William H. Parker

Fibroids and infertility: an updated systematic review of the evidence

OBJECTIVE To investigate the effect of fibroids on fertility and of myomectomy in improving outcomes. DESIGN Systematic literature review and meta-analysis of existing controlled studies. SETTING Private center for Reproductive endocrinology and infertility. PATIENT(S) Women with fibroids and infertility. INTERVENTION(S) A systematic literature review, raw data extraction and data analysis. MAIN OUTCOME MEASURE(S) Clinical pregnancy rate, spontaneous abortion rate, ongoing pregnancy/live birth rate, implantation rate, and preterm delivery rate in women with and without fibroids, and in women who underwent myomectomy. RESULT(S) Women with subserosal fibroids had no differences in their fertility outcomes compared with infertile controls with no myomas, and myomectomy did not change these outcomes compared with women with fibroids in situ. Women with intramural fibroids appear to have decreased fertility and increased pregnancy loss compared with women without such tumors, but study quality is poor. Myomectomy does not significantly increase the clinical pregnancy and live birth rates, but the data are scarce. Fibroids with a submucosal component led to decreased clinical pregnancy and implantation rates compared with infertile control subjects. Removal of submucous myomas appears likely to improve fertility. CONCLUSION(S) Fertility outcomes are decreased in women with submucosal fibroids, and removal seems to confer benefit. Subserosal fibroids do not affect fertility outcomes, and removal does not confer benefit. Intramural fibroids appear to decrease fertility, but the results of therapy are unclear. More high-quality studies need to be directed toward the value of myomectomy for intramural fibroids, focusing on issues such as size, number, and proximity to the endometrium.

Ovarian Conservation at the Time of Hysterectomy and Long-Term Health Outcomes in the Nurses' Health Study

OBJECTIVE: To report long-term health outcomes and mortality after oophorectomy or ovarian conservation. METHODS: We conducted a prospective, observational study of 29,380 women participants of the Nurses’ Health Study who had a hysterectomy for benign disease; 16,345 (55.6%) had hysterectomy with bilateral oophorectomy, and 13,035 (44.4%) had hysterectomy with ovarian conservation. We evaluated incident events or death due to coronary heart disease (CHD), stroke, breast cancer, ovarian cancer, lung cancer, colorectal cancer, total cancers, hip fracture, pulmonary embolus, and death from all causes. RESULTS: Over 24 years of follow-up, for women with hysterectomy and bilateral oophorectomy compared with ovarian conservation, the multivariable hazard ratios (HRs) were 1.12 (95% confidence interval [CI] 1.03–1.21) for total mortality, 1.17 (95% CI 1.02–1.35) for fatal plus nonfatal CHD, and 1.14 (95% CI 0.98–1.33) for stroke. Although the risks of breast (HR 0.75, 95% CI 0.68–0.84), ovarian (HR 0.04, 95% CI 0.01–0.09, number needed to treat=220), and total cancers (HR 0.90, 95% CI 0.84–0.96) decreased after oophorectomy, lung cancer incidence (HR=1.26, 95% CI 1.02–1.56, number needed to harm=190), and total cancer mortality (HR=1.17, 95% CI 1.04–1.32) increased. For those never having used estrogen therapy, bilateral oophorectomy before age 50 years was associated with an increased risk of all-cause mortality, CHD, and stroke. With an approximate 35-year life span after surgery, one additional death would be expected for every nine oophorectomies performed. CONCLUSION: Compared with ovarian conservation, bilateral oophorectomy at the time of hysterectomy for benign disease is associated with a decreased risk of breast and ovarian cancer but an increased risk of all-cause mortality, fatal and nonfatal coronary heart disease, and lung cancer. In no analysis or age group was oophorectomy associated with increased survival. LEVEL OF EVIDENCE: II

Ovarian conservation at the time of hysterectomy for benign disease

Objective: Prophylactic oophorectomy is often recommended concurrent with hysterectomy for benign disease. The optimal age for this recommendation in women at average risk for ovarian cancer has not been determined. Methods: Using published age-specific data for absolute and relative risk, both with and without oophorectomy, for ovarian cancer, coronary heart disease, hip fracture, breast cancer, and stroke, a Markov decision analysis model was used to estimate the optimal strategy for maximizing survival for women at average risk of ovarian cancer. For each 5-year age group from 40 to 80 years, 4 strategies were compared: ovarian conservation or oophorectomy, and use of estrogen therapy or nonuse. Outcomes, as proportion of women alive at age 80 years, were measured. Sensitivity analyses were performed, varying both relative and absolute risk estimates across the range of reported values. Results: Ovarian conservation until age 65 benefits long-term survival for women undergoing hysterectomy for benign disease. Women with oophorectomy before age 55 have 8.58% excess mortality by age 80, and those with oophorectomy before age 59 have 3.92% excess mortality. There is sustained, but decreasing, benefit until the age of 75, when excess mortality for oophorectomy is less than 1%. These results were unchanged following multiple sensitivity analyses and were most sensitive to the risk of coronary heart disease. Conclusion: Ovarian conservation until at least age 65 benefits long-term survival for women at average risk of ovarian cancer when undergoing hysterectomy for benign disease.

Risk factors for uterine rupture after laparoscopic myomectomy

Case reports for uterine rupture subsequent to laparoscopic myomectomy were reviewed to determine whether common causal factors could be identified. Published cases were identified via electronic searches of PubMed, Google Scholar, and hand searches of references, and unpublished cases were obtained via E-mail queries to the AAGL membership and AAGL Listserve participants. Nineteen cases of uterine rupture after laparoscopic myomectomy were identified. The removed myomas ranged in size from 1 through 11 cm (mean, 4.5 cm). Only 3 cases involved multilayered closure of uterine defects. Electrosurgery was used for hemostasis in all but 2 cases. No plausible contributing factor could be found in one case [corrected]. It seems reasonable for surgeons to adhere to techniques developed for abdominal myomectomy including limited use of electrosurgery and multilayered closure of the myometrium. Nevertheless, individual wound healing characteristics may predispose to uterine rupture.

Total laparoscopic hysterectomy

Alternatives to hysterectomy can provide excellent treatment outcomes for many women. In general, these alternatives are underused. For some women, however, alternative treatments fail and hysterectomy provides the best approach. The goal of future research should be to define better this group of women. For women who require hysterectomy, the laparoscopic approach affords the benefit of less postoperative discomfort, shorter hospital stay, and quicker recovery. The surgical techniques and instruments for laparoscopically directed hysterectomy are still in development. Few randomized, prospective studies that involve large numbers of patients have compared the risks and benefits of this approach with standard hysterectomy. In addition, data on the effectiveness of the operation, as performed by large numbers of gynecologists, are still not clear. Although the potential for real benefit exists, it is hoped that further study will clarify the place of laparoscopic-assisted hysterectomy in the nonsurgical and surgical treatment offered to patients.

Surgical management of leiomyomas for fertility or uterine preservation.

Leiomyomas are the most common pelvic tumors in women. These tumors are not always symptomatic but can cause abnormal uterine bleeding and anemia, pelvic pressure and pain, urinary frequency, and adverse reproductive outcomes—symptoms that can diminish the quality of life of women. Myomectomy is the primary treatment modality for women with symptomatic leiomyomas who are of reproductive age and desire future fertility. Myomectomy can significantly improve symptoms and quality of life and, in some clinical situations, improve reproductive outcomes. There are robust surgical outcome data supporting the use of a minimally invasive approach such as laparoscopy and hysteroscopy over laparotomy. Perioperative outcomes and return to normal activity are significantly better with a minimally invasive approach. Reproductive outcomes are not adversely affected. Detailed preoperative imaging is required for minimally invasive procedures to be successful. There are several evidence-based techniques that can be used to reduce blood loss during surgery. The role of robotic technology in enhancing surgical outcomes has not been clearly defined.

Outcome of Occult Uterine Leiomyosarcoma After Surgery for Presumed Uterine Fibroids: A Systematic Review

There is concern that morcellation of occult leiomyosarcomas during surgery to treat presumed myomas may substantially worsen patient outcome. We reviewed the existing medical literature to better understand whether such a risk was demonstrable and, if so, what the magnitude of that risk might be. We identified 4864 articles initially, of which 60 were evaluated in full. Seventeen were found to have outcomes information and are included in this review. Six studies addressed the question of whether morcellation of occult leiomyosarcomas resulted in inferior outcomes as compared with en bloc uterine and tumor removal. In these 6 studies, results suggested that en bloc removal may result in improved survival and less recurrence; however, the data are highly biased and of poor quality. There is no reliable evidence that morcellation, power or otherwise, substantially results in tumor upstaging. There is no evidence from these 17 studies that power morcellation differs in any way from other types of morcellation or even simple myomectomy insofar as patient outcome. Whether electromechanical morcellation poses a unique danger to the patient with occult leiomyosarcoma is an unanswered question and one clearly in need of more extensive investigation before conclusions are drawn and policies created.

Rapamycin Prevents Seizures After Depletion of STRADA in a Rare Neurodevelopmental Disorder

Blocking mTORC1 rescues the neural progenitor cell migratory defect caused by depletion of the STRADA pseudokinase and reduces seizures in patients with a rare neurodevelopmental disorder. Preventing Seizures with Rapamycin The discovery of new treatments for rare neurodevelopmental disorders associated with epilepsy and intellectual disability is often limited by small patient sample sizes that delay initiation of clinical trials. Mutations in the gene STRADA cause brain malformations, seizures, and failure to develop social language in children, with no known successful treatment. In a new study, Parker and colleagues now show that the protein STRADA modulates the mammalian target of rapamycin (mTOR) signaling pathway and that loss of STRADA results in unchecked mTOR activity. Depletion of STRADA in mouse neural progenitor cells resulted in loss of polarity, impaired migration, and inability to form layers in the cerebral cortex. Impaired migration was also identified in fibroblasts from patients lacking STRADA, and all of these effects were prevented with the mTOR inhibitor rapamycin, an immunosuppressant drug in clinical use. The authors then treated five children with rapamycin (sirolimus) beginning at 3 to 8 months of age, and abatement of seizures was observed in all of the children. Early treatment with mTOR pathway inhibitors may be beneficial for children with this neurodevelopmental disorder or with other conditions associated with enhanced mTOR signaling such as tuberous sclerosis complex and fragile X syndrome. A rare neurodevelopmental disorder in the Old Order Mennonite population called PMSE (polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome; also called Pretzel syndrome) is characterized by infantile-onset epilepsy, neurocognitive delay, craniofacial dysmorphism, and histopathological evidence of heterotopic neurons in subcortical white matter and subependymal regions. PMSE is caused by a homozygous deletion of exons 9 to 13 of the LYK5/STRADA gene, which encodes the pseudokinase STRADA, an upstream inhibitor of mammalian target of rapamycin complex 1 (mTORC1). We show that disrupted pathfinding in migrating mouse neural progenitor cells in vitro caused by STRADA depletion is prevented by mTORC1 inhibition with rapamycin or inhibition of its downstream effector p70 S6 kinase (p70S6K) with the drug PF-4708671 (p70S6Ki). We demonstrate that rapamycin can rescue aberrant cortical lamination and heterotopia associated with STRADA depletion in the mouse cerebral cortex. Constitutive mTORC1 signaling and a migration defect observed in fibroblasts from patients with PMSE were also prevented by mTORC1 inhibition. On the basis of these preclinical findings, we treated five PMSE patients with sirolimus (rapamycin) without complication and observed a reduction in seizure frequency and an improvement in receptive language. Our findings demonstrate a mechanistic link between STRADA loss and mTORC1 hyperactivity in PMSE, and suggest that mTORC1 inhibition may be a potential treatment for PMSE as well as other mTOR-associated neurodevelopmental disorders.

Bilateral Oophorectomy versus Ovarian Conservation: Effects on Long-term Women's Health

Bilateral oophorectomy at the time of hysterectomy for benign disease is commonly practiced to prevent the subsequent development of ovarian cancer. Currently, bilateral oophorectomy is performed in 55% of all U.S. women having a hysterectomy, with approximately 300,000 prophylactic oophorectomies performed every year. Observational studies show that estrogen deficiency, resulting from premenopausal or postmenopausal oophorectomy, is associated with higher risks of coronary artery disease, stroke, hip fracture, Parkinsonism, dementia, cognitive impairment, depression, and anxiety. These studies suggest that bilateral oophorectomy may do more harm than good. In women not at high risk for development of ovarian or breast cancer, removing the ovaries at the time of hysterectomy should be approached with caution.

Elective oophorectomy for benign gynecological disorders

Objective: To review the risks and benefits of elective oophorectomy and to make a clinical recommendation for an appropriate age when benefits of this procedure outweigh the risks. Design: The risks and benefits of oophorectomy as detailed in published articles are reviewed with regard to quality-of-life issues and mortality outcomes in oophorectomized versus nonoophorectomized women from five diseases linked to ovarian hormones (coronary heart disease, ovarian cancer, breast cancer, stroke, and hip fracture). Results: Numerous reports link oophorectomy to higher rates of cardiovascular disease, osteoporosis, hip fractures, dementia, short-term memory impairment, decline in sexual function, decreased positive psychological well-being, adverse skin and body composition changes, and adverse ocular changes, as well as more severe hot flushes and urogenital atrophy. The potential benefits associated with oophorectomy include prevention of ovarian cancer, a decline in breast cancer risk, and a reduced risk of pelvic pain and subsequent ovarian surgery. In our study of long-term mortality after oophorectomy using Markov modeling, preservation of ovaries until women are at least aged 65 years was associated with higher survival rates. For women between ages 50 and 54 with hysterectomy and ovarian preservation, the probability of surviving to age 80 was 62% versus 54% if oophorectomy was performed. This 8% difference in survival is primarily due to fewer women dying from cardiovascular heart disease and/or hip fracture. This survival advantage far outweighs the 0.47% increased mortality rate from ovarian cancer prevented by oophorectomy. If surgery occurred between ages 55 and 59, the survival advantage was 4%. After age 64 there were no significant differences in survival rates. Prior literature supports our conclusion of a benefit over risk for ovarian conservation. Conclusions: Elective oophorectomy is associated with short-and long-term health consequences that merit serious consideration. For women with an average risk of ovarian cancer, ovarian conservation until at least age 65 seems to benefit long-term survival.