoporosis, coronary heart disease, heart failure, sexual dysfunction, and early death. Replacing estrogen mitigates some of these risks, although it may not completely protect against the increased risk of parkinsonism, glaucoma, mood disorders, and sexual dysfunction [1].

Comment

The ovaries are both reproductive and endocrine organs. They secrete hormones both before menopause (primarily estrogen, progesterone, and testosterone) and after (primarily testosterone, androstenedione, and dehydroepiandrosterone). Ovarian hormones have important reproductive actions; however, they also have important endocrine actions mediated by receptors spread throughout most tissues and organs of the body [2]. Removal of the ovaries reduces the risk of ovarian (by 80–90%) and breast (by 50–60%) cancer; however, it increases the risk of all-cause mortality (28%), lung cancer (45%), coronary heart disease (33%), stroke (62%), cognitive impairment (60%), parkinsonism (80%), psychiatric symptoms (50–130%), osteoporosis and bone fractures (50%), and impaired sexual function (40–110%). The magnitude of the risk varies depending on the study referenced, the age at the time of oophorectomy, and the use of estrogen therapy after the surgery [2].

With regard to bilateral oophorectomy prior to the natural age of menopause, medical practice should follow the principle of 'primum non nocere' (first do no harm). Bilateral oophorectomy performed electively at the time of hysterectomy for a benign indication is now under scrutiny and critical reappraisal because the long-term risks may outweigh the benefits in the majority of women [2]. The scientific debate about the risks and benefits of prophylactic bilateral oophorectomy continues, and many women continue to undergo prophylactic oophorectomy in 2015 [3-5]. We suggest that the evidence is sufficient to change this practice. At the time of hysterectomy for a benign condition, if the ovaries are normal and the woman does not carry a high-risk genetic variant (e.g. BRCA1 or BRCA2 mutation) or does not have a strong family history of ovarian cancer, the ovaries should be conserved. This conservative practice is particularly important in younger women [2,4].

The concept of hormone replacement therapy should be re-introduced in clinical practice. Women who experience premature or early menopause, regardless of cause, are exposed to risk from abnormal estrogen deprivation. The guideline-based recommendation to use the lowest possible dose of estrogen therapy for the shortest amount of time needed to control menopausal symptoms is not appropriate for these women. Instead, rather than aiming only for symptom relief, there is a need to replace the lost endocrine function of the ovary, much as thyroid hormone is administered following thyroidectomy. Higher doses of estradiol may be needed to approximate premenopausal serum estradiol levels. For example, estrogen-containing hormonal contraception (which provides much higher doses of estrogen than menopausal hormone therapy) is used in women with primary ovarian insufficiency (POI) to provide both hormone replacement and contraception.

Although monitoring serum estradiol levels is not recommended as part of current estrogen therapy guidelines, this recommendation should be reconsidered for women given estrogen replacement for premature or early menopause. Although there is a lack of data on the precise range of estradiol levels (serum or tissue) necessary to protect the brain and heart, there is evidence for the range associated with bone preservation [6,7]. Monitoring serum estradiol levels was not useful with conjugated equine estrogens which contain numerous estrogenic components other than estradiol, but could be useful with the formulations of estradiol used more commonly now. Consider the case of a young oophorectomized woman who continues to have bothersome vasomotor symptoms and sexual dysfunction despite a dose of 100 μg of transdermal estradiol. Is she adequately absorbing the estradiol? Is the dose simply too low? Or, is the estradiol level in a premenopausal range but she is androgen deficient? These are important clinical questions that have not been addressed in clinical trials.

In addition to losing estrogen, women who undergo bilateral salpingo-oophorectomy before the natural age of menopause also lose about 50% of their androgen production [8,9]. Although testosterone therapy is not currently routinely recommended for women who have had early oophorectomy or POI [10], sexual dysfunction in women with early menopause is common, and evidence suggests that replacing testosterone in oophorectomized women with sexual dysfunction may be beneficial [11,12]. However, the long-term safety and efficacy of testosterone therapy in women have not been established, and standardized testosterone preparations are not readily available for women in most countries.

If there is a clear indication for bilateral oophorectomy in a premenopausal woman, or if a woman has experienced POI, several key concepts should be considered:

1. The results of the Women’s Health Initiative trials do not apply directly to women who have experienced premature or early menopause.

2. Most women who undergo bilateral oophorectomy or POI prior to age 45, and who do not have a history of a hormone-sensitive cancer or another specific contraindication, will benefit from hormone therapy not only for vasomotor symptom management but also for the prevention of adverse cardiovascular, bone, and neuro-cognitive effects related to premature estrogen deficiency (estrogen replacement therapy).

3. Several medical societies recommend continuing estrogen therapy at least until the age of natural menopause in women with premature or early menopause [1].

4. Although data are lacking, higher doses of estrogen (at least the equivalent of 100 μg of transdermal estradiol) may be needed to approximate blood estradiol concentrations similar to those of menstruating women.

5. Women with premature or early menopause who experience sexual dysfunction may benefit from testosterone therapy, although questions remain regarding long-term safety and efficacy of this treatment.

In summary, women who undergo bilateral oophorectomy or experience POI before the average age of menopause should receive adequate hormonal treatment [1].

Stephanie S. Faubion
Women’s Health Clinic, Division of General Internal Medicine, Mayo Clinic, Rochester, MN, USA
and
Carol L. Kuhle
Women’s Health Clinic, Division of General Internal Medicine, Mayo Clinic, Rochester, MN, USA
and
Lynne T. Shuster
Women’s Health Clinic, Division of General Internal Medicine, Mayo Clinic, Rochester, MN, USA
and
Walter A. Rocca
Division of Epidemiology, Department of Health Sciences Research, and Department of Neurology, Mayo Clinic, Rochester, MN, USA

References

1. Faubion SS, Kuhle CL, Shuster LT, Rocca WA. Long-term health consequences of premature or early menopause and considerations for management. Climacteric 2015;18:483-91
http://www.ncbi.nlm.nih.gov/pubmed/25845383 
2. Rocca WA, Ulrich LG. Oophorectomy for whom and at what age? Primum non nocere. Maturitas 2012;71:1-2
http://www.ncbi.nlm.nih.gov/pubmed/22079872 
3. Llaneza P, Pérez-López FR. Rethinking elective bilateral oophorectomy at the time of hysterectomy for benign disease. Maturitas 2013;76:109-10
http://www.ncbi.nlm.nih.gov/pubmed/23849176 
4. Harmanli O. Save the ovaries in reproductive years… and maybe the uterus, too?
Menopause 2014;21:561-2
http://www.ncbi.nlm.nih.gov/pubmed/24755899 
5. Harmanli O, Shinnick J, Jones K, St Marie P. Obstetrician-gynecologists’ opinions on elective bilateral oophorectomy at the time of hysterectomy in the United States: a nationwide survey. Menopause 2014;21:355–60
http://www.ncbi.nlm.nih.gov/pubmed/23942250 
6. Rogers A, Saleh G, Hannon RA, Greenfield D, Eastell R. Circulating estradiol and osteoprotegerin as determinants of bone turnover and bone density in postmenopausal women. J Clin Endocrinol Metab 2002;87:4470-5
http://www.ncbi.nlm.nih.gov/pubmed/12364420 
7. Ettinger B, Pressman A, Sklarin P, Bauer DC, Cauley JA, Cummings SR. Associations between low levels of serum estradiol, bone density, and fractures among elderly women: the study of osteoporotic fractures. J Clin Endocrinol Metab 1998;83:2239-43
http://www.ncbi.nlm.nih.gov/pubmed/9661589
8. Davison SL, Bell R, Donath S, Montalto JG, Davis SR. Androgen levels in adult females: changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab 2005;90:3847-53
http://www.ncbi.nlm.nih.gov/pubmed/15827095 
9. Shifren JL. Androgen deficiency in the oophorectomized woman. Fertil Steril 2002;77(Suppl 4):S60-2
http://www.ncbi.nlm.nih.gov/pubmed/12007904 
10. Wierman ME, Arlt W, Basson R, et al. Androgen therapy in women: a reappraisal: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2014;99:3489–510 
http://www.ncbi.nlm.nih.gov/pubmed/25279570 
11. Shifren JL, Braunstein GD, Simon JA, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med 2000;343:682-8 
http://www.ncbi.nlm.nih.gov/pubmed/10974131
12. Buster JE, Kingsberg SA, Aguirre O, et al. Testosterone patch for low sexual desire in surgically menopausal women: a randomized trial. Obstet Gynecol 2005;105:944–52  
http://www.ncbi.nlm.nih.gov/pubmed/15863529