Testosterone: Satisfying Sex Once More per Month

Here's a summary of another study on testosterone in women, this time in women not on estrogen or estrogen plus progesterone. Duration longer than in previous studies: 52 weeks. On average, women on testosterone reported satisfying sex once more per month. Main question is: Is the unknown long-term risk of testosterone worth the benefit to your sex life? Many of my patients would say that contented sex, even if it only happens once more per month above baseline, is worth it. --SG

Testosterone Improves Sexual Function in Women Not Taking Estrogen
Posted 01/16/2009

Robert A. Wild, MD, PhD, MPH
Author Information

Summary

Davis SR, Moreau M, Kroll R, et al, for the APHRODITE Study Team. Testosterone for low libido in postmenopausal women not taking estrogen. N Engl J Med 2008;359:2005-2017.

Therapy with a testosterone patch placed on the abdomen and delivering 300 µg daily provides some benefit to postmenopausal women with hypoactive sexual desire disorder (HSDD) who are not using estrogen therapy (ET) or estrogen plus progestin therapy (EPT), according to this randomized, double-blind, placebo-controlled study. The Phase III Research Study of Female Sexual Dysfunction of Women on Testosterone without Estrogen was initiated to determine the efficacy and safety of the testosterone patch in postmenopausal women not receiving estrogen who are suffering from HSDD and included women from 65 centers in the United States, Canada, Australia, the United Kingdom, and Sweden. The trial was conducted for 52 weeks and included 814 healthy postmenopausal women (aged 20-70 y) who were randomly assigned to receive a patch delivering either 150 µg or 300 µg testosterone per day or placebo. Participants were seen at baseline and at weeks 6, 12, 24, 36, and 52.

Efficacy was measured through women's responses on a weekly sexual activity log for 24 weeks and their scores on a Profile of Female Sexual Function and a Personal Distress Scale that were completed at baseline and at weeks 12 and 24. Adverse events were assessed at each visit through week 52. Some women continued treatment for a second year to provide additional safety data. The primary endpoint was a change through week 24 in frequency of satisfying sexual episodes over 4 weeks.

Baseline scores for frequency of satisfying sexual events, sexual desire, and distress were similar among groups. By week 24, the increase in 4-week frequency of satisfying events was significantly greater in the group with the 300 µg/day patch, with an increase of 2.1 episodes versus 0.7 episodes for placebo; P < 0.001. There was an increase in satisfying episodes of 1.2 in 4 weeks for the group receiving 150 µg testosterone. Both groups receiving testosterone had significantly increased scores for sexual desire and decreased scores for distress by week 24. The overall incidence of adverse events among groups was similar, with incidence of androgenic events highest in the 300-µg group, mainly increased hair growth. Breast cancer occurred in three women in the testosterone groups by week 52 and in an additional woman receiving hormone in the extension phase.

Commentary by Robert A. Wild, Md, Phd, Mph

Prior clinical trials (typically lasting 3-6 mo) with exogenous testosterone have been well conducted. The majority of trials show modest overall improvement in desire, sexual responsiveness, and frequency of orgasm as well as the number of satisfying sexual episodes (an endpoint required by the Food and Drug Administration [FDA] as evidence of efficacy). The short duration of these trials has worried those concerned about potential for serious adverse effects. Studies have been restricted to postmenopausal women taking ET or EPT.

Here, Davis et al assess testosterone therapy in postmenopausal women presumably estrogen deficient for up to 2 years. Efficacy was shown in women who had natural menopause but not in those with surgically induced menopause (probably because of a lack of statistical power). It is reasonable to ask whether the absolute increase of satisfying sexual episodes of 2.1 per month (1.4 more events per month than in the placebo group) was of value. The article does not indicate whether the women were asked if this was meaningful for them. Baseline data suggest it probably was. The mean number of such episodes almost doubled for the high-dose group (84% vs. 28% for placebo).

All groups had reaction at the application site (49.5%-52.8%, which is high) and various androgenic events (acne, alopecia, and voice deepening in less than 8% of each group). A little more than half in each group completed 52 weeks. Reasons for dropping out are well illustrated. Increased unwanted hair growth was significantly more common with 300 µg of testosterone per day (19.9% vs. 10.5% in the placebo group). Of greater concern are the four cases of breast cancer in the groups receiving testosterone, including one case detected 3 months after the extension period ended, versus zero in the placebo group. This could simply be due to chance, yet it is potentially worrisome and cannot be ignored. Findings suggest the need for caution until we understand more about testosterone's possible link with breast cancer and until we are better able to predict which patients are more likely to have negative effects.

Transdermal testosterone is available in Europe for use in surgically postmenopausal women who have persistent symptoms of HSDD despite adequate nonconjugated ET. However, the FDA in the United States is concerned about potential adverse effects over the long term. Breast cancer risk and potential detrimental lipoprotein physiology with unknown cardiovascular disease risk, as well as androgenic side effects (well documented here), have been the major challenges. The reported lipid profiling in this study is reassuring yet not definitive. Small, dense lipoprotein particle concentrations are a better predictor of events but were not measured. The pharmaceutical industry sponsored and analyzed this multisite study.

Because of a lack of FDA-approved testosterone patches in the United States for women, compounding pharmacy preparations for transdermal testosterone are often prescribed. If this route is chosen, full disclosure of off-label use and documentation of the known and unknown risks is strongly recommended. With the breast cancer concern and the need for studies with large numbers of women enrolled to answer this concern, it is likely that the FDA will continue to be very conservative regarding this issue.

From the NAMS First to Know e-newsletter released December 23, 2008

For more, please visit http://www.menopause.org/news.aspx

Libido: Bay Area Boosts

Libido is one of my favorite topics both as an area of physical, mental and spiritual inquiry and as a scholarly pursuit. Plus it's just fun to rev it up as much as possible especially when in a long-term monogamous relationship.

Now, as an aside, let me reassure my friends who are depleted and gave up caring about libido months or years ago: you can get your game back. My heart and pharmacoepia especially goes out to fellow depleted moms. That reminds me - I need to do a blog post on Depleted Mom Syndrome.

We are blessed in the Bay Area (and in New York and Los Angeles, and tell me if there are more libidinously enriching parts of our fine country) to have many places that offer succor to the libidinally-challenged.

My personal fave haunt is S Factor in San Fran, but also available in other cities. What is "S?" It's a hybrid form of movement that weaves yoga, pilates and connecting to your erotic creature. It's completely hot and a lot of fun. Take an intro class or sign up for a private with my dear friend, Michelle Cordero. Since I have a tendency to overachieve, I have attended 3 intros, devoured Sheila Kelly's book on "S" and practiced every DVD she's put out. My husband and I haven't figured out a way for me to attend a session in San Francisco - at two hours plus the commute time - it just doesn't fit into my schedule. But maybe your schedule? Get the intro schedule right here.

Here is Sheila teaching Oprah how to move.

Did you see the cover of last Sunday's NYT's Style Section with the orgasmic woman on the front page? So great. The article was about the Bay Area's OneTaste Urban Retreat Center, a co-ed gathering space with a focus on pleasing women. Where do I sign up? The founder, Nicole Daedone, is the creatrix of the joint, and at 41, she is tapping into a hugely unmet need among women -- the idea that we access freedom, full embodiment, and full-throttle living through our sexualty. A core of 38 men and women live in the SOMA location, but OneTaste offers workshops, a thriving online community (read: free), and a residential program. Check 'em out right here.

My brain tends to cluster around groupings of three, so here is another favorite resource: famous Bay Area sex coaches Celeste and Danielle. I met these women three years ago over lunch at Cafe Gratitude in Berkeley. They offer sex therapy, workshops and hands-on-in-the-bedroom, down and dirty sex couching (they wear gloves!). I have one patient with low libido who had picture-perfect hormones, and we discussed Celeste and Danielle's workshops. She asked her husband to go to their workshop, "Become an Extraordinary Lover," and that was the only intervention she needed to reconnect deeply and wildly with her man.

Wish it were always so easy....

For the rest of us, libido is a complex and very interdependent mix of the right hormonal balance (the players are estrogen, progesterone, testosterone, DHEA, cortisol among others) plus emotional connectivity, healthy body image, time and commitment. More on that later, in the meantime, enjoy your local resources and share via the comments section other discoveries for raising your libido.

Latest Conventional Care for Ovarian Insufficiency

Here's an article from last month's New England Journal of Medicine summarizing where we are with Primary Ovarian Insufficiency. Remission occurs in 5-10% of women, including spontaneous pregnancy. Sorry but the links don't work unless you subscribe online to the New England Journal.

Primary Ovarian Insufficiency

Lawrence M. Nelson, M.D.

This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author's clinical recommendations.

A 30-year-old woman presents with a history of no menses since she stopped taking oral contraceptives 6 months ago in order to conceive. She had undergone puberty that was normal in both timing and development, with menarche at 12 years of age. At 18 years of age, she started taking oral contraceptives for irregular menses. She reports stress at work. Her weight is 59 kg, and her height 1.66 m; her body-mass index (the weight in kilograms divided by the square of the height in meters) is 21.3. There is no galactorrhea, hirsutism, or acne. The pelvic examination is normal, a pregnancy test is negative, the prolactin level is normal, and the follicle-stimulating hormone (FSH) level is in the menopausal range. How should she be evaluated and treated?

The Clinical Problem

The ovary is unique in the endocrine system in that an entirely new secretory structure is developed within it each month — the graafian follicle, which arises from a microscopic primordial follicle. Menopause, defined as the permanent cessation of menses, results from the depletion of potentially functional primordial follicles. The mean (±SD) age at the time of natural menopause is 50±4 years.¹ Menopause before the age of 40 years is considered to be premature.

Primary ovarian insufficiency is the preferred term for the condition that was previously referred to as premature menopause or premature ovarian failure; other terms used for this condition include primary ovarian failure and hypergonadotropic hypogonadism, as well as the misnomer, gonadal dysgenesis.^2,3 The condition is considered to be present when a woman who is less than 40 years old has had amenorrhea for 4 months or more, with two serum FSH levels (obtained at least 1 month apart) in the menopausal range.^4,5 The condition differs from menopause in that there is varying and unpredictable ovarian function in approximately 50% of cases, and about 5 to 10% of women conceive and deliver a child after they have received the diagnosis.^4,6,7,8,9 Thus, the term "primary ovarian insufficiency," as originally suggested by Albright, meets the need to describe a continuum of impaired ovarian function rather than a dichotomous state.^2,3 This term may also be less stigmatizing than the terms that were used previously.

In 90% of the cases of primary ovarian insufficiency, the cause remains a mystery. Spontaneous 46,XX primary ovarian insufficiency can occasionally occur as part of a syndrome (Table 1, and the Supplementary Appendix, available with the full text of this article at NEJM.org). In addition, several single genes (e.g., bone morphogenetic protein 15 [BMP15], diaphanous homolog 2 [DIAPH2], and inhibin alpha subunit [INHA]) have been associated with nonsyndromic primary ovarian insufficiency, but their clinical relevance is not clear. Structural abnormalities in the X chromosome apart from specific gene mutations may also be a cause.

View this table: [in this window] [in a new window] Table 1. Representative Syndromes with Which Spontaneous 46,XX Primary Ovarian Insufficiency Has Been Associated.

Primary ovarian insufficiency occurs through two major mechanisms: follicle dysfunction and follicle depletion.⁵ Follicle dysfunction indicates that follicles remain in the ovary, but a pathologic process prevents their normal function (e.g., as a result of an FSH-receptor mutation).¹⁰ Follicle depletion indicates that no primordial follicles remain in the ovary. This condition may be due to the failure of an adequate initial pool of primordial follicles to be established in utero, an accelerated expenditure of follicles, or autoimmune or toxic destruction of follicles. Table 2 lists examples of known clinical causes of primary ovarian insufficiency according to the mechanism.

View this table: [in this window] [in a new window] Table 2. Mechanisms and Causes of Spontaneous Primary Ovarian Insufficiency.

This review focuses on spontaneous 46,XX primary ovarian insufficiency, which affects approximately 1 in 100 women by the time they are 40 years of age.¹³

Strategies and Evidence

Evaluation

There is no menstrual history that is characteristic of the development of spontaneous 46,XX primary ovarian insufficiency.⁵ In most cases, the condition develops after a normal puberty and established regular menses, although primary amenorrhea may be the presenting feature in about 10% of cases.⁴ Occasionally, menses stop abruptly. In some women, menses fail to resume after a pregnancy or after they have stopped taking hormonal contraceptives. Most commonly, there is a prodrome of oligomenorrhea, polymenorrhea, or dysfunctional uterine bleeding.

Once pregnancy has been ruled out, clinicians evaluating women with secondary amenorrhea should address several questions: Is this condition the earliest manifestation of a decline in general health, such as uncontrolled diabetes mellitus, or of an underlying condition, such as celiac disease?^14,15 Is it related to excessive exercise, inadequate caloric intake, or emotional stress? Has the woman undergone prior radiation therapy or chemotherapy? Is there galactorrhea (suggestive of hyperprolactinemia) or are there signs of androgen excess? Although the list of potential causes of secondary amenorrhea is long, the majority of cases are accounted for by four conditions: the polycystic ovary syndrome, hypothalamic amenorrhea, hyperprolactinemia, and primary ovarian insufficiency.¹⁴ It is inappropriate to attribute amenorrhea to stress without further evaluation.

Diagnostic criteria have not been established by any professional organization. A commonly used definition requires that there be at least 4 months of amenorrhea.^4,16 However, because approximately 50% of women with primary ovarian insufficiency have intermittent ovarian function leading to intermittent and unpredictable menses, rather than complete amenorrhea, a more practical definition is 4 months or more of "disordered" menses (amenorrhea, oligomenorrhea, polymenorrhea, or metrorrhagia) in association with menopausal FSH levels.

Symptoms of estrogen deficiency develop in many, but not all, patients. These symptoms include vasomotor symptoms (hot flashes and night sweats), sleep disturbance, and dyspareunia related to vaginal dryness. However, not all patients have profound estrogen deficiency, and a vaginal examination often shows effects suggesting normal estrogen levels.

Although most cases of primary ovarian insufficiency occur sporadically, there is a positive family history, with an affected first-degree relative, in approximately 10 to 15% of cases.¹⁷ Thus, patients should be queried about family history as well as about other autoimmune disorders (including hypothyroidism, adrenal insufficiency, and hypoparathyroidism) that might relate to an autoimmune polyglandular syndrome. The condition may also be associated with the dry-eye syndrome, myasthenia gravis, rheumatoid arthritis, or systemic lupus erythematosus.^18,19 A family history of the fragile X syndrome, intellectual disability, dementia, tremor or ataxia, or symptoms similar to those associated with Parkinson's disease might point to a premutation in the fragile X mental retardation 1 (FMR1) gene.²⁰

The physical examination may reveal evidence of an associated disorder such as hyperpigmentation or vitiligo (which is associated with autoimmune adrenal insufficiency), thyroid enlargement, or stigmata indicative of Turner's syndrome, such as short stature, webbed neck, and high, arched palate.

After pregnancy is ruled out, the initial evaluation of amenorrhea should include, at a minimum, the measurement of serum prolactin, FSH, and thyrotropin levels.¹⁴ In cases of amenorrhea caused by stress (i.e., hypothalamic amenorrhea), the serum FSH level is in the low or normal range. If the FSH level is in the menopausal range, as defined by the reporting laboratory, the test should be repeated in 1 month along with a serum estradiol measurement. A progestin-withdrawal test (in which a progestin is administered and then withdrawn in order to determine whether vaginal bleeding ensues after its withdrawal) was previously used as a diagnostic test of ovarian function, but it is not currently recommended. Nearly 50% of women with primary ovarian insufficiency have withdrawal bleeding in response to the test, despite the presence of menopausal-level gonadotropins, and in the case of these women, relying on this bioassay would delay the diagnosis.⁴

In cases of primary ovarian insufficiency that are not associated with a syndrome, the laboratory tests that are recommended to determine the cause include a karyotype analysis and testing for an FMR1 premutation and for adrenal antibodies (with the use of indirect immunofluorescence or 21-hydroxylase [CYP21] immunoprecipitation); pelvic ultrasonography should also be performed. Approximately 2% of women with isolated spontaneous 46,XX primary ovarian insufficiency and 14% with familial spontaneous 46,XX primary ovarian insufficiency have an FMR1 premutation, which confers a risk of having a child with fragile X syndrome.²⁰ The results of adrenal antibody testing are positive in approximately 4% of women with primary ovarian insufficiency. These women have steroidogenic cell autoimmunity, and lymphocytic autoimmune oophoritis is the mechanism of the ovarian insufficiency (Figure 1). Ovarian antibodies lack specificity, and testing for them is not warranted.²¹ Pelvic ultrasonography identifies cases involving enlarged, multifollicular ovaries, which may undergo torsion, such as in isolated 17,20-lyase deficiency or autoimmune oophoritis (Table 2). An ovarian biopsy does not provide information that is helpful in the management of primary ovarian insufficiency and is therefore not indicated; pregnancy may occur even after examination of a biopsy specimen has shown that follicles are absent.⁶

View larger version (66K): [in this window] [in a new window] Figure 1. Transvaginal Ultrasound Scan from a Patient with Spontaneous 46,XX Primary Ovarian Insufficiency Who Had Follicle Dysfunction Due to Autoimmune Oophoritis. The ovary appears normal, with the presence of multiple follicles, despite amenorrhea, estrogen deficiency, and menopausal-level gonadotropins. Autoimmune oophoritis with thecal infiltration by lymphocytes was confirmed histologically by means of an ovarian biopsy performed when the patient was 26 years of age.9

Management

The diagnosis of primary ovarian insufficiency affects a woman's physical and emotional well-being, and the management of the condition should address both. Other associated endocrine deficiencies, as well as anxiety, depression, or both, may develop. The presence of an abnormal karyotype, an iatrogenic cause, or a premutation in the FMR1 gene has additional health implications that are beyond the scope of this article.

Emotional Health

Unexpected infertility is a life-altering diagnosis for many women.²² Shyness and social anxiety, impaired self-esteem, and a perceived low level of social support are more frequent among women with spontaneous 46,XX primary ovarian insufficiency than among women who do not have this condition.^23,24 Many women report experiencing severe emotional distress²⁵ and want guidance on how to cope with the emotional sequelae, but few ask for it directly. It is best to schedule a return office visit to inform women of this diagnosis; patients should be encouraged to identify sources of emotional support.²⁴

Hormone-Replacement Therapy

Early menopause has been associated with an increased incidence of fractures²⁶ and increased total mortality and mortality due to ischemic heart disease.^27,28,29 In a study of women who were part of the Women's Health Initiative, combined hormone-replacement therapy (estrogen with progestin) increased the risk of cardiovascular events; however, it is invalid to apply the results of this study, which involved menopausal women who were, on average, 63 years of age,³⁰ to young women with primary ovarian insufficiency. (Menopause is a physiologic condition, whereas primary ovarian insufficiency is a pathologic condition in which women have low serum estradiol levels as compared with other women of similar age.) Although data from randomized, controlled trials are lacking, most experts agree that physiologic estrogen and progestin replacement is reasonable in the case of young women with primary ovarian insufficiency and should be continued until they reach the age when menopause usually occurs.³

The average serum estradiol level during the menstrual cycle in women with a normal menstrual history is approximately 100 pg per milliliter.³¹ Although no studies have directly compared various hormonal therapies for women with primary ovarian insufficiency, a dose of 100 µg of estradiol per day, administered by transdermal patch, achieves average serum estradiol levels in this range and effectively treats symptoms. Transdermal estradiol has little effect on hemostatic factors, and in case–control studies, it has been associated with a lower risk of venous thromboembolism than has oral estrogen.^32,33,34 Evidence supports the use of cyclic medroxyprogesterone acetate at a dose of 10 mg per day for 12 days each month as the preferred progestin. This regimen fully induces secretory endometrium and provides protection against endometrial cancer.^35,36 Data regarding the effects on the endometrium of oral micronized progesterone when it is given in conjunction with a full replacement dose of estrogen are not available.³⁷ Patients should keep a menstrual calendar and take a pregnancy test if a menstrual period is late. Pregnancy may occur while a woman is taking estrogen and progestin therapy, and the therapy should be stopped if the pregnancy test is found to be positive. Oral contraceptives provide more steroid hormone than is needed for physiologic replacement and are therefore not recommended as first-line management.

Maintaining Bone Health

Women with primary ovarian insufficiency have reduced bone mineral density as compared with controls.³⁸ Thus, bone mineral density should be measured, and women should be educated regarding strategies to maintain bone health. No data are available specifically for these women with regard to the recommended daily intake of calcium and of vitamin D and the recommended frequency and intensity of weight-bearing exercise, but it seems reasonable to follow the guidelines developed for perimenopausal and postmenopausal women by the North American Menopause Society: intake of 1200 mg of elemental calcium per day and maintenance of adequate vitamin D status, which is defined as a serum 25-hydroxyvitamin D level of 30 ng per milliliter (75 nmol per liter) or higher.³⁹ Vitamin D deficiency is common, and it has been recommended that adults with inadequate exposure to the sun take at least 800 to 1000 IU of vitamin D₃ per day.⁴⁰ Women should be encouraged to engage in a variety of exercises, such as jogging, walking, and stair climbing, along with resistance exercises.⁴¹ Bisphosphonates are not advised if pregnancy is possible, since these agents have long skeletal half-lives and the effects on the fetus are uncertain.⁴²

Associated Disorders

There is a 50% risk of the development of adrenal insufficiency in women with adrenal autoimmunity.⁴³ Patients with positive tests for adrenal antibodies should be evaluated annually with the use of a corticotropin stimulation test. Longitudinal data are lacking to guide the optimal follow-up for patients with negative tests for adrenal antibodies at the initial examination. Theoretically, one would expect adrenal-cell antibodies to be present when the ovarian insufficiency develops if the mechanism is steroidogenic cell autoimmunity. If both tests for adrenal autoimmunity, as measured by indirect immunofluorescence and 21-hydroxylase immunoprecipitation, are negative at the initial examination, a reasonable strategy is not to repeat the testing unless it is otherwise clinically indicated. However, all patients with primary ovarian insufficiency should be educated regarding the symptoms of adrenal insufficiency and should undergo evaluation of adrenal function if such symptoms develop.

There is an increased incidence of the dry-eye syndrome and ocular-surface disease in women with primary ovarian insufficiency, as compared with controls (20% vs. 3%), and women who have either of these disorders benefit from referral to an ophthalmologist.¹⁸ Thyroid autoimmune disease, most commonly Hashimoto's thyroiditis, is present in 14 to 27% of women^19,44 at initial diagnosis. It is reasonable to measure thyrotropin levels and test for the presence of thyroid peroxidase antibodies. Other autoimmune disorders, such as myasthenia gravis, rheumatoid arthritis, and systemic lupus erythematosus, have also been reported in association with primary ovarian insufficiency,¹⁹ but such cases are infrequent, and testing for these and other autoimmune conditions should be predicated on symptoms and signs that are suggestive of the condition.

Family Planning

Patients who wish to avoid pregnancy should use a barrier method or possibly an intrauterine device. The effectiveness of oral contraceptives has not been studied in women with primary ovarian insufficiency, and there are anecdotal reports of women who have conceived while complying with the oral contraceptive regimen,⁴⁵ perhaps because of a failure of the oral contraceptive to suppress the high FSH levels that are characteristic of this condition.

Patients should understand that spontaneous remission resulting in pregnancy occurs in 5 to 10% of cases.⁸ Generally, remissions are temporary, but they may (although rarely) last for years.⁵ Currently, there are no known markers that are associated with an increased rate of remission, and there are no therapies that have been shown to restore ovarian function and fertility. Some couples are averse to adoption and to reproductive technologies and are content not to become parents or to accept the low but real chance that the infertility will resolve spontaneously. For couples who decide to pursue parenthood actively, the options are adoption, foster parenthood, egg donation, and embryo donation; ovarian transplantation has been performed in rare cases in which the patient has an identical twin with normal ovarian function.⁴⁶ There is no medical urgency to proceed to egg donation, because the rates of pregnancy with egg donation appear to be similar among older and younger women.⁴⁷ Women with primary ovarian insufficiency who become pregnant as a result of oocyte donation may have an increased risk of delivering infants who are small for gestational age and of having pregnancy-induced hypertension and postpartum hemorrhage,^48,49,50 but these findings are controversial.⁵¹

Areas of Uncertainty

Studies involving women with the FMR1 premutation have established that this mechanism of primary ovarian insufficiency is associated with a clinical spectrum of impaired ovarian function that involves a continuum of occult, biochemical, and overt ovarian insufficiency; a better understanding is needed of the spectrum of disease associated with other causes of primary ovarian insufficiency (Table 3).^3,52,53,54 In addition, research is needed on strategies to improve fertility for women who have follicles remaining in the ovary. The magnitude of long-term risks associated with the disorder (including cardiovascular disease and osteoporosis) and the optimal means of reducing these risks are uncertain.

View this table: [in this window] [in a new window] Table 3. Clinical States Included in the Spectrum of Primary Ovarian Insufficiency.

Guidelines

Several professional organizations recommend that women with primary ovarian insufficiency undergo testing for a premutation in the FMR1 gene.^55,56,57 The American Society for Reproductive Medicine and the International Menopause Society recommend estrogen-replacement therapy for women with primary ovarian insufficiency.^14,58

Conclusions and Recommendations

The woman in the vignette has amenorrhea and a menopausal FSH level. Confirmation of the elevated FSH level and a low estradiol level would confirm the diagnosis of primary ovarian insufficiency. This information is highly emotionally charged and should be discussed with the patient at a return visit to the office rather than by telephone, with recognition of the emotional effect of the diagnosis. Patients should understand that remission may occur and that pregnancy, though unlikely, occurs in 5 to 10% of cases. A karyotype analysis, tests for the FMR1 premutation and adrenal autoimmunity, a pelvic ultrasound examination, and measurement of bone mineral density are indicated at the time of diagnosis. Women with primary ovarian insufficiency should be encouraged to maintain a lifestyle that optimizes bone and cardiovascular health, including engaging in regular weight-bearing exercise, maintaining an adequate intake of calcium (1200 mg daily) and vitamin D (at least 800 IU daily), eating a healthy diet to avoid obesity, and undergoing screening for cardiovascular risk factors, with treatment of any identified risk factors. Although there are no data from randomized trials to guide the use of hormonal therapy in women with this condition, a reasonable regimen would be 100 µg of transdermal estradiol and 10 mg of oral medroxyprogesterone acetate daily for the first 12 days of each month. Women should keep a menstrual calendar and have a pregnancy test promptly in the case of late menses.

Dr. Nelson reports being an inventor on three United States patents directed to MATER (a potential antigen in autoimmune primary ovarian insufficiency) and its applications (U.S. patent numbers 7,189,812; 7,217,811; and 7,432,067), as well as one pending United States patent application (U.S. patent application number 11/586,160) and foreign counterparts. No other potential conflict of interest relevant to this article was reported.

I thank my colleague Mary Ryan, M.L.S., for literature searches and helpful discussions and Marcy Lash, M.D., for reviewing the manuscript before submission.

Source Information

From the Integrative Reproductive Medicine Unit, Intramural Research Program on Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.

An audio version of this article is available at NEJM.org.

Address reprint requests to Dr. Nelson at the Integrative Reproductive Medicine Unit, NICHD–Intramural Research Program on Reproductive and Adult Endocrinology, CRC, Rm. 1-3330, 10 Center Dr., MSC-1103, Bethesda, MD 20892, or at lawrence_nelson@nih.gov.

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Thyroid Treatment in Infertility Lowers Miscarriage Rates

In women with infertility who have thyroid autoimmunity (TIA), they fare better when treated with levothyroxine as compared to placebo. Women are 5-10 times more likely to make antibodies against the thyroid than men.

Here are the results of a large group of pregnant women, 12% of whom were TIA-positive. Half of the TAI-positive group was treated with levothyroxine during gestation, whereas the other half was left untreated. The endpoints of the study were to assess the outcome of pregnancy and changes in thyroid function by comparing the group of TAI-positive women without treatment with those who were treated and with healthy pregnant controls. Drastic reductions in the rates of miscarriage (75%) and premature delivery (69%) were reported among TAI-positive women who had received levothyroxine since early gestation and throughout pregnancy. Thyroid function test results were normal for women with TAI who received levothyroxine, whereas 19% of women in the control group became subclinically hypothyroid at the time of parturition. Published by Negro et al, 2006.

Higher TSH Associated with Weight Gain

Here is a good review of a study showing that higher thyroid stimulating hormone (TSH, the most sensitive indicator of thyroid function) is associated with weight gain, and the increase is linear. Optimum TSH is < 2.5.

News Author: Laurie Barclay, MD
CME Author: Hien T. Nghiem, MD

March 25, 2008 — Modest increases of thyroid-stimulating hormone (TSH) within the reference range may be associated with weight gain, according to the results of a large, community-based study reported in the March 24 issue of the Archives of Internal Medicine.

"Overt hypothyroidism and hyperthyroidism may be associated with weight gain and loss," write Caroline S. Fox, MD, MPH, from the National Heart, Lung, and Blood Institute's Framingham Heart Study in Framingham, Massachusetts, and colleagues. "We assessed whether variations in thyroid function within the reference (physiologic) range are associated with body weight."

This study included 2407 participants in the Framingham Offspring Study who attended 2 consecutive routine examinations, were not receiving thyroid hormone therapy, and had baseline serum thyrotropin (TSH) concentrations of 0.5 to 5.0 mIU/L and follow-up concentrations of 0.5 to 10.0 mIU/L. During 3.5 years of follow-up, the relationship of baseline TSH concentrations with body weight and body weight change was determined.

From the lowest to highest TSH concentration quartiles at baseline, adjusted mean weight increased progressively from 64.5 to 70.2 kg in women (P < .001 for trend) and from 82.8 (lowest quartile) to 85.6 kg (highest quartile) in men (P = .007 for trend). Mean body weight increased by 1.5 ± 5.6 kg in women and 1.0 ± 5.0 kg in men during 3.5 years of follow-up.

Although baseline TSH concentrations were not associated with weight change during follow-up, an increase in TSH concentration at follow-up was positively associated with weight gain in women
(0.5 - 2.3 kg across increasing quartiles of TSH concentration change; P < .001 for trend) and men (0.4 - 1.3 kg across quartiles of TSH concentration change; P = .007 for trend).

"Thyroid function (as assessed by serum TSH concentration) within the reference range is associated with body weight in both sexes," the study authors write. "Our findings raise the possibility that modest increases in serum TSH concentrations within the reference range may be associated with weight gain."

Limitations of the study include observational design precluding determination of causality; lack of measurement of free thyroxine levels; sample nearly entirely white, with possible lack of generalizability to other ethnic groups; and inability to account for other covariates known to be associated with body weight and weight change, including diet and physical activity.

"The identification of change in thyroid function as a risk factor for weight gain might help guide research into the identification, prevention, and treatment of individuals at risk for the development of excess adiposity," the study authors write. "Confirmation of our findings in other samples is warranted, and in particular more longitudinal studies are warranted."

The National Heart, Lung, and Blood Institute's Framingham Heart Study supported this study. Two of the study authors have been supported by the National Heart, Lung, and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases. The other study authors have disclosed no relevant financial relationships.

In an accompanying editorial, Roy E. Weiss, MD, PhD, and Rebecca L. Brown, MD, from the University of Chicago Medical Center in Chicago, Illinois, address potential mechanisms linking thyroid function and obesity.

"Assuming preservation of tissue responsiveness to thyroid hormone levels, the absence of reciprocal changes in T3 and T4 levels suggests a central modification of the HPT [hypothalamic-pituitary-thyroid] axis in obesity," Drs. Weiss and Brown write. "Elucidation of the mechanisms by which obesity alters the HPT axis may give clues to the other metabolic abnormalities seen in this condition. There is no evidence at this time to advocate lowering serum TSH concentrations to treat obesity."

Drs. Weiss and Brown have disclosed no relevant financial relationships.

Arch Intern Med. 2008;168:568-569, 587-592.

Clinical Context

In the United States, the prevalence of obesity is rising. Obesity is associated with the increased risk for diabetes, vascular disease, all-cause mortality, and cancer. Known predictors of obesity and weight gain include a low level of physical activity, increased energy intake, parity, smoking cessation, inflammation, depression, and genetic factors. It has been recognized that thyroid dysfunction is a cause of weight change. Studies have suggested that variation in thyroid function within the reference range may be related to weight change.

The aim of this study was to determine whether variations in thyroid function are associated with body weight.

Study Highlights

• From the Framingham Offspring Study, participants (n = 2407) who attended 2 consecutive routine examinations, were not receiving thyroid hormone therapy, and had baseline serum TSH concentrations of 0.5 to 5.0 mIU/L and follow-up concentrations of 0.5 to 10.0 mIU/L were included in this study.
• The prevalence of obesity at baseline was 14.3%, and the mean baseline serum TSH concentration was 1.91 mIU/L in women and 1.70 mIU/L in men.
• Baseline TSH concentrations were related to body weight and change in body weight during 3.5 years of follow-up.
• Results revealed that at baseline, adjusted mean weight increased progressively from 64.5 to 70.2 kg in the lowest to the highest TSH concentration quartiles in women (P < .001 for trend) and from 82.8 (lowest quartile) to 85.6 kg (highest quartile) in men (P = .007 for trend).
• Baseline TSH concentrations were not associated with weight change during follow-up.
• During 3.5 years of follow-up, mean (SD) body weight increased by 1.5 (5.6) kg in women and 1.0 (5.0) kg in men.
• Weight increased by 1.9 kg per every 1-unit increase in log TSH concentration (P < .001) in women and by 1.0 kg per every 1-unit increase in log TSH concentration (P = .007) in men.
• An increase in TSH concentration at follow-up was positively associated with weight gain in women (0.5 - 2.3 kg across increasing quartiles of TSH concentration change; P < .001 for trend) and men (0.4 - 1.3 kg across quartiles of TSH concentration change; P = .007 for trend).
• Limitations to this study included the observational design of the study; lack of measurement of free thyroxine levels; sample nearly entirely white, with possible lack of generalizability to other ethnic groups; and inability to account for other covariates that may affect body weight, such as diet and physical activity.

Pearls for Practice

• Risk factors leading to obesity include low level of physical activity, increased energy intake, parity, smoking cessation, inflammation, depression, and genetic factors.
• Thyroid function within the reference range is associated with body weight in both sexes, suggesting that modest increases in serum TSH concentrations within the reference range may be associated with weight gain.

APO-E Gene and Alzheimer's Disease

Apolipoprotein E4 (APOE4) is a genetic risk factor for development of late-onset Alzheimer's disease. Caucasian and Japanese carriers of 2 e4 alleles (i.e., you got a bad gene from both parents) have a 10- to 30-fold increased risk of developing AD by age 75 compared to lucky individuals not carrying any e4 alleles. The gene is encoded on chromosome 19.

More good news: it is associated with a 40-50% increased risk of cardiovascular disease. And fish oil doesn't help - in APOE4s it may raise LDL and lower HDL.

The following is from Medscape authoress Ekaterina Rogaeva, PhD.

APOE Gene on Chromosome 19q13.2

The APOE gene is a genetic locus for inherited susceptibility to late-onset AD (>65 years) that was confirmed in multiple studies. It encodes a lipoprotein involved in cholesterol metabolism and has three common alleles: epsilon 4 (AD-associated), epsilon 3 (neutral), and epsilon 2 (AD-protective). The frequency of the epsilon 2 allele is reduced in AD subjects (~2% versus ~10% in the general population), whereas the frequency of the epsilon 4 allele is significantly increased in individuals with AD (up to 40%). In addition, the epsilon 4 allele is associated with a decreased age at onset: from 90 years for the non-epsilon 4 carriers to ~70 years in patients homozygous for the epsilon 4 allele.

Nevertheless, genetic testing based on the APOE epsilon 4 allele is ambiguous when used as the sole criterion to diagnose AD since not all epsilon 4 carriers will develop disease and epsilon 4 association is not entirely specific to AD. However, in the future, APOE genotypes could be useful in combination with other clinical measures or genetic variations. Indeed, in at least half of AD cases there is no known cause of the disease, suggesting the existence of additional environmental and genetic factors responsible for late-onset AD.

Thyroid Function Linked with Alzheimer's

You don't want your thyroid function to be too high or too low if you're worried about developing Alzheimer's. I love it when we figure out that moderation is the best for our health.

This is the first part in a series I'm highlighting on hormones and the big "A."

This is from a Medscape article by Pauline Anderson & Hien T. Nghiem, MD:

The study, published in the July 28, 2008 issue of the Archives of Internal Medicine, did not find an association between extreme thyroid hormone levels and Alzheimer's disease in men.

Between March 1977 and November 1979, Dr. Zaldy Tan and his colleagues measured thyrotropin levels of 1864 participants in the Framingham longitudinal, community-based, observational study who had been free of dementia for 3 years (this window of time minimized the risk of inadvertently including patients with early Alzheimer's disease in this study). They later divided these hormone levels into tertiles according to serum concentrations.

Thyroid Function Intricately Linked to Central Nervous System

At this baseline and then biennially, researchers used neurologic and neuropsychological examinations, plus interviews and various other expert sources, to establish dementia status of the study participants, whose mean initial age was 71 years.

During a mean follow-up of 12.7 years (range, 1 - 25 years), Alzheimer's disease developed in 209 participants (including 142 women [12.8%]). After adjusting for confounders such as age, educational level, smoking, body mass index, and various cardiovascular risks, the researchers observed that women with the lowest serum thyrotropin concentrations (<> 2.1 mIU/L) were more than twice as likely to have Alzheimer's disease vs women with mid-range levels of the hormone (hazard ratio, 2.39; 95% confidence interval [CI], 1.47 - 3.87; P < .001 for those in the lowest levels and hazard ratio 2.15; 95% CI, 1.31 - 3.52; P = .003 for those in the highest levels).

Short version: Keep your TSH between 1-2.1. In addition to thyroid dysfunction, multiple studies have shown that insulin resistance, high cortisol levels, and decreased estrogen and testosterone levels are associated with the development of dementia.

So prevent insulin resistance (no flour, no sugar, no stress & exercise), normalize your cortisol levels, and keep your estrogen and testosterone in the normal range....