b See Chapter 51, Menopause, p. 264 \200\223274, for a full review of hor- mone therapy. Prognosis Mortality of women with POI left untreated may be i 2-fold. Estrogen de \201 ciency leads to the following: i Risk of cardiovascular and cerebrovascular disease \200 i Risk of osteoporosis. Up to 2 /3 of women with POI and a normal karyotype have d bone mineral density (BMD), with a z score of \200\2231 or less despite a t least intermittent HT. This may be due to a combination of factors, including an initial delay in initiating HT, poor compliance with HT, and estrogen \200\234underdosing. \200 \235 Further reading Barlow DH (1996). Premature ovarian failure. Bailli \200\231re Clin Obstet Gynecol 10(3):361 \200\223384. Kalantaridou SN, Davis SR, Nelson LM (1998). Premature ovarian failure. Endocrinol Metab Cl in 27(4):989 \200\2231006. Welte, CK (2008). Primary ovarian insuf \201 ciency: a more accurate term for premature ov arian fail- ure. Clin Endocrinol 68:499 \200\223509. 50-Draznin-Chap50.indd 263 3/31/2011 2:58:34 PM CHAPTER 51 Menopause 264 Menopause De \201 nition The menopause is the permanent cessation of menstruation as a result of ova rian failure (see Box 51.1 ) and is a retrospective diagnosis made after 12 months of ameno rrhea. The average age of women at the time of the menopause is 750 years, although smokers reach the menopause 72 years earlier. The perimenopause encompasses the menopause transition and the \201 rst year following the last menstrual period. Box 51.1 Physiology The physiology of the menopause remains poorly understood. Ovaries have a \201 nite numbe r of germ cells, with maximal numbers at 20 weeks of intrauterine life. Thereafter, there i s a gradual reduction in the number of follicles until the perimenopause when there is an e xponential loss of oocytes until the store is depleted at the time of the menopause. Table 51.1 summarizes hormonal changes during the menopausal transition. Inhibin B and anti-M llerian hormone (AMH) are ovarian glycoprotiens produced by follicles as they develop from pre-antral to antral stages. Both may participate in ovarian paracrin e regulation and, with other molecules, regulate the rate of attrition of follicles. Inhibi n B and AMH fall with ovarian aging, before any detectable rise in FSH, and are thus early markers of incipient ovarian failure and onset of perimenopause. In the early perimenopausa l period, FSH levels \202 uctuate, but the grad- ual rise in FSH levels maintains estradi ol production by the ovarian fol- licles. So, contrary to previous belief, average serum es tradiol levels may be high at the onset of the meno-pause transition, falling only toward t he end as the follicles are depleted. 51-Draznin-Chap51.indd 264 4/2/2011 6:50:48 PM 5 1 D r a z n i n C h a p 5 1 . i n d d Table 51.1 Hormonal changes during the menopausal transition 2 6 5 Advanced perimenopause Premenopause (from age 36 years) Early perimenopause Menopause Menstrual cycle Regular, ovulatory Irregular, often short cycles, increasingly anovulatory Oligomenorrhea Amenorrhea Persistently i i i FSH Rising but within normal range Intermittently raised, especially in follicular phase Inhibin B Declining Low Low Very low E2 Normal > Normal Normal/low Low D E F I N T O N I I 4 / 2 2 6 5 / 2 0 1 1 6 : 5 0 : 4 8 P M CHAPTER 51 Menopause 266 Long-term consequences \200 Osteoporosis: During the perimenopausal period there is an ac celerated loss of BMD, with postmenopausal women being more susceptible to osteoporotic fra ctures. Ischemic heart disease (IHD): Postmenopausal women are 2 \200\2233 x more likely to develop IHD than are premenopausal women, even after age adjustments. The menopause is associated with an increase in risk factors for atherosclerosis, including less favorable lipid pro \201 le, d insulin sensitivity, and an i thrombotic tendency. Dementia: Women are 2 \200\2233 x more likely to develop Alzheimer disease than men. It is suggested that estrogen de \201 ciency may play a role in the development of dementia. Clinical presentation There are marked cultural differences in the frequency of symptoms re lated to the menopause. In particular, vasomotor symptoms and mood disturbances are more co mmonly reported in Western countries. Menstrual disturbances (90%) Cycles gradually become increasingly anovulatory and variable in length from about 4 years prior to the menopause. Oligomenorrhea often pre- cedes perman ent amenorrhea. In 10% of women, menses cease abruptly with no preceding transitional perio d. Hot \202 ashes (40%) These are often associated with sweats and skin \202 ushing. They are highly variable and thought to be related to \202 uctuations in estrogen concentra- t ions. They tend to resolve spontaneously within 5 years of menopause. Urinary symptoms (50%) There is atrophy of urethral and bladder mucosa after the menopause and d sensitivity of A-adrenergic receptors of the bladder neck in the perimenopausal perio d. This may result in urinary incontinence and an i risk of urinary tract infections. Sexual dysfunction (40%) Vaginal atrophy may result in dyspareunia and vaginal dryness. Add itionally, falling androgen levels may reduce sexual arousal and libido. Mood changes (25 \200\22350%) Anxiety, memory problems, dif \201 culty in concentration, a nd irritability have all been attributed to the menopause. Women with a history of affec- t ive disorders are at i risk of mood disturbances in the perimenopausal period. 51-Draznin-Chap51.indd 266 4/2/2011 6:50:48 PM EVALUATION (IF HT IS BEING CONSIDERED) 267 Evaluation (if HT is being considered) History \200 Perimenopausal symptoms and their sev erity \200 Assess risk factors for cardiovascular disease and osteoporosis. \200 Assess risk factors for breast cancer and thromboembolic disease. \200 History of active liver disease Examination \200 BP \200 Breasts \200 Pelvic examination, including cervical smear Investigations FSH levels \202 uctuate markedly in the perimenopausal period and correlat e poorly with symptoms. A raised FSH in the perimenopausal period may not necessarily indic ate infertility, so contraception, if desired, should con- tinue until the menopause. Mammography is indicated prior to starting estrogen replacement ther- apy and then following national guidelines. Endometrial biopsy does not need to be performed routinely but is used in women with abnormal uterine bleeding and an abnormal US. 51-Draznin-Chap51.indd 267 4/2/2011 6:50:48 PM CHAPTER 51 Menopause 268 Hormone replacement therapy (HT) The aim of treatment of postmenopausal women is to allevia te meno- pausal symptoms. HT is no longer indicated for the prevention of chronic disease i n postmenopausal women. However, women who have POI should receive HT unless there is an absolute contraindication, until the age of 50 years. Bene \201 ts of HT Hot \202 ashes These respond well to estrogen therapy in a dose-dependent manner. Start w ith a low dose and increase gradually as required to control symp- toms. Higher doses may b e required after hysterectomy, particularly in younger women. For 75% of women, vasomotor symptoms are resolved, so the dose is tapered to the lowest one to control symptoms. The dose of HT should be gradually reduced over weeks, as sudden with drawal of estrogen may precipitate the return of vasomotor symptoms. In women with a contraindication to HT or who are intolerant of it, nonhormonal therapies are available, summarized in Table 51.2. Urinary symptoms A trial of HT, local or systemic, may improve stress and urge incontinence as well as the frequency of cystitis. Table 51.2 Alternatives to HT Symptom Management Vasomotor symptoms Venlafaxine (75 mg od), paroxetine (20 mg od), and \202 uoxetine (20 mg od) have been sho wn to signi \201 cantly reduce the frequency and severity of hot \202 ashes, with minima l side effects. Gabapentin (300 mg tid) has also been shown to reduce the frequency and sev erity of hot \202 ashes. Side effects include dizziness, somnolescence, and weight gain. Megestrol acetate in a dose of 20 mg bid also reduces hot \202 ashes by up to 70%, but it s use is limited by side effects, particularly weight gain. Clonidine is less effective, re ducing the occurrence of \202 ushes by 20%, and is often associated with disabling side e ffects such as dizziness, drowsiness, and dry mouth. Vaginal lubri-cants, e.g., Replens Genitourinary symptoms Osteoporosis Selective estrogen receptor modulators (SERMs), e.g., raloxifene; however, these may exacer bate vasomotor symptoms if present. Bisphosphonates, e.g., alendronic acid and risedronate 51-Draznin-Chap51.indd 268 4/2/2011 6:50:48 PM HORMONE REPLACEMENT THERAPY (HT) 269 Vaginal atrophy Systemic or local estrogen therapy improves vaginal dryness and dys- pareun ia. A maximum of 6 months \200\231 use of vaginal cream is recommended unless combined with a progestin, as systemic absorption may increase the risk of endometrial hyperplasia. An estradiol vaginal ring (Estring ) has little stimulatory effect on endometrial tissue a nd does not increase serum estradiol concentrations. Concomitant progestin therapy is there fore not necessary. If estrogens are contraindicated, then vaginal moisturizers, e.g., Repl ens , may help. Osteoporosis HT has been shown to increase BMD in the lumbar spine by 3 \200\2235%/year and at the femoral neck by about 2%/year by inhibiting bone resorption. There is an associated 30 \200\22350% reduction in fracture risk, protection being highest in women on HT for at least 10 years. The Women \200\231s Health Initiative trial (WHI) con \201 rmed that HT reduces the risk o f both hip and vertebral fractures by a third. Timing of initiation of treatment to achieve maximal bone protection remains controversial. Evidence suggests that initiation of HT soo n after the menopause is associated with the lowest hip fracture risk, but discontinuation of HT ultimately results in bone loss to pretreatment levels. Colorectal cancer Observational studies have shown that HT may protect against colon can- c er. This has been con \201 rmed by WHI, which showed a 20% reduction in the incidence of c olon cancer in HT users. However, HT should currently not be prescribed solely to prevent c olorectal cancer. Risks of HT (see Box 51.2 ) Breast cancer No personal or family history of breast cancer There is an i risk of breast cancer in HT us ers, which is related to the duration of use. The risk increases by 35% following 5 years o f use and falls to never-used risk 5 years after discontinuing HT. For women aged 50 not using HT, about 45 in every 1000 will have cancer diagnosed over the following 20 years, that is, up to age 70. This number increases to 47/1000 women using HT for 5 years, 51/1000 using Box 51.2 Summary of contraindications to HT Absolute \200 Undiagnosed vaginal bleeding \200 Past history of endometrial cancer \200 Pregnancy \200 Active DVT \200 Active endometrial cance \200 Breast cancer Relative-seek advice Family or past history of thromboembolism \200 Ischemic heart disease \200 Cerebrovascu lar disease \200 Active liver disease. \200 Hypertriglyceridemia 51-Draznin-Chap51.indd 269 4/2/2011 6:50:48 PM CHAPTER 51 Menopause 270 HT for 10 years, and 57/1000 after 15 years of use. The risk is highest in women on combine d HT compared with estrogens alone. Mortality has not been shown to be i in breast cancer developing in women on HT. Family history of breast cancer Risk of breast cancer may be i 4-fold as a result of family history, but there is little evidence that the risk is i further by the use of HT. HT may be used short term at lower doses in these women if severe vasomotor symptoms are present, after counseling regarding the above risks. Past history of breast cancer Avoid HT in women with a past history of breast cancer. Venous thromboembolism (DVT) HT increases the risk approximately 3-fold, resulting in an ex tra 2 cases/10,000 woman-years. The risk is highest in the \201 rst year of use of HT and has been shown to be halved by aspirin or statin therapy. This risk is i in women who already have risk factors for DVT, including previous DVT, card iovascular disease, and within 90 days of hospitaliza- tion. Many suggest discontinuation o f HT with any hospitalization. Low-risk women \200 Absolute risk remains small \200\22430 per 100,000 women. \200 Stop HT during immobilization or use prophylactic anticoagulation. Family history of DVT If HT is being considered because of severe vasomotor symptoms, do a thrombophilia screen. If positive, then avoid HT or use it with anticoagula- tion therapy. Women with a positive family history of thromboembolism are still at a slightly i risk them selves, even if the results of the thrombophilia screen are negative, so prescribe HT with caution after counseling the patient. Transdermal E2 may be preferable. Past history of DVT/PE Risk of recurrence is 5% per year, so avoid HT unless the patient is on long-term warfarin therapy. Cerebrovascular disease HT has been shown to increase the risk of ischemic stroke in older women, particularly in the presence of atrial \201 brillation. HT should therefore not be used in women with a history of cerebrovascular disease or atrial \201 bril- lation unle ss they are anticoagulated. Endometrial cancer There is no i risk in women taking continuous com-bined HT prepara- tion s. Women using sequential combined preparations do not appear to have an i risk of endometr ial cancer initially, but the risk of endometrial hyperplasia does increase with long-term use (>5 years) despite regular withdrawal bleeds, so these women need regular follow-up. Wo men with cured stage I tumors may safely take HT. 51-Draznin-Chap51.indd 270 4/2/2011 6:50:48 PM HORMONE REPLACEMENT THERAPY (HT) 271 Ovarian cancer It is unclear if HT may be associated with an i risk of ovarian cancer. A co uple of large casecontrol studies have shown anrisk of ovarian can- cer in long-term (>10 y ears) users of unopposed estrogen replacement therapy. There are few data available on the risk of ovarian cancer in women taking combined HT. How ever, studies have also shown that HT does not have a negative effect in ovarian cancer sur vivors. Gallstones The risk of gallstones is i 2-fold in HT users. Migraine Migraines may increase in severity and frequency in HT users. A trial of HT is still worthwhile if indications are present, providing there are no focal neurological signs associated with the migraine. Mod i \201 cation in the dose of estrogen or its preparation may improve symptoms. Endometriosis and uterine \201 broids The risk of recurrence of endometriosis or of growt h of uterine \201 broids is low on HT. Liver disease Use transdermal estrogens to avoid hepatic metabolism and monitor liver funct ion in women with impaired liver function tests. Do not use HT in the presence of active li ver disease or liver failure. Areas of uncertainty with HT Cardiovascular disease (CVD) Data from >30 observational studies suggest that HT may reduce the risk of developing CVD by up to 50%. However, randomized placebo-con- trolled trials, e.g., the Heart and Estrogen-Progestin Replacement Study (HERS) and the WHI trial, have fai led to show that HT protects against CVD. Currently, HT should not be prescribed to prevent cardiovascular dis- ease. Analysis of the WHI showed that women 50 \200\22359 had cardiac protec- tion on HT, whereas older women ha d increased risk. These data support the primary prevention hypothesis. Alzheimer disease Recent evidence suggests that the risk of developing Alzheimer disease ma y be reduced by up to 50% in women receiving HT, particularly if started early in the menop ause. However, in women with established Alzheimer disease, there is no evidence to suggest rever sal of cognitive dysfunction following initiation of HT. There is currently insuf \201 cie nt evidence to recommend the use of HT to prevent Alzheimer disease. In postmenopausal women without dementia, HT may improve certain aspects of cognitive function. 51-Draznin-Chap51.indd 271 4/2/2011 6:50:48 PM CHAPTER 51 Menopause 272 Mood disturbances There has been a strongly held belief that HT improves well-being and QoL in perimenopausal and post-menopausal women. However, in recent trials in which QoL was as sessed, notably HERS and WHI, in women many years after menopause, the improvement in QoL a nd improved sleep was only seen in women with vasomotor symptoms. Side effects commonly associated with HT Breast tenderness usually subsides within 4 \200 \2236 months of use. If trouble- some, use a lower estrogen dose and increase it gradually. Mood changes commonly associated with progestin therapy can be man- aged by changing the dose or preparation of progestin. Irregular vaginal bleeding may be a problem in women on a continu- ous combined preparation . It usually subsides after 6 \200\22312 months of treat- ment. Spotting persists in 10%; p atients may change to a cyclic preparation. b See Box 51.3. Summary of WHI trial \200 WHI was a ran-domized, controlled trial of effects of continuou s combined conjugated estrogen and medroxyprogesterone acetate on healthy postmenopausal wome n, with a mean follow-up 5.2 years. Mean age was 63 years, with 66% of women >60 years of age. \200 70% of partici-pants were overweight or obese and 50% were current or past smokers. Absolute risk was highest in the older age group (>65 years). Box 51.3 Whom and how to investigate for irregular uterine bleeding Sequential cyclical HT \200 Three or more cycles of bleeding before the ninth day of prog estin therapy or change in the duration or intensity of uterine bleeding Continuous combined HT \200 In \201 rst 12 months if bleeding is heavy or extended, if it continues after 12 months of use, or if it starts after a period of amenorrhea Endometrial assessment \200 Essential in women with irregular uterine bleeding. Vaginal U S, looking at endometrial thickness, is a sensitive method of detecting endometrial disease. Endometrial thickness of <5 mm excludes disease in 96 \200\22399% of cases, a sensitivity s imilar to that of endometrial biopsy. However, speci \201 city is poor, so if the endometrium is >5 mm (as it will be in 50% of postmenopausal women on HT), endometrial biopsy will be required to rule out carcinoma 51-Draznin-Chap51.indd 272 4/2/2011 6:50:49 PM HORMONE REPLACEMENT THERAPY (HT) 273 Results of WHI cannot be extrapolated to younger HT users (<55 years of age). It is unclear whether different HT preparations or routes of administration would necessarily have the same bene \201 t/risk pro- \201 le. Dietary phytoestrogens Phytoestrogens are found in foods such as soybeans, cereals, and see ds. Although they have estrogen-like activity, data from clinical trials are con- \202 ic ting. It appears that the effect of phytoestrogens on vasomotor symp- toms is modest at bes t. Research does suggest that soy protein has a favorable effect on plasma lipid concentration s and may reduce the risk of cardiovascular disease. However, the actual daily dose require d is unclear. Finally, data regarding the effect of phytoestrogens on bone loss and breast cancer risk ar e inconclusive. Phytoestrogen supplements cannot therefore be recommended for the preventio n of chronic disease in peri- and post- menopausal women until they are adequately evaluate d in clinical trials. HT regimens Estrogen preparations b See Table 51.3. Only symptomatic women should be treate d with HT and dose tapered to the lowest dose to control symptoms. Route of administration Oral route is the most popular. Disadvantages are as follows: \200 First-pass hepatic metabolism means that plasma estrogen levels are variable. Transdermal patches avoid the \201 rst-pass effect and are thus ideal in women with liver disease or hypertriglyceridemia. Additionally, patches provide constant sy stemic hormone levels. However, 10% of women develop skin reactions. Patients should try to avoid moisture and rotate patch sites to limit side effects. Gels have the advantages of patches, but skin irritation is less common. Progestin preparat ions b See Table 51.4. These must be added in non-hysterectomized women to avoid endometria l hyperplasia and subsequent carcinoma. Sequential cyclical regimen Give progestin for a minimum of 12 days a month. It is usually given for the \201 rst 12 days of each calendar month. As the estrogen dose is tapered, Table 51.3 Estrogen preparations Preparation Dose Conjugated estrogens (PO) 0.625 \200\2231.25 mg daily Transdermal estro-gen/progestin Daily or intermittently 51-Draznin-Chap51.indd 273 4/2/2011 6:50:49 PM CHAPTER 51 Menopause 274 Table 51.4 Estrogen preparations Cyclical dose (days 1 \200\22312) Continuous daily dose Progestin Medroxyprogesterone acetate (least androgenic) 5 mg 2.5 mg intermittent progestin 4 \227 a year may be feasible. However, the risk of endometrial hyp erplasia on such a regimen is unknown. Ninety percent of women have a monthly withdrawal bleed; 10% may be amenorrheic with no har mful consequences. Bleeding should start after the ninth day of progestin therapy. Continuous combined regimen Lower doses of progestin are given on a daily basis. Uterine bl eeding is usually light in amount but timing is unpredictable. Bleeding should stop in 90% of women within 12 months, in the majority in 6 months. This regimen is suggested for older women who do not want monthly withdrawal bleeds, but in the WHI trial continuous combined therapy was associated with i risk of breast cancer. The impact of other forms of HT is unknown. Further reading Arlt W (2006). Androgen therapy in women. Eur J Endocrinol 154:1 \200\22311 . Davis SR, et al. (2008). Testosterone for low libido in postmenopausal women not taking est rogen. N Engl J Med 359:2005 \200\2232017. Humphries KH, Gill S (2003). Risks and bene \201 ts of hormone replacement therapy: the ev idence speaks. CMAJ 168:1001 \200\2231010. Million Women Study Collaborators (2003). Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362:419 \200\223423. Rymer J, Wilson R, Ballard K (2003). Making decisions about hormone replacement therapy. BM J 326:322 \200\223326. Writing Group for Women \200\231s Health Initiative Investigators (2002). Risks and bene \201 ts of estrogen plus progestin in healthy postmenopausal women: principal results from the Women \200\231s Health Initiative randomized controlled trial. JAMA 288:321 \200\223333 . 51-Draznin-Chap51.indd 274 4/2/2011 6:50:49 PM INTRODUCTION 275275 Oral contraceptive pill (OCP) Introduction The OCP is very effective contraception, with approximately 5 per 100 users be coming pregnant per year. Ethinylestradiol (EE2) \200 The standard dose is 30 mcg, but in older women or those with possible cardiovascular risk factors, 20 mcg EE2 may be appropriate. \200 A dose of 50 mc g EE2 may be indicated in patients on antiepileptic medication but is otherwise associated with an excess risk of arterial and venous thromboem bolism. Progestin \200 Commonly used OCPs contain second-generation progestagens, such as levonor gestrel (150 \200\223250 mg) and norethisterone or norithindrone (1 mg). OCPs containing third-generation progestagens (e.g., norgestimate and desogestrel) are less androgenic; however, they may be associated with an i risk of thr omboembolism. Yasmin contains a new progestagen, drospirenone, which is derived from spironolactone. It therefore has antimineralocorticoid activity. It may have antiandrogenic properties. For a list of OCP preparations b see Box 52.1. OCP side effects \200 Breakthrough bleeding \200 Mood changes \200 Nausea \200 Flui d retention and weight gain \200 Breast tenderness and enlargement \200 Headache \200 Reduced libido \200 Chloasma 52-Draznin-Chap52.indd 275 3/31/2011 2:59:41 PM CHAPTER 52 Oral contraceptive pill (OCP) 276 Box 52.1 OCP preparations First generation \200 Norinyl-1 Second generation \200 BiNovum \200 Brevinor \200 Loestrin 20/30 \200 Logynon \200 Microgynon 30/30 ED \200 Norimin \200 Ovranette \200 Ovysmen \200 Synphase \200 TriNovum Third generation \200 Cilest \200 Femodene/ED \200 Femodette \200 Katya 30/75 \200 Marvelon \200 Mercilon \200 Sunya 20/75 \200 Triadene Fourth generation \200 Yasmin Bene \201 ts Ovarian cancer The risks of ovarian cancer are halved in women who have been taking the OCP for 5 years or more. This risk reduction persists long after dis- continuation of the OCP. Acne The OCP reduces free testosterone concentrations by suppressing ovar- ian production o f androgens and by i hepatic SHBG production. OCP with low androgenic progestins often resu lt in an improvement in acne. Menstrual disorders OCPs are associated with reduced menstrual \202 ow and can therefore improve menorrhagia. They also reduce dysmenorrhea. 52-Draznin-Chap52.indd 276 3/31/2011 2:59:41 PM RISKS 277 Risks Venous thromboembolism The risk of venous thromboembolism in nonpregnant women (5 per 100,0 00 women per year) is i 3-fold in women on the OCP. The risk is highest in the \201 rst y ear of use, increases with age, and is i in obese women. The risk of venous thromboembolism appears to be higher in women taking OCPs containing desogestrel or gestodene. Women with a family history of thromboembolism should undergo a thrombophilia screen before starting the OCP (see Table 52.1 for contraindications). Arterial thrombosis There is a 10-fold excess risk of IHD in female smokers over the age of 35 years who are on the OCP. The risk of IHD does not seem to be signi \201 - cantly i in nonsmokers who take a low-dose OCP. The relative risk of ischemic stroke is only slightly i in women taking a low-dose OCP. The risk is i in women over the age of 35 years, smokers Table 52.1 OCP contraindications* Absolute Relative History of heart disease, ischemic or valvular Migraine Pulmonary hypertension Sickle cell disease History of arterial or venous thrombosis Gallstones History of cerebrovascular disease In \202 ammatory bowel disease High risk of thrombosis, e.g., factor V Leiden, antiphospholipid antibodies Hypertension Liver disease Hyperlipidemia Migraine if severe or associated with focal aura Diabetes mellitus Breast or genital tract cancer Obesity Pregnancy Smokers Presence of two or more relative contraindications Age >35 years and a smoker Otosclerosis Family history of thrombosis Family history of breast cancer Consider using a progesterone-only pill in women with contraindications to the combined OCP . 52-Draznin-Chap52.indd 277 3/31/2011 2:59:41 PM CHAPTER 52 Oral contraceptive pill (OCP) 278 or women with hypertension. The risk of hemorrhagic stroke does not seem to be i by taking the OCP. Risk of either arterial or venous thrombosis returns to normal within 3 months of discontinuing the OCP. Hypertension Hypertension may be caused by the OCP, and if already present, may be more res istant to treatment. Hepatic disease Raised hepatic enzymes may be seen in women on the OCP. The inci- dence of benign hepatic tumors is also increased. Gallstones The risk of developing gallstones is slightly increased by taking the OCP (RR = 1.2). Breast cancer (controversial) There may be a slightly i risk of breast cancer in women usin g the OCP (RR = 1.3), particularly in those who began taking the OCP in their teens. The ri sk does not seem to be related to the duration of exposure to the OCP nor to the EE2 dose. The relative risk of developing breast cancer returns to normal 10 years after discontinuing the OCP. Cervical cancer Use of the OCP appears to be associated with an excess risk of cervical can cer in women who are human papillomavirus (HPV) positive. The risk increases with the durat ion of OCP use. It is not known whether the risk falls again following discontinuation of t he OCP. Thrombophilia screen \200 Antithrombin III \200 Protein C \200 Protein S \200 Facto r V Leiden Hormonal emergency contraception This refers to contraception that a woman can use after un protected sexual intercourse to prevent pregnancy. A single 1.5 mg dose of the progestin levonorgestrel is highly ef \201 cacious with a preg nancy rate of 2 \200\2234% if taken within 72 hours of sexual inter- course. It is most eff ective the earlier it is taken. The dose is repeated if vomiting occurs within 3 hours of t aking the pill. The mechanism of action is not clear but is thought to be due to inhibi- tion of ovulation as well as an d likelihood of endometrial implantation. Side effects include nausea in up to 60% of women, vomiting in 10 \200\22320%. Consider ant iemetic 1 hour before taking contraception. Other side effects are breast tenderness, fatig ue, and dizziness. Contraindication is pregnancy. Women should be advised to use barrier contraception until their next period. 52-Draznin-Chap52.indd 278 3/31/2011 2:59:41 PM PRACTICAL ISSUES 279 98% of women menstruate within 3 \200\2234 weeks of taking levonorgestrel. They should be e ncouraged to seek medical advice if they do not bleed in that time. If pregnancy does occur, levonorgestrel is not known to be teratogenic. Practical issues Age and the OCP Women with no risk factors for arterial or venous thrombosis may con- tinue to use the combined OCP until the age of 50 years. Those with risk factors for thromboembolism and IHD should avoid the OCP after the age of 35 years, particularly if they are smokers. All women on the OCP after the age of 35 years should be on the low- est effective estrogen dose (e.g., 20 mcg EE2). Regarding contraception after the menopause, assume that the woman is fertile for the \201 rst year after the last menstrual period if >50 years. Breakthrough bleeding Causes include the following: \200 Genital tract disease \200 Ins uf \201 cient estrogen dose \200 Inappropriate progestin \200 Missed pill \200 Takin g 2 packets continuously \200 Gastroenteritis \200 Drug interactions, e.g., antibiotics , hepatic enzyme inducers Antibiotics and the OCP Broad-spectrum antibiotics interfere with intestinal \202 ora, th ereby reducing bioavailability of the OCP. Additional methods of contraception should be us ed. OCP and surgery Stop the OCP at least 4 weeks before major surgery and any surgery to the l egs. Resume after mobile for at least 2 weeks. With emergency surgery, stop the OCP and start antithrombotic prophylaxis Further reading Petitti DB (2003). Combination estrogen-progestin oral contraceptives. N En gl J Med 349:1443 \200\2231450. 52-Draznin-Chap52.indd 279 3/31/2011 2:59:41 PM CHAPTER 53 Testicular physiology 280 Testicular physiology Anatomy Normal adult male testicular volume is 15 \200\22330 mL. Testicular temperature is 2 C lower than the rest of body because of the scrotal location. This is necessary for nor mal spermatogenesis. There are two main units with differing functions: Interstitial cells: Comprised of Leydig cells, which are found in between the seminiferous tubules and close to the blood vessels. These cells produce testosterone. Seminiferous tubules: Make up 90% of testicular volume. Spermatogenesis occurs here, in the presence of high intratesticular concentrations of test osterone. They are made up of germ cells and Sertoli cells. Sertoli cells support spermatog enesis and secrete various hormones, including inhibin and, in the embryo, M llerian inhib itory factor (AMH). The former inhibits FSH secretion from the pituitary gland and the latt er is responsible for suppressing female sex organ development during sexual differentiatio n in utero. See Fig. 53.1 for testosterone biosynthesis. Cholesterol StAR 17 HSD 17, 20 lyase Pregnenolone 17OH pregnenolone Dehydroepiandrosterone 17 HSD 3 HSD Aromatase Testosterone Estradiol Progesterone 17OH progesterone Androstenedione 21 OH 11 Deoxycortisol Deoxy- corticosterone 11 OH Corticosterone Cortisol 18-OH corticosterone Aldosterone Fig. 53.1 Testosterone biosynthesis pathway. 53-Draznin-Chap53.indd 280 3/31/2011 3:00:08 PM REGULATION OF TESTICULAR FUNCTION 281 Regulation of testicular function Regulation of androgen production Hypothalamic hormones G onadotropin-releasing hormone (GnRH) is secreted by thehypothalamus in a pulsatile manner i n response to sex hormones and gonadal peptides, neurotransmitters, and neuropeptides (kiss peptin, leptin, etc.). Episodic GnRH secretion is present at birth, is inhibited across midchild- hood, and then i s augmented initially during sleep in early puberty and then throughout the day in adulthoo d. It stimulates the secretion of lutein- izing hormone (LH) and follicle-stimulating hormo ne (FSH) by the pituitary gland. The pattern of GnRH secretion is crucial for normal gonadotropin secretion. Faster pulse fr equencies are essential for LH secretion, whereas slower frequencies favor FSH secretion. C ontinuous administration of GnRH abolishes both LH and FSH secretion. Pituitary hormones LH binds to Leydig cell receptors and stimulates the synthesis and secre - tion of testosterone. FSH binds to Sertoli cell receptors and stimulates the production of seminiferous tubule \202 uid as well as a number of substances thought to be important for spermatogenesis. Their secretion is regulated by GnRH pulses and through negative feed- back from testicular hormones and peptides. Testis Testosterone is the main androgen produced by the Leydig cells of the testis. Small amounts of androstenedione, DHEA, and dihydrotestoster- one (DHT) are also produced. Testos terone has a circadian rhythm with maximum secretion at around 8 A.M. and minimum at around 9 P.M. Small amounts of estradiol are also produced in the testis by the con- version from testost erone. Additionally, most of the circulating estradiol in men occurs as a result of aromati zation of androgens in adipose tissue. FSH, in the presence of adequate testosterone levels , stimulates the secretion of inhibin B by Sertoli cells. This in turn acts as a potent inh ibitor of FSH secretion. The secretion of pituitary gonadotropins is tightly regulated by testicu- lar function. LH secretion is inhibited by testosterone and its metabolites whereas, FSH secretion is contro lled by both inhibin B and testosterone. High concentrations of testosterone or of inhibin B results in a negative feedback inhibition of FSH secretion ( b see Fig. 53.2 ). Testicular function is also under paracrine control. Inhibin and insulin- like growth facto r-1 (IGF-1) act with LH to enhance testosterone produc- tion, whereas cytokines inhibit Ley dig cell function. 53-Draznin-Chap53.indd 281 3/31/2011 3:00:08 PM CHAPTER 53 Testicular physiology 282 Regulation of spermatogenesis b See Fig. 53.2. Both FSH and LH are required for the initiation of spermatogenesisat puberty. LH, by stimul ating Leydig cell activity, plays an important part in the early phases of sperm production , when high intratesticular concentra- tions of testosterone are essential. FSH, through it s action on the Sertoli cells, is vital for sperm maturation. The whole process of spermatogenesis takes approximately 74 days, fol- lowed by another 12 \200\22321 days for sperm transportation through theepididymis. This means that events that may affect spermatogenesis may not be appar- ent for up to 3 months. Hypothalamus GnRH +ve \210\222ve Pituitary gland +ve LH FSH Inhibin \210\222ve +ve Testosterone Sertoli cells Leydig cells +ve Spermatozoa Fig. 53.2 Regulation of spermatogenesis. 53-Draznin-Chap53.indd 282 3/31/2011 3:00:08 PM PHYSIOLOGY 283 Physiology Testosterone transportation From 2 to 4% of circulating testosterone is free and therefore biologically active. The rest is bound to proteins, particularly albumin and sex hor- mone binding globulin (SHBG). Testosterone metabolism Testosterone is converted in target tissues to the more potent andr ogen DHT in the presence of the enzyme 5A reductase. There are multiple 5A-reductase isoenz ymes; type 2 is the isoenzyme responsible for DHT synthesis in the genitalia, genital skin, and hair follicles. It is therefore essential for normal male virilization and sexual deve lopment. Both testosterone and DHT exert their activity by binding to androgen receptors, the latter more avidly than testosterone. The androgen receptor is encoded by a gene found on the lon g arm of the X chromosome (Xq). Testosterone may alternatively be converted into estradiol through the action of the aromat ase enzyme, found in greatest quantities in the testes and adipose tissue. Testosterone and its metabolites are inactivated in the liver and excreted in the urine. Androgen action \200 Male sexual differentiation during embryogenesis \200 Development and maintenance of male secondary sex characteristics after puberty Normal male sexual function and behavior \200 Spermatogenesis \200 Regulation of gonado tropin secretion Estrogen metabolism in males \200 Estradiol daily production rate in men: 35 \200\22345 m cg \200 Source of circulating estradiol: \200 Peripheral aromatization of testosterone (60%) \200 Testes (20%) \200 Peripheral conversion from estrone (20%) \200 2 \200\223 3% free estradiol that is biologically active; the rest is bound to SHBG Estrogen action in males \200 Pubertal growth and fusion of the epiphyses \200 Maintena nce of bone density \200 Regulation of gonadotropin secretion . Further reading De Ronde W, Pols HAP, Van Leeuwen JPTM, et al. (2003). The importance of oe strogens in males. Clin Endocrinol 58(5):529 \200\223542. 53-Draznin-Chap53.indd 283 3/31/2011 3:00:08 PM CHAPTER 54 Male hypogonadism 284 Male hypogonadism De \201 nition Male hypogonadism is the failure of testes to produce adequate amounts of t estosterone, spermatozoa, or both. Epidemiology Klinefelter \200\231s syndrome (XXY) ( b see p. 289 \200\223290) is the most c ommon congenital cause and is thought to occur with an incidence of 1:500 live births. Acquired hypogonadism is even more common, affecting 1:200 men. Evaluation of male hypogonadism Presentation \200 Failure to progress through puberty \200 Sexual dysfunction \200 In fertility \200 Nonspeci \201 c symptoms, e.g., lethargy, reduced libido, mood changes, weight gain The clinical presentation depends on the following: \200 Age of onset (congenital vs. acq uired) \200 Severity (complete vs. partial) \200 Duration (functional vs. permanent) 54-Draznin-Chap54.indd 284 4/1/2011 6:11:20 PM SECONDARY HYPOGONADISM 285 Secondary hypogonadism (hypogonadotropic hypogonadism) De \201 nition This is hypogonadism as a result of hypothalamic or pituitary dysfunction. Diagnosis \200 Low serum testosterone \200 Low \200\223normal or low LH and FSH (normal inhibin B and anti-M llerian hormone) Causes b See Box 54.1. Idiopathic hypogonadotropic hypogonadism (IHH) \200 The congenital form is indistinguishable from Kallmann syndrome apart from the absence of anosmia. >90% o f patients are men. \200 GnRH receptor gene mutation is an uncommon cause of IHH. Box 54.1 Causes of secondary hypogonadism