In two randomized trials, two different doses of the oral gonadotropin-releasing hormone antagonist elagolix significantly reduced endometriosis-related dysmenorrhea and nonmenstrual pelvic pain but ...had hypoestrogenic adverse effects.
Menopause and its transition represent significant risk factors for the development of vulvovaginal atrophy-related sexual dysfunction. The objective of this study was to review the hormonal and ...nonhormonal therapies available for postmenopausal women with vulvovaginal atrophy-related sexual dysfunction, focusing on practical recommendations through a literature review of the most relevant publications in this field.
This study is a literature review.
Available vaginal estrogen preparations are conjugated equine estrogens, estradiol vaginal cream, a sustained-release intravaginal estradiol ring, or a low-dose estradiol tablet. Vaginal estrogen preparations with the lowest systemic absorption rate may be preferred in women with history of breast cancer and severe vaginal atrophy. Vaginal lubricants and moisturizers applied on a regular basis have an efficacy comparable with that of local estrogen therapy and should be offered to women wishing to avoid the use of vaginal estrogens.
Oral, transdermal, or vaginal estrogen preparations are the most effective treatment options for vulvovaginal atrophy-related sexual dysfunction. Selective estrogen receptor modulators such as lasofoxifene and ospemifene showed a positive impact on vaginal tissue in postmenopausal women. Vaginal dehydroepiandrostenedione, vaginal testosterone, and tissue selective estrogen complexes are also emerging as promising new therapies; however, further studies are warranted to confirm their efficacy and safety.
With the advent of assisted reproductive technology in the past three decades, the clinical importance of fallopian tubes has been relatively overlooked. However, successful spontaneous conception ...requires normal function of the tube to provide not only a conduit for the gametes to convene and embryo to reach the uterine cavity, but also a physiologically optimized environment for fertilization and early embryonic development. In this review, after a brief description of normal human tubal anatomy and histology, we will discuss tubal transport and its principal effectors, including ciliary motion, muscular contractility and tubal fluid. Furthermore, we will discuss the ciliary ultrastructure and regulation of ciliary beat frequency by ovarian steroids, follicular fluid, angiotensin system, autonomic nervous system and other factors such as adrenomedullin and prostaglandins. In the last section, we describe the adverse impact of various pathological conditions, such as endometriosis, infection and smoking on tubal function and ciliary motility.
In two identical, double-blind, randomized, 6-month phase 3 trials, elagolix (an oral gonadotropin-releasing hormone antagonist), administered with hormonal add-back therapy (estradiol, 1 mg, and ...norethindrone acetate, 0.5 mg, once daily) was more effective in reducing heavy menstrual bleeding in women with uterine fibroids than placebo. Bone loss was attenuated with add-back therapy, as compared with elagolix alone.
Obesity-related infertility is one of the most common problems of reproductive-age obese women who desire childbearing. The various types of bariatric surgeries have proved effective in controlling ...excessive weight gain, improving fertility, and preventing certain maternal and fetal complications in these women. This article summarizes the current evidence regarding the impact of bariatric surgery on obesity-related infertility and in vitro fertilization (IVF) outcomes. We have also attempted to draw conclusions about maternal and fetal risks and the benefits of bariatric surgery. Laparoscopic adjustable gastric banding and Roux-en-Y procedures are the two most commonly performed bariatric surgeries. Bariatric surgery was believed to improve menstrual irregularity and increase ovulation rate in anovulatory obese women, which lead to increased pregnancy rates. Although there are data in the literature suggesting the improvement of both the ovulatory function and the spontaneous pregnancy rates in obese women who lost weight after bariatric surgery, most of these are case-control studies with a small number of patients. The data are insufficient to determine an ideal time interval for pregnancy after bariatric surgery; however, the general consensus is that pregnancy should be delayed 12 to 18 months after bariatric surgery to avoid nutritional deficiencies. Few data exist regarding IVF success rates in women who have undergone bariatric surgery. One pairwise study discussed five patients who underwent bariatric surgery followed by IVF that resulted in three term pregnancies in three patients after the first IVF cycle. Many studies reported reductions in obesity-related pregnancy complications such as gestational diabetes and hypertensive disorders after bariatric surgery. Although data are inconsistent, some studies reported increased rate of preterm delivery and small for gestational age infants after bariatric surgery. Pregnancies after bariatric surgery may be considered high risk due to the concerns for vitamin deficiencies and gastrointestinal symptoms related to the surgery. Therefore the follow-up of these pregnancies might require a team approach including a maternal fetal medicine specialist, bariatric surgeon, and nutritionist.
To evaluate safety outcomes from clinical studies of a 12-month contraceptive vaginal system (CVS) releasing an average of segesterone acetate (SA) 150 mcg and ethinyl estradiol (EE) 13 mcg daily.
We ...integrated clinical safety data from nine studies in which women used the CVS for 21 consecutive days and removed it for 7 days of each 28-day cycle. Four studies used the final manufactured CVS, including a 1-year pharmacokinetic study, two 1-year phase 3 trials and a second-year treatment extension study. We assessed safety by evaluating adverse events women reported in a daily diary. We also included data from focused safety studies evaluating endometrial biopsies, vaginal microbiology and liver proteins from one of the phase 3 studies.
The combined studies included 3052 women; 2308 women mean age 26.7±5.1 years; mean body mass index (BMI) 24.1±3.7 kg/m2 received the final manufactured CVS, of whom 999 (43.3%) completed 13 cycles of use. Women using the final CVS most commonly reported adverse events of headache (n=601, 26%), nausea (n=420, 18%), vaginal discharge/vulvovaginal mycotic infection (n=242, 10%) and abdominal pain (n=225, 10%). Few (<1.5%) women discontinued for these complaints. Four (0.2%) women experienced venous thromboembolism (VTE), three of whom had risk factors for thrombosis Factor V Leiden mutation (n=1); BMI>29 kg/m2 (n=2). During 21,482 treatment cycles in the phase 3 studies evaluable for expulsion, women reported partial expulsions in 4259 (19.5%) cycles and complete expulsions in 1509 (7%) cycles, most frequently in the initial cycle 499/2050 (24.3%) and 190/2050 (9.3%), respectively. Safety-focused studies revealed no safety concerns.
The 1-year SA/EE CVS has an acceptable safety profile. Additional studies are warranted in obese women at higher risk of VTE.
This 1-year contraceptive vaginal system represents a new long-term, user-controlled and procedure-free option with a safety profile similar to other combination hormonal contraceptives. The same precautions currently used for combination hormonal contraceptive prescriptions apply to this new contraceptive vaginal system.
OBJECTIVE:To evaluate the efficacy and safety of elagolix, an oral, nonpeptide gonadotropin-releasing hormone antagonist, over 12 months in women with endometriosis-associated pain.
METHODS:Elaris ...Endometriosis (EM)-III and -IV were extension studies that evaluated an additional 6 months of treatment after two 6-month, double-blind, placebo-controlled phase 3 trials (12 continuous treatment months) with two elagolix doses (150 mg once daily and 200 mg twice daily). Coprimary efficacy endpoints were the proportion of responders (clinically meaningful pain reduction and stable or decreased rescue analgesic use) based on average monthly dysmenorrhea and nonmenstrual pelvic pain scores. Safety assessments included adverse events, clinical laboratory tests, and endometrial and bone mineral density assessments. The power of Elaris EM-III and -IV was based on the comparison to placebo in Elaris EM-I and -II with an expected 25% dropout rate.
RESULTS:Between December 28, 2012, and October 31, 2014 (Elaris EM-III), and between May 27, 2014, and January 6, 2016 (Elaris EM-IV), 569 participants were enrolled. After 12 months of treatment, Elaris EM-III responder rates for dysmenorrhea were 52.1% at 150 mg once daily (Elaris EM-IV=50.8%) and 78.1% at 200 mg twice daily (Elaris EM-IV=75.9%). Elaris EM-III nonmenstrual pelvic pain responder rates were 67.8% at 150 mg once daily (Elaris EM-IV=66.4%) and 69.1% at 200 mg twice daily (Elaris EM-IV=67.2%). After 12 months of treatment, Elaris EM-III dyspareunia responder rates were 45.2% at 150 mg once daily (Elaris EM-IV=45.9%) and 60.0% at 200 mg twice daily (Elaris EM-IV=58.1%). Hot flush was the most common adverse event. Decreases from baseline in bone mineral density and increases from baseline in lipids were observed after 12 months of treatment. There were no adverse endometrial findings.
CONCLUSION:Long-term elagolix treatment provided sustained reductions in dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia. The safety was consistent with reduced estrogen levels and no new safety concerns were associated with long-term elagolix use.
CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov, NCT01760954 and NCT02143713.
This multicenter, randomized trial compared the effects of clomiphene citrate plus placebo, metformin plus placebo, and combination therapy in infertile women with the polycystic ovary syndrome. The ...rate of live birth was significantly higher with clomiphene than with metformin; there was no significant difference between the rates with combination therapy and with clomiphene alone. Multiple birth was a complication associated with clomiphene but was infrequent. These data support the use of clomiphene over metformin for the treatment of infertility in women with the polycystic ovary syndrome.
In infertile women with the polycystic ovary syndrome, the rate of live birth was significantly higher with clomiphene than with metformin.
The polycystic ovary syndrome affects 7 to 8% of women
1
and may be the most common cause of female infertility.
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Anovulation,
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early pregnancy loss,
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and later pregnancy complications
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have all been implicated in the low fecundity of women with this disorder. Obesity is also common in such women,
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and this condition alone appears to have an adverse effect on reproduction.
6
,
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The cause of the polycystic ovary syndrome is poorly understood, and both the diagnosis and treatment of the disorder are controversial.
5
,
8
,
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Women with this syndrome have hyperandrogenism,
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morphologic changes in the ovary (polycystic),
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inappropriate gonadotropin secretion (elevated . . .
Aberrant up-regulation of aromatase in eutopic endometrium and implants from women with endometriosis has been reported. Aromatase induction may be mediated by increased cyclooxygenase-2 (COX-2). ...Recently, we demonstrated that progesterone receptor (PR)-A and PR-B serve an antiinflammatory role in the uterus by antagonizing nuclear factor κB activation and COX-2 expression. PR-C, which antagonizes PR-B, is up-regulated by inflammation. Although estrogen receptor α (ERα) is implicated in endometriosis, an antiinflammatory role of ERβ has been suggested. We examined stage-specific expression of aromatase, COX-2, ER, and PR isoform expression in eutopic endometrium, implants, peritoneum, and endometrioma samples from endometriosis patients. Endometrial and peritoneal biopsies were obtained from unaffected women and those with fibroids. Aromatase expression in eutopic endometrium from endometriosis patients was significantly increased compared with controls. Aromatase expression in endometriosis implants was markedly increased compared with eutopic endometrium. Aromatase mRNA levels were increased significantly in red implants relative to black implants and endometrioma cyst capsule. Moreover, COX-2 expression was increased in implants and in eutopic endometrium of women with endometriosis as compared with control endometrium. As observed for aromatase mRNA, the highest levels of COX-2 mRNA were found in red implants. The ratio of ERβ/ERα mRNA was significantly elevated in endometriomas compared with endometriosis implants and eutopic endometrium. Expression of PR-C mRNA relative to PR-A and PR-B mRNA was significantly increased in endometriomas compared with eutopic and control endometrium. PR-A protein was barely detectable in endometriomas. Thus, whereas PR-C may enhance disease progression, up-regulation of ERβ may play an antiinflammatory and opposing role.
OBJECTIVE:To investigate the safety and efficacy of elagolix, an oral gonadotropin-releasing hormone antagonist, with hormonal add-back therapy for up to 12 months in women with heavy menstrual ...bleeding associated with uterine leiomyomas.
METHODS:Elaris UF-EXTEND was a phase 3 extension study that evaluated an additional 6 months (up to 12 months total) of elagolix 300 mg twice daily with hormonal add-back therapy (estradiol 1 mg and norethindrone acetate 0.5 mg once daily) in women who completed an initial 6 months of the same treatment in one of two preceding phase 3 studies. The primary endpoint was the percentage of women with both less than 80 mL menstrual blood loss during final month and a 50% or greater reduction in menstrual blood loss from baseline to final month. Safety evaluations included adverse events and bone mineral density changes. The planned sample size of UF-EXTEND was based on estimated rollover and discontinuation rates in the two preceding studies.
RESULTS:From September 2016 to March 2019, 433 women were enrolled in UF-EXTEND. Of these women, 218 received up to 12 months of elagolix with add-back therapy; the mean±SD age of this group was 42.4±5.4 years and 67.3% were black. The percentage of women who met the primary endpoint in this elagolix with add-back group was 87.9% (95% CI 83.4–92.3). The most frequently reported adverse events with up to 12 months of elagolix plus add-back therapy were hot flush (6.9%), night sweats (3.2%), headache (5.5%), and nausea (4.1%). Mean percent decreases in bone mineral density from baseline to extension month 6 were significantly less with elagolix plus add-back therapy than with elagolix alone {between-group difference in lumbar spine−3.3 (95% CI −4.1 to −2.5)}.
CONCLUSION:Up to 12 months of elagolix with add-back therapy provided sustained reduction in menstrual blood loss in women with uterine leiomyomas, with the addition of add-back therapy attenuating the hypoestrogenic effects of elagolix alone. No new or unexpected safety concerns were associated with an additional 6 months of elagolix with addback therapy.
CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov, NCT02925494.
FUNDING SOURCE:AbbVie Inc funded this study.
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