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Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115
Address all correspondence and requests for reprints to: Robert Barbieri, M.D., Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115. E-mail: rbarbieri{at}partners.org.
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Abstract |
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Objective: This invited review highlights a selection of reports from leading journals over the past 2 yr that have significantly advanced our understanding of female reproduction from conception to menopause.
Synthesis: During fetal life, in utero exposures may be important determinants of later pubertal and adult endocrine physiology. Epigenetic mechanisms are likely involved in the fetal programming of adult endocrine function. With regards to the polycystic ovary syndrome, recent clinical trials have confirmed the central role of clomiphene for ovulation induction in women with this disease. In addition, an expert panel has recommended that all women with polycystic ovary syndrome have a glucose tolerance test because of the high prevalence of impaired glucose tolerance in this population. In menopausal women the precise impact of estrogen therapy on cardiovascular biology remains to be delineated fully. Evolving data indicate that when initiated near the onset of menopause, estrogen therapy has fewer cardiovascular risks than when it is administered decades after the menopause.
Conclusions: The essence of reproduction is the successful transmission of germ-line DNA to a succeeding generation. Advances in genetics and endocrinology are converging to advance significantly our understanding of the biology of reproduction and our ability to influence reproductive processes. These advances will translate into new treatments for the prevalent medical problems of reproduction.
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In Utero Determinants of Pubertal and Adult Endocrine Function |
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Evolving research Barker et al. (1) championed the innovative hypothesis that the in utero nutrient environment programs physiological processes that persist into adult life and impact patterns of disease. The "thrifty phenotype" hypothesis proposed that nutritional deficiencies in fetal life resulted in reduced fetal somatic growth as manifested in low birth weight, and programmed central metabolic processes toward an increased risk of developing insulin resistance and dyslipidemia (1). Epigenetic mechanisms, such as DNA methylation, are thought to be one process by which the fetal environment influences the adult phenotype (2). Other mechanisms such as alterations in nutritional status and body composition may also play an important role.
In humans, low birth weight is often followed by catch-up weight gain, with an exaggerated accumulation of central adipose tissue and insulin resistance. For example, in one study of 22 girls and seven boys who were born with a mean birth weight of 2.1 kg, abdominal fat mass as determined by dual-energy x-ray absorptiometry at 4 yr of age was significantly greater than that observed in 22 age-matched controls with a normal birth weight (1.2 vs. 0.8 kg; P < 0.0003). The body mass index (BMI) of the two groups was similar at the dual-energy x-ray absorptiometry testing (15.7 vs. 15.6 kg/m2) (3). In addition, children born with low birth weight have higher fasting insulin and lower adiponectin concentrations than children with a normal birth weight (4). In adults with a history of low birth weight, fasting circulating glucose and insulin are increased, and a glucose challenge causes exaggerated increases in insulin and glucose (5).
In one small trial, 38 prepubertal girls with precocious pubarche (pubic hair appearing before age 8 yr) and a history of low birth weight were randomized at a mean age of 7.9 yr to receive metformin (425 mg daily for 2 yr, followed by 850 mg daily for 2 yr) or remain untreated for 4 yr. After 4-yr therapy, the girls treated with metformin had less body fat, less visceral fat, less insulin resistance, and lower androgen levels than the girls who did not receive metformin. Long-term metformin therapy may reduce body fat, insulin resistance, and androgen excess in low birth weight girls with precocious pubarche (6).
Maternal hyperglycemia and childhood obesity
Evolving research Maternal hyperglycemia as evidenced by an abnormal glucose tolerance test may be associated with an increased risk of childhood obesity. In a cohort study of 27,229 singleton pregnancies, a positive association between maternal hyperglycemia and childhood obesity at age 5–7 yr was reported. In this study the risk of having a child greater than the 95th percentile for weight at age 5–7 yr was 28% greater for pregnant women with a 1-h glucose between 112 and 140 mg/dl compared with a 1-h glucose of less than 95 mg/dl after a glucose challenge test. Among women with untreated gestational diabetes, the risk of having a child greater than the 95th percentile for weight at age 5–7 yr was increased 82% compared with pregnant women with a normal glucose challenge test (7). In turn, childhood and adolescent obesity is likely to be associated with increased rates of adult heart disease (8) (9). Based on these findings, children of mothers with hyperglycemia during pregnancy should be evaluated for early intervention when evidence of abnormal weight gain is present.
Polycystic ovary syndrome (PCOS)
Evolving research PCOS is characterized by both reproductive and metabolic abnormalities. Recent research indicates that many women with PCOS have evidence of widespread multisystem dysfunction, including: 1) endothelial dysfunction and inflammation (10), 2) an atherogenic serum lipoprotein profile (11), 3) increased coronary artery calcium (12), 4) nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (13), and 5) obstructive sleep apnea (14). The relative contribution of PCOS vs. obesity to these problems is not yet fully delineated.
Clinical practice The Androgen Excess Society issued a position statement recommending that women with PCOS be screened for impaired glucose tolerance and diabetes with a 2-h oral glucose tolerance test. In follow-up of the initial screen, women with normal glucose tolerance should be screened every 2 yr. Women with impaired glucose tolerance should be screened annually. A minority opinion recommended limiting the 2-h oral glucose tolerance test to women with PCOS and a BMI of 30 kg/m2 or greater (15).
The Endocrine Society published a guideline concerning hirsutism focused on diagnosis and treatment (16). The task force recommended testing for elevated circulating androgens in women with moderate to severe hirsutism and in women with the sudden onset, or rapidly progressive hirsutism, or when hirsutism is associated with signs of virilization, menstrual dysfunction, or obesity. For the hormonal treatment of hirsutism, the task force recommended an estrogen-progestin contraceptive with the addition of an antiandrogen at 6 months if the hirsutism was not adequately treated by estrogen-progestin therapy. The task force concluded that insulin-sensitizing agents were not especially effective for the treatment of hirsutism.
The Thessaloniki PCOS Consensus Workshop Group (17) reported their guidelines for the treatment of anovulatory infertility in women with PCOS. It recommend a sequential, four-step approach to treatment: 1) lifestyle change, including diet and exercise, to achieve an optimal BMI; 2) clomiphene citrate; 3) FSH injections or laparoscopic ovarian surgery; and 4) in vitro fertilization. In addition, it recommended against the routine use of metformin for ovulation induction in women with PCOS based on recent randomized trials that indicate clomiphene alone is superior to metformin alone (18), and metformin plus clomiphene is not superior to clomiphene alone (19). The Workshop Group noted that clinical trials have demonstrated that letrozole and anastrozole have similar efficacy to clomiphene for ovulation induction in women with PCOS but that they are not approved for the treatment of infertility (20, 21). They caution against the use of these agents until safety can be demonstrated.
Bariatric ("baro" is Greek for "weight") surgery is an effective treatment for severe obesity, and the number of bariatric procedures performed annually is rapidly increasing. Bariatric surgery appears to be an effective approach to the treatment of diabetes in overweight men and women (22). Bariatric centers are reporting that surgery is successful in the treatment of anovulation, hirsutism, and insulin resistance associated with PCOS. For example, in one cohort study, 24 severely obese women with PCOS and a mean age of 34 yr were treated with Roux-en-Y gastric bypass. The initial BMI was 50 kg/m2. The women were followed for a mean of 28 months. The mean excess weight loss 12 months after surgery was 57%. All 24 women resumed normal menses, and 77% of the women reported improvement in their hirsutism (23). Similar results have been reported in another small cohort (24). In this study, 12 women with PCOS and severe obesity (mean BMI 50 kg/m2) underwent bariatric surgery. One year after the surgery, the mean weight loss was 41 kg. Preoperatively, the women had elevated levels of free testosterone and fasting insulin. Postoperatively, these analytes returned to the normal range (Fig. 1
). For women with PCOS and long-standing severe obesity, there is a low probability that diet and exercise will result in normalization of BMI. For these women, bariatric surgery is a reasonable treatment alternative. After bariatric surgery pregnancy should be delayed until the patient reaches a stable weight, typically 12–18 months after surgery (25).
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Evolving research
The two most widely used hormonal contraceptives are estrogen-progestin and progestin-only contraceptives. Estrogen-progestin contraceptives cannot be used by some women due to increased risk of vascular complications such as venous thromboembolism (VTE). Progestin-only contraceptives are associated with a high rate of discontinuation because of breakthrough bleeding. A novel approach to continuous hormonal contraceptive is the use of selective progestin receptor modulators (SPERMs) that have predominantly progesterone antagonist activity. SPERMs can inhibit ovulation, disrupt endometrial receptivity for an embryo, and induce endometrial quiescence, resulting in light menses or amenorrhea. In a small pilot study, the SPERM, VA2914, at doses of 5 or 10 mg daily was demonstrated to both block ovulation and induce amenorrhea in approximately 80% of treated women (26). Treatment with VA2914 was associated with LH, FSH, and estradiol levels in the follicular phase range. Endometrial pathology demonstrated an inactive endometrium and no evidence for endometrial hyperplasia in this small sample (Fig. 2).
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). "Break-through" bleeding was reported by more women in the continuous treatment group than in the cyclical group (13 vs. 7%; P = 0.03). Women on continuous therapy reported less menstrual pain. Continuous treatment resulted in a 51% greater decrease in urinary estrone glucuronide compared with cyclical treatment. Pregnanediol glucuronide measurements indicated that "escape" ovulation occurred more frequently in the cyclical treatment group than in the continuous treatment group. Pelvic ultrasound demonstrated that continuous treatment was associated with fewer ovarian follicles and a smaller ovarian volume than cyclical treatment. In combination these findings indicate that continuous therapy produced more pronounced ovarian suppression than cyclical therapy. These results indicate that continuous estrogen-progestin contraception should be considered a first-line contraceptive option. Translation of these findings into practice is likely to require significant education of both clinicians and patients.
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Endometriosis
Evolving research Endometriosis, the presence of endometrial glands and/or stroma outside of the uterus, affects approximately 5% of women of reproductive age. The main presenting problems of women with endometriosis are pelvic pain, infertility, or an ovarian cystic mass caused by the disease. The growth of endometriosis lesions is stimulated by estrogen and inhibited by androgens. Classical treatment of endometriosis involves suppression of LH, FSH, and ovarian estradiol production by GnRH analogs or surgical removal of both ovaries. Evolving research has demonstrated that direct inhibition of estradiol production in endometriosis lesions using aromatase inhibitors may have a role in the treatment of endometriosis.
Endometriosis lesions are stimulated to grow by estrogen, and the lesions can convert androgen to estrogen locally due to an abnormal increase in aromatase enzyme activity. In endometriosis lesions, the cascade that results in the overexpression of aromatase includes up-regulation of upstream stimulatory factor 2, which activates the promoter of steroidogenic factor-1. In turn, steroidogenic factor-1 activates the promoters of both steroidogenic acute regulatory protein and the aromatase enzyme, resulting in increased local conversion of androgen to estrogen (30). It is believed that the estrogen generated locally within the endometriosis lesion stimulates the growth of the lesion.
In pilot studies, aromatase inhibitors have been demonstrated to have a potential role in the treatment of pelvic pain caused by endometriosis. In premenopausal women the administration of aromatase inhibitors as monotherapy is associated with a high rate of ovarian cyst formation, likely due, in part, to the stimulation of FSH secretion (31). Most pilot studies of aromatase inhibitors have used combinations that include an aromatase inhibitor, plus a GnRH analog, or a "high-dose" progestin or an estrogen-progestin contraceptive (32). In one clinical trial, women with severe endometriosis and pelvic pain were randomized to treatment with the GnRH analog, goserelin, or to goserelin plus the aromatase inhibitor, anastrozole. The combination of goserelin plus anastrozole produced significantly greater reported pain relief than goserelin alone (33).
Clinical practice Estradiol stimulates the growth of endometriosis lesions. GnRH analogs are effective treatment for the pelvic pain associated with endometriosis because they inhibit pituitary secretion of LH and FSH, in turn, inhibiting ovarian estradiol production. However, GnRH analog treatment is associated with bone loss and vasomotor symptoms, limiting the long-term use of this agent. Recent trials indicate that both parenteral progestins and estrogen-progestin contraceptives are effective treatment of pelvic pain caused by endometriosis and do not cause as much bone loss as the GnRH analogs.
In one trial 274 women with pelvic pain and surgically documented endometriosis were randomized to depot medroxyprogesterone acetate (DPMA) 104 mg sc injection or depot leuprolide acetate (LA) 11.25 mg im injection every 3 months for 6 months (34). The dropout rate was 35% in the DPMA and 26% in the LA groups. More patients in the DPMA group (n = 7) than the LA group (n = 1) withdrew because of reported lack of efficacy of the treatment after one injection. Of the women who completed 6-month treatment, more than 80% in both the DPMA and LA groups reported significant improvement in dysmenorrhea, dyspareunia, pelvic pain, and pelvic tenderness. Pelvic induration (a physical examination finding associated with endometriosis-induced inflammation and scarring) was improved in a greater percentage of women who received LA (87%) than DMPA (74%). LA treatment reduced bone density at the lumbar spine and hip by 3.95 and 1.65%, respectively. DMPA treatment reduced bone density at the lumbar spine and hip by 1.1 and 0.30%, respectively. Compared with LA treatment, DMPA was associated with significantly less bone loss at the lumbar spine and hip. Given the similar efficacy of LA and DMPA in the treatment of pelvic pain, and the reduced bone impact of DMPA, it should be considered as a treatment option for women with endometriosis who do not respond to estrogen-progestin contraceptives or analgesics.
Currently used estrogen-progestin contraceptives are "progestin" dominant, as evidenced by the atrophic endometrium observed in many women on these contraceptives. Estrogen-progestin contraceptives used in monthly cycles, or extended cycles, have long been a first-line therapy in the treatment of pelvic pain caused by endometriosis, but high-quality evidence has not been available to support this clinical practice. A recently reported randomized clinical trial tested the efficacy of ethinyl estradiol (35 µg)-norethindrone (1 mg) in a 21 active pill, monthly cycle vs. placebo in women with pelvic pain caused by endometriosis (35). The estrogen-progestin treatment resulted in significantly greater improvement in pelvic pain than the placebo. Dysmenorrhea was reduced by 45% in the estrogen-progestin group and 14% in the placebo group (P < 0.0001). This study supports the use of estrogen-progestin treatment either in a monthly or extended-cycle format for the treatment of pelvic pain caused by endometriosis.
Pregnancy
Evolving research Universal screening for hypothyroidism in pregnant women is not recommended by the majority of professional organizations that have published guidelines on this subject. Testing for hypothyroidism in pregnancy is recommended for symptomatic women, or women with a personal or family history of thyroid disease (36, 37). A recent study evaluated the clinical efficiency of a case finding approach to identifying hypothyroidism in pregnant women based on risk factors. The investigators reported that in a cohort of 1560 pregnant women, 74% had no risk factor, and 26% had at least one risk factor for thyroid disease (38). Risk factors included a personal or family history of thyroid disease, a personal or family history of autoimmune disease, current or past treatment with thyroid medications, or thyroid surgery. Among the women without risk factors, 1% were hypothyroid based on a TSH more than 4.2 mIU/liter. Among the women with risk factors, 6.8% had a TSH more than 4.2 mIU/liter. The investigators concluded that a case finding approach to identifying hypothyroidism in pregnant women using risk factors to guide testing fails to identify about 30% of cases. An editorial accompanying the article noted that ongoing clinical trials will eventually inform our approach to screening, but until those data are available, that universal screening was acceptable because of its potential benefits and low cost and low risk (39).
Clinical practice Recent randomized trials reported that the administration of vaginal progesterone (200 mg nightly) or im 17-hydroxyprogesterone caproate (250 mg weekly) reduced the risk of spontaneous preterm birth in women with singleton pregnancy and a history of a prior preterm less than 34-wk gestation (40, 41). In one trial, 17-hydroxyprogesterone caproate therapy reduced preterm birth, and was associated with a significant reduction in the use of supplemental oxygen for the newborns and a significant reduction in mild intraventricular hemorrhage (41). Pending demonstration of a clear benefit of progesterone treatment on neonatal outcome, women with a history of preterm birth should be counseled about the risks and benefits of treatment, and may be offered progesterone therapy.
Assisted reproductive technology
Evolving research The technology for successfully cryopreserving human oocytes for use in assisted reproduction is rapidly advancing (42). This technology may be useful in preserving fertility potential in a number of clinical situations: 1) women undergoing cancer chemotherapy (43), 2) women who are aging but not ready to conceive, and 3) adolescents who are known to be mosaics for Turner syndrome and likely to become menopausal before attempts at conception. Embryo cryopreservation has long been a successful technology widely used in infertility therapy. Until recently, oocyte cryopreservation has been technically possible, but extremely inefficient. In the past, approximately 100 cryopreserved oocytes were needed to achieve one pregnancy. Evolving technology, including the use of intracytoplasmic sperm injection to fertilize cryopreserved oocytes, and improvements in both advanced vitrification and slow-freezing methods have resulted in an increase in the efficiency of using human cryopreserved oocytes in assisted reproduction (44). Although the technique is currently considered experimental, this is likely to become the fastest growing area of fertility therapy during the next decade.
Clinical practice Assisted reproduction combined with preimplantation genetic diagnosis is often used for couples at risk for a genetic disorder. In this process, embryos unaffected by the genetic disorder are identified by PCR or fluorescent in situ hybridization techniques for uterine transfer. This technology has been used to achieve a nonaffected newborn in over 100 different single gene disorders, such as cystic fibrosis, thalassemia, and various X-linked disorders. An evolution of this technology is to conceive an unaffected child and use the unaffected newborn’s cord blood for stem cell transplantation to an older sibling affected by a life-threatening genetic disorder. For example, for a couple that is heterozygote for Fanconi’s anemia with a living child with the disorder, in vitro fertilization and preimplantation genetic diagnosis can be used to identify embryos that are human leukocyte antigen-matched with the affected child, and are not carrying two abnormal alleles for the disease. Newborns conceived from these unaffected, human leukocyte antigen-matched embryos are excellent hematopoietic stem cell donors for their affected older sibling. For an initial transplantation attempt, the fetal stem cells in the cord and placenta can be used (45). Other genetic disorders, such as thalassemia, can also be treated with this evolving technology (46).
Menopause
Evolving research Recent laboratory studies indicate that naturally occurring lipids may have estrogen antagonist properties that modulate estradiol biology. 27-hydroxycholesterol is a cholesterol metabolite that is present in atherosclerotic lesions and appears to be a competitive antagonist to estradiol in endothelium (47). In endothelial cells, 27-hydroxycholesterol was demonstrated to inhibit estradiol-stimulated production of nitric oxide through both transcription-mediated and nontranscription mechanisms. In mice, elevated levels of 27-hydroxycholesterol decreased estrogen-dependent expression of vascular nitric oxide synthase and inhibited re-endothelialization in a model of carotid artery injury. 27-hydroxycholesterol, and other endogenous antiestrogens, may influence the effects of estradiol on the endothelium.
Clinical practice In the Women’s Health Initiative (WHI), hormone therapy with conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) resulted in an increased risk of cardiovascular events, stroke, and deep venous thrombosis. After discontinuing hormone therapy, these risks rapidly recede (48). Analysis of the WHI data indicates that hormone therapy with either CEE-MPA or CEE-only has divergent effects on cardiovascular risk when initiated close to the onset of menopause or distant from the menopause (49). The risk of hormone therapy induced coronary heart disease increased with the length of time from the onset of menopause. For women initiating hormone therapy less than 10 yr from menopause, the hazard ratio (HR) for coronary heart disease was 0.76 (95% confidence interval 0.5–1.16), for 10–19 yr from the menopause, the HR was 1.10, and for 20 or more years from the menopause, the HR was 1.28 (P for trend = 0.02). Hormone therapy increased the risk of stroke (HR 1.32, 95% confidence interval 1.12–1.56), regardless of the time from onset of menopause or the age of the subject. In a substudy of the WHI, women 50–59 yr of age who received CEE-alone had less coronary-artery calcium burden than women treated with placebo (50). These studies suggest that estrogen may have a direct beneficial effect on cardiac vascular function in women who are recently menopausal. The main indication for the use of hormone therapy is the treatment of vasomotor symptoms, which typically become clinically significant before- or coincident with the menopause. Because the safety profile of hormone therapy is improved if it is initiated closer to the onset of menopause, these findings should be reassuring to both clinicians and patients.
The route of estrogen treatment and the type of progestin used may influence the risk of adverse events with hormone therapy. In menopausal women, transdermal estradiol treatment may be associated with a smaller risk of VTE than oral estrogen treatment. In a case-control study with 271 cases of VTE and 610 controls [Estrogen and Thromboembolism Risk study (51)], oral estrogen treatment was associated with a 4-fold increased risk of VTE compared with no estrogen therapy. Transdermal estrogen treatment did not significantly increase the risk of VTE (51). In this study, micronized progesterone and MPA use did not increase the risk of VTE, but norethindrone acetate use was associated with an increased risk of VTE. In menopausal women, estrogen therapy combined with micronized progesterone may be associated with a smaller risk of breast cancer than estrogen therapy combined with other progestins, such as norethindrone acetate (52).
The risks and benefits of androgen therapy in menopausal women are a focus of active clinical research. The Endocrine Society recently published a guideline concerning androgen therapy in women (53). The main practice recommendations were: 1) there is no established standard for diagnosing androgen deficiency in women; 2) in surgically menopausal women with decreased libido who are receiving estrogen, evidence indicates that short-term treatment with testosterone is associated with a modest increase in libido and the number of satisfying sexual experiences; and 3) androgen therapy should not be widely used in menopausal women because the indications are not well defined, and long-term safety data are not available. The postmenopausal ovary secretes significant quantities of androgen (54). In postmenopausal women with intact ovaries, it is unlikely that exogenous testosterone therapy will be widely used until long-term safety data are available and the goal of therapy is clearly defined. With an increasing life span, more women are in menopause for decades of their lives. Continued intense focus on the endocrinology of menopause is likely to yield advances both in the biology of aging and interventions that will maximize the quality of life.
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Abbreviations: BMI, Body mass index; CEE, conjugated equine estrogen; DPMA, depot medroxyprogesterone acetate; HR, hazard ratio; LA, leuprolide acetate; MPA, medroxyprogesterone acetate; PCOS, polycystic ovary syndrome; SPERM, selective progestin receptor modulator; VTE, venous thromboembolism; WHI, Women’s Health Initiative.
Received April 4, 2008.
Accepted May 14, 2008.
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