Ovarian cancer is the second most common gynecologic malignancy in women worldwide, and the No. 1 cause of death among all gynecologic malignancies.¹ Although scientific advancements have increased ovarian cancer survival rates, much research is still needed. Many women with ovarian cancer undergo treatments that terminate ovarian function, resulting in uncomfortable signs and symptoms such as hot flashes, mood swings, insomnia, atrophic vaginitis, fatigue, and depression. Use of hormone therapy (HT) could alleviate these symptoms, but many practitioners hesitate to prescribe it because of their fear of precipitating a recurrence of ovarian cancer. Few studies have assessed HT use in women who have undergone treatment for ovarian cancer, but none of them seem to show any contraindications for this therapy (except in women with the endometroid type of epithelial ovarian cancer). This literature review focuses on the safety of HT in women who have received treatment, and may or may not be in remission, after a diagnosis of ovarian cancer.

Recent developments in ovarian cancer treatment have led to an increase in the number of survivors of this disease. However, many women treated for ovarian cancer with ovarian ablation via bilateral salpingo-oophorectomy (BLSO), chemotherapy, and/or radiation experience menopausal signs and symptoms (S/S) such as hot flashes, mood swings, insomnia, atrophic vaginitis, fatigue, and depression.¹ Many ovarian cancer survivors desire intervention to ease these menopausal S/S, but studies regarding hormone therapy (HT) use in this patient population, as well as recommendations for or against HT use, are limited.

Malignancies of the ovary can be classified into three categories based on the original cell type or the result of metastasis from another source in the body. The most common type of ovarian cancer includes epithelial neoplasms, which account for about 90% of ovarian cancers.^1,2 These neoplasms form from the mesothelial cells on the surface of the ovary and tend to affect women in their 60s. Epithelial neoplasms are divided into five subtypes: papillary serous, clear cell, mucinous, endometroid, and Brenner’s. The most common subtype is papillary serous, but the endometroid type is the one associated with the highest number of estrogen receptors (ERs).¹

The second category of ovarian cancer includes germ cell neoplasms, which are similar to testicular germ cell tumors.¹ These cancers commonly occur in women in their 20s or 30s, who typically have a better prognosis than their elder counterparts.  Germ cell neoplasms, which represent  3% of ovarian cancers, produce biologic markers such as cancer antigen 125, alpha-fetoprotein, and human chorionic gonadotropin. These markers can be measured and followed to monitor a woman’s response to treatment.

The third category of ovarian cancer includes sex cord and stromal tumors, which account for 5% of all ovarian malignancies.1 Within this category are granulose cell tumors and ovarian thecomas, both of which are associated with hormonal effects that can cause secondary male characteristics, precocious puberty in young girls, or hyperplasia and vaginal bleeding in postmenopausal women.

Loss of alleles and mutations of the p53 tumor suppressor gene have been found in 55% of ovarian cancers.¹ About 90% of ovarian cancers are believed to develop spontaneously, although 10%-12% of the epithelial subtype have a genetic predisposition. Hereditary ovarian cancer occurs in one of two different forms. The first and most common is inherited breast and ovarian cancer syndrome, which results from germ line autosomal dominant mutations in the BRCA1 and/or BRCA2 gene on chromosomes 17 and 13, respectively. Lifetime ovarian cancer risk is up to 63% in women with a BRCA1 mutation and 48% in those with a BRCA2 mutation.³ A less common form of hereditary ovarian cancer is Lynch II syndrome, also known as hereditary nonpolyposis colorectal cancer syndrome. DNA mismatch repair (MMR) gene mutations are the main cause of this form, which includes a variant of cancers such as colon cancer and reproductive tissue malignancies. In women with DNA MMR gene mutations, lifetime risk of this type of ovarian cancer is ~12%.¹

In the female reproductive system, the ovaries are the primary source of estrogen production, as well as the main target site for estrogen action. Cells in the ovaries produce both estradiol (E2) and estrone (E1). Two other estrogens, 16-alphahydroxyestrone and 4-hydroxyestradiol, are classified as carcinogenic estrogens because they can covalently modify DNA.  By contrast, 2-hydroxyestrone and 2-methoxyestradiol are anticarcinogenic.⁴ 

Estrogen receptors alpha and beta exist normally in the nuclei of ovarian cells and ovarian cancer cells. Like breast cancer cells, ovarian cancer cells may be estrogen dependent through gene up-regulation. Studies have demonstrated the proliferative effects of estrogens on these cells.² Much speculation surrounds the relative roles of ER-alpha and ER-beta in ovarian cancer, because ER-beta levels are high in the normal ovary and predominate over ER-alpha, whereas the converse is true in ovarian cancers.^5,6 Studies suggest that ER-beta loss is an important event in the development of ovarian cancer because ER-beta decreases with tumor progression.⁵ Of interest, ER-alpha and ER-beta, when complexed with estrogen, have been shown to have very different functions regarding gene transcription. Estrogen activates gene transcription in the presence of ER-alpha and inhibits transcription in the presence of ER-beta.⁷ As a consequence; molecules that activate or induce reexpression of ER-beta in ovarian cancer cells are thought to block proliferation.^2,5

An initial search of the CINAHL Plus with Full Text database using the terms ovarian cancer and hormone replacement therapy identified 70 references. A vast majority of these articles (>65) described an association between HT use and an increased risk for ovarian cancer and other genital or female cancers in women who did not have these cancers prior to HT use. The authors then searched the CINAHL database, Cochrane Database Systematic Reviews, and the Medline database using the terms ovarian cancer, hormone replacement therapy, and recurrence. Three references were retrieved from CINAHL and four from Medline. None were retrieved from the Cochrane Database.

One of the first studies evaluating the effect of HT on survival in women following ovarian cancer treatment was reported by Eeles et al⁸ in 1991. The investigators audited patient records of 373 women aged £50 years who had undergone BLSO. They identified 78 women who had received estrogen therapy following the cancer diagnosis and sent questionnaires to the general practitioners of the women whose records indicated that they had not received HT. Outcomes for overall survival and disease-free survival from the chart reviews and the questionnaires were compared. The results, which accounted for stage of cancer, tumor differentiation, cell type, and time to relapse, showed no significant difference between the groups receiving and not receiving HT. Limitations included sample size, lack of randomization, and differences in the time that women received HT postovarian cancer diagnosis.⁸

Results of a 2000 descriptive epidemiologic study by Bebar and Ursic-Vrscaj⁹ suggested that HT does not have a notable effect on the progression of epithelial carcinoma of the ovary. This small study, conducted on 31 women, lasted 55 months. Among the 3 women who experienced disease progression during the study, 2 died. An additional woman without evidence of ovarian cancer progression was diagnosed with a new primary malignancy of the breast.⁹

Results of a study evaluating the influence of HT on survival of women with a diagnosis of serous ovarian cancer were reported by Ursic-Vrscaj et al¹⁰ in 2001. Each of 24 patients evaluated following HT use was compared with 2 patients from a control group who had the same diagnosis, year of diagnosis, stage of disease, cellular differentiation, residual tumor after first surgery, and disease-free survival. HT use did not have a statistically significant effect on disease-free or overall survival.¹⁰

In 2005, Mitchell et al¹¹ reported the results of a retrospective chart review of 30 women surviving >5 years after ovarian cancer diagnosis. These researchers had gathered information regarding date of diagnosis, age, stage, histology, symptoms, HT history, and any cancer recurrence. HT was used post-diagnosis by 11 women, including 2 on estradiol 1 mg, 4 on conjugated equine estrogens (CEE) 0.625 mg, and 5 on CEE/medroxyprogesterone acetate 0.625/2.5 mg. Chisquare tests were used to compare stage of cancer and patient status between women receiving estrogen and those not on estrogen. Results from this small sample showed no differences between groups regarding any baseline factor except HT use. HT users, relative to nonusers, were more likely to have no evidence of disease recurrence.¹¹

In 2006, Mascarenhas et al¹² reported the results of a retrospective analysis of 799 women with any type of ovarian cancer diagnosis in which they ascertained whether HT use, before or after diagnosis, affected 5-year survival. Other variables were age at diagnosis, use of oral contraceptives, body mass index before diagnosis, smoking history, ages at menarche and menopause, parity, tubal ligation, and family history of ovarian cancer. The researchers found that women who used HT after diagnosis had a better survival rate than did nonusers, although the researchers acknowledged that this finding might have reflected a subtle selection bias. Analyses were repeated, focusing on the ovarian tumor histologic subtype: serous, mucinous, or endometroid. Although each sample size was small, the women diagnosed with a serous type who used HT before and after their cancer diagnosis had a lower risk of dying within the first 5 years of diagnosis (hazard ratio, 0.69). Women with either of the other two subtypes of ovarian cancer did not seem to have a survival advantage.¹²

To determine the effect of HT on survival following a diagnosis of invasive epithelial ovarian cancer, Guidozzi and Daponte¹³ randomized 130 women aged <59 years to continuous CEE use or no use; participants were followed for 48 months. Results were reported in 1999. Five women (3 in the CEE group and 2 controls) were lost to follow-up; final analysis was performed on 59 CEE users and 66 nonusers. Among women in these groups, 9 assigned to the CEE group refused to use or stopped using their medication and 5 in the control group started using CEE. A total of 32 cancer recurrences were reported in the CEE group and 41 in the control group. In the CEE and control groups, respectively, the median disease-free interval was 34 versus 27 months (P = .785), and overall survival was 44 months versus 34 months (P = .354). Therefore, disease-free interval and overall survival with epithelial ovarian carcinoma were not adversely affected by postoperative use of CEE. A limitation was the small study sample.¹³

The vast majority of research on HT use following an ovarian cancer diagnosis has involved women with epithelial neoplasms, likely because these are the most common type of ovarian cancer and because they have low levels of positive ERs, especially of the alpha type.¹⁴ Owing to the limited number of studies, one cannot exclude the possibility that HT may contribute to cell proliferation in patients whose tumors express ERs.¹⁵ However, no study has shown whether or not the presence of these receptors affects HT response.¹⁶ Biglia et al¹⁷ found no biological evidence that HT used post-ovarian cancer diagnosis increased the risk for recurrence. When considering survival after an ovarian cancer diagnosis and use of HT, the study by Mascarenhas et al12 showed longer survival for women with serous epithelial tumors than for those with mucinous or endometroid types. Of note, although most gynecologic cancers are not estrogen dependent, endometroid ovarian cancer does have ERs, making it susceptible to growth with availability of increasing serum estrogen levels. Therefore, HT is contraindicated for women with this diagnosis.¹⁸

Many women who receive an ovarian cancer diagnosis choose to undergo ovarian ablation via chemotherapy, radiation, and/or BLSO. Some women will endure symptoms such as hot flashes, mood swings, insomnia, atrophic vaginitis, fatigue and depression, which result from loss of the hormones produced by the ovaries.15 Consensus of the few studies performed shows no contraindication to HT use following ovarian cancer diagnosis because quality of life (QoL) is usually improved and survival is unaffected.^11-20 Additional research, including large-scale randomized controlled trials, is warranted.

Ovarian cancer is the fourth-leading cause of cancer-related death in women²¹ and the leading cause of gynecologic cancer deaths worldwide.²² However, with advanced treatment regimens, survival rates and length of survival have increased. As of 2006, overall 1-year survival following an ovarian cancer diagnosis was almost 76%.²¹ As with most cancers, survival after treatment for ovarian cancer is directly related to stage at diagnosis. Highest survival rates occur in women diagnosed during the initial stage. Even among women who do respond to ovarian cancer treatment, 80% go on to experience a recurrence.²¹

For women diagnosed with ovarian cancer, nurse practitioners should pay special attention to the QoL they describe. Because of the advanced stage of disease at diagnosis and the high incidence of recurrence, these patients often cycle through ongoing depression, sexual dysfunction, mood swings, insomnia, pain, and fatigue. Depending on the tumor type of ovarian cancer, HT may diminish these symptoms without affecting overall survival. However, women with endometroid types of ovarian cancer can have reduced survival with HT, so HT should not be prescribed in these cases. Other non-hormonal treatments  for menopausal symptom relief can be helpful and would not cause concerns for effect on survival.

Women with a history of epithelial ovarian cancer and menopausal symptoms tend not to be given HT because of continued concern that a recurrence of a hormonally-influenced cancer could be linked to HT use (HT use is positively associated with an increased risk of primary ovarian cancer).^23-25 But if a woman with epithelial ovarian cancer feels that HT may improve her QoL by relieving some physical and emotional S/S, no evidence, at least according to studies done so far, contraindicates estrogen use in these cases. As always, the lowest effective HT dose is suggested.²⁶ This therapy may also make patients with active disease more comfortable, without affecting overall survival.