Key points
- •
Long-acting reversible contraception (LARC) methods are safe, effective, and have minimal risk of user error; thus they have become the recommended option for most women with complicated chronic illnesses.
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The severity of asthma symptoms increases around the time of menses.
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Many women with irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) have exacerbations of symptoms with menses.
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Women with chronic renal disease often experience menorrhagia and irregular menses, which often improves with transplant.
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Estrogen-containing contraceptives are not recommended in women with hypertension who are older than 35, use tobacco, have poorly controlled disease, or are on medications for hypertension.
- •
Progesterone stabilizes red cell membranes and significantly decreases the frequency of sickling crises.
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Withdrawal of progesterone (even in small amounts such as in the periovulatory period) leads to a significant decline in the seizure threshold and an increase in seizure frequency and severity.
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Women who have migraines with aura are more susceptible to stroke, and thus the use of estrogen-containing contraceptives (ECCs) in women with migraines with aura is contraindicated.
- •
Early referral of women with cancer to a reproductive endocrinologist with expertise in potential therapies to preserve fertility is important.
This chapter highlights the interactions with and influences of female physiology on major medical disease processes. The chapter also reviews how medical diseases affect female physiology. Many disease processes act directly; for example, renal failure commonly induces abnormal uterine bleeding. Other diseases act indirectly through their therapies, such as cancer chemotherapy, which may lead to ovarian failure. Multiple chapters in this text discuss important aspects of female physiology. This chapter serves as an addendum to those discussions. When considering specific drug interactions and doses, the clinician is encouraged to review current pharmacologic literature.
In general, the impact of female physiology on medical disease is primarily via the effects of estrogen and to a lesser extent progesterone. Other hormones, such as prolactin, oxytocin, and gonadotropins, play minor roles. Estrogen and progesterone affect almost all major organ systems in both tonic and cyclic modes. The effects of the female hormones are mediated directly through receptors (estrogen alpha, estrogen beta, progesterone) and indirectly through their effects on other organ systems, such as smooth muscle relaxation and changes in prostaglandin levels. The responses induced by estrogen and progesterone may be theorized, in a teleologic sense, as promoting successful reproduction. Pathology occurs when the normal hormonal effects overlap a disease process that is already present.
Medical diseases affect female physiology at all levels of the hypothalamic-pituitary-ovarian-genital axis, from anovulation to vaginal atrophy. Medical diseases also affect female physiology in a horizontal manner, throughout every stage of a woman’s life. Thus medical diseases must be seen in both a vertical and a horizontal context (i.e., a three-dimensional manner). Because gynecologists commonly act as consultants to other health professionals, we are often asked to help with complications stemming from gynecologic issues. Though different clinicians direct the treatment of lupus, multiple sclerosis, or epilepsy, modulating the effects of female physiology on these disease processes is the role of the gynecologist.
Pulmonary disease
Asthma is more common in boys up until puberty. After puberty, the ratio reverses with women more at risk for asthma until menopause. Asthma is one of several major diseases in which the severity of symptoms is increased around the time of menses ( Box 8.1 ). Premenstrual asthma is well described, affecting up to 40% of reproductive-age women who have asthma, with symptoms including increasing cough, wheezing, and shortness of breath. Up to 50% of hospitalizations for women with asthma in their 20s occur around the time of menses. Women with premenstrual asthma have been shown to have a measurable decline in respiratory function with the end of the menstrual cycle ( ). Data suggest that combination oral contraceptive pills (cOCPs) may blunt this effect and mildly decrease the severity of the asthma ( ). The variability of symptoms between cycles may be caused by the hormonal fluctuations from one cycle to the next.
Asthma
Atopic reactions
Epilepsy
Eating disorders
Irritable bowel syndrome
Menstrual migraines
Mental health disorders
Multiple sclerosis
Inflammatory bowel disease
Rheumatoid arthritis
Supraventricular tachycardia
Sickle cell disease
Type 1 diabetes
Hormones can affect asthmatic symptoms through several mechanisms. One theory is that the increased symptomology is related to the estrogen- and progesterone-mediated increase in both serotonin and histamine release from granulocytes and mast cells ( ). Estrogen also increases eosinophilic adhesion to the bronchial lining. In addition, progesterone induces degranulation of eosinophils. Interestingly, both estrogen and progesterone also have antiinflammatory properties, and it may be that the withdrawal of estrogen and progesterone at the end of the cycle contributes to a fluctuation in prostaglandin levels that leads to increased bronchial reactivity and premenstrual asthma.
Regarding the effects of asthma on female physiology, a few small series have noted an increased incidence of abnormal menstrual cycles in women with severe asthma ( ). Whether this is due to glucocorticoid medications or whether this is a direct effect from severe pulmonary disease on the hypothalamus is unclear. It should be noted that multiple studies have found that women with early menarche have twice the risk of asthma in early adulthood ( ). Women who are taking inhaled glucocorticoids may be at increased risk for osteopenia and osteoporosis ( ). Clinicians who care for women with asthma beyond their third decade should obtain vitamin D levels and council the women about adequate calcium intake. There are conflicting reports about the effect of menopause and hormone replacement therapy on asthma symptoms and severity; some have noted an improvement in symptoms, whereas others have noted a worsening ( ; ). Increasing evidence exists to suggest that there may be a perimenopausal/menopausal phenotype of new-onset asthma characterized by neutrophilic airway inflammation and high frequency of severe exacerbations ( ). Other data suggest that independent of asthma onset, asthma exacerbation after menopause tends to be more severe ( ). Given these data, clinicians must be wary of any asthma in a perimenopausal or menopausal patient.
It is now common for women with cystic fibrosis (CF) to reach reproductive age. Tsang and colleagues, in a review of reproductive problems, noted that women with cystic fibrosis tend to have shorter stature, delayed puberty with delayed growth spurts, and delayed menarche ( ). The degree of delay is related to the severity of the disease. Additionally, because of the effects of estradiol on mucin production, periods of the menstrual cycle with high estradiol levels are associated with worse lung function ( ). Girls with cystic fibrosis tend to be as sexually active as their peers; however, they tend to have less counseling regarding contraception than their peers. Estrogen-based contraceptives are acceptable for women with cystic fibrosis as long as they do not have pulmonary hypertension, active liver disease, or a history of thromboembolism ( ). Long-acting reversible contraception (LARC), including the progesterone intrauterine devices (IUDs) and progesterone implants, are also a safe, effective, and practical option for these young women. Issues of sexuality may be problematic for young women with severe cystic fibrosis because of poor body image secondary to chronic disease, infections, and gastrointestinal disturbances from pancreatic problems, as well as enlarged rib cages from chronic hyperventilation in some patients. Thus counseling on sexuality should occur in conjunction with contraceptive counseling.
There is an emerging body of evidence suggesting that fertility is affected in women with cystic fibrosis. Cervical mucus is thicker in women with cystic fibrosis, which may lead to altered fertility. Oligomenorrhea, amenorrhea, and ovulatory dysfunction are increased in women with cystic fibrosis proportionally to the severity of disease. Finally, alterations in uterine levels of bicarbonate, which affects sperm capacitation, also affect fertility in women with cystic fibrosis ( ). Though a full discussion of the management of subfertility and infertility treatment options is beyond the scope of this chapter, intrauterine insemination, intracytoplasmic sperm injection, and in vitro fertilization have all been successfully performed in women with CF.
Immune and allergic disease
The profound effect that female physiology has on immunity is best exemplified by the remarkably increased survival of women compared with men from infectious causes of disease. Estrogen and progesterone have multiple effects on the immune processes through numerous cellular sites. This is manifest in multiple disease processes ( Box 8.2 ). In most women the effects are mild, but in women constitutionally or genetically predisposed to atopic reaction or autoimmune disease, the effects can be significant.
B cell
Inhibited bone marrow B-cell lines with high concentrations of estrogen
Increased antibody production through inhibition of T-cell suppression
Enhanced interleukin-10 response
T cell
Lower doses of estrogen are stimulatory, higher doses of estrogen are inhibitory, primarily through TNF
Stimulation of inhibitory T-cell pathways and T-cell cytokines
Low-level stimulation of interleukins
Monocytes
Increased monocyte apoptosis inhibiting differentiation
Inhibited dendritic cell differentiation (in vitro)
Inhibited migration of inflammatory cells with decreased migration at higher estrogen levels
Mast cells and granulocytes
Estrogen increases serotonin and histamine release through estrogen alpha receptors
Progesterone promotes IgE production
General inflammation
Increased presence of estrogen beta receptors over estrogen alpha receptors with generalized inflammation
Increased sensitization of sensory neural tissue leading to increased neurogenic inflammation
Increased fibroblast activity and improved wound healing
Increased stimulation of the hypothalamus-pituitary-adrenal axis
Increased anaphylaxis * and allergic reactions
*Includes drug induced and radiologic contrast media induced.
IgE, Immunoglobulin E; TNF, tumor necrosis factor.
The overall effect may be grossly simplified in noting estrogen’s effect on the B cell as an immune enhancer ( ). In contrast, on T cells, estrogen tends to act as an inhibitor ( ). Importantly, estrogen effects vary by the level and type of estrogen. At lower levels, as in most of the menstrual cycle, estrogen stimulates immune responses. However, at high estrogen levels such as occur during pregnancy, estrogen generally inhibits immune cellular responses. The effects of estrogen on inflammation have important implications for wound healing. Women tend to heal more effectively than men because estrogen stimulates fibroblast activity and nerve growth. Estrogen’s positive effect on reepithelialization lasts until several years after menopause ( ). Interestingly, hormone replacement therapy improves wound healing ( ).
B-cell–dominated autoimmune diseases have a higher incidence and severity in women ( ). Estrogen enhances the hypersensitivity responses from both B-cell activity and granulocyte action in allergic responses ( ). Women are more at risk for eczema, atopic irritations, hypersensitivity, and anaphylaxis from foods, medications, radiologic contrast media, and anesthesia compared with men ( ). Granulocytes, eosinophils, mast cells, and basophils are all enhanced by estrogen ( ). Estrogen also enhances serotonin and histamine release. In contrast, cellular-mediated immune mechanisms, primarily controlled through T cells, tend to be functionally inhibited by estrogen. At high, pregnancy levels of estrogen, there is functional inhibition of T-cell function, leading to improvement of T-cell–mediated autoimmune diseases such as rheumatoid arthritis or multiple sclerosis during pregnancy ( ). During periods of estrogen withdrawal, late luteal phase, menstruation, postpartum, and early menopause, there are often clinical rebounds and an increase in disease flares with the release of T-cell suppression.
For the gynecologist asked to consult on women with autoimmune diseases, important strategies include completing screening for breast and cervical cancer routinely as one would for the general population; ensuring that any pregnancy is planned, not only to allow time for medication optimization, balancing disease stability with fetal risk, but also because the best pregnancy outcomes occur when autoimmune diseases are quiescent; and ensuring adequate and safe contraception for the reasons given earlier. Estrogen-containing contraceptives (ECCs) (including the vaginal ring, the transdermal patch, and cOCPs) are acceptable for women with systemic lupus erythematosus (SLE) if they do not have antiphospholipid antibody syndrome (APAS) or a history of thrombosis ( Table 8.1 ) ( ). Women with SLE are also at risk for menstrual irregularities; thus a hormonal contraceptive may also help with cyclic regulation ( ). However, LARC methods are also safe, have similar benefits as far as cyclic regulation, are more effective contraceptives, and are less susceptible to user error than all ECCs, but especially cOCPs. ECCs have not been shown to increase the severity of disease or the number of flares in premenopausal women with SLE ( ).
| Medical Disorder | Contraindicated Contraception | Rationale/Complication |
|---|---|---|
| Systemic lupus erythematosus with antiphospholipid antibodies or thrombosis | Estrogen-containing contraception * (ECC) | Increased venous thrombosis (VTE) risk |
| Crohn disease | Any oral contraception | Decreased absorption |
| ECC † | Increased VTE risk | |
| Severe dyslipidemia | ECC | Increased VTE risk |
| Hypertension with risk factors ‡ | ECC | Increased VTE, stroke, and myocardial infarction risk |
| Renal transplant | ECC | Increased VTE risk Increased metabolism |
| Thrombophilias | ECC | Increased VTE risk |
| Diabetes with risk factors § | ECC | Increased VTE risk |
| Malabsorptive bariatric surgery | Any oral contraception | Decreased absorption |
| Migraine with aura | ECC | Increased VTE |
| Epilepsy on enzyme-inducing antiepileptic drugs | Progesterone-only oral contraception Progesterone implant | Increased metabolism |
* Includes combined oral contraception, vaginal ring, and the transdermal patch.
† In cases of extensive or active disease, prior bowel resection, very active disease, corticosteroid use, or immobilization.
‡ Risk factors include poor control, tobacco use, age older than 35, other chronic medical condition leading to vascular degradation, end organ damage, use of antihypertensives.
§ Risk factors include end organ damage, vascular disease, hyperlipidemia, poorly controlled disease.
Most autoimmune diseases do not flare around the time of menses. However, for those women with menstrual exacerbation, hormonal contraceptives may help decrease periodic variability. SLE does not seem to affect menstrual regularity or severity, nor does it appear to affect the timing of menopause. However, some antiinflammatory medications, including glucocorticoids and antineoplastic agents, affect not only the hypothalamic-pituitary-ovarian (HPO) axis but also the ovarian follicles, thus affecting both the menstrual cycle and menopausal timing ( Table 8.2 ). Women with severe end-organ disease often develop downregulation of the HPO axis, also affecting the above (see Chapter 26 ). Hormone replacement therapy (HRT) is safe in women with mild disease and no history of APAS or thrombosis but has been shown to increase the number of mild, but not severe, flares in lupus patients (Andreoli, 2017; ).
| Major Risk | Moderate Risk | Minimal Risk |
|---|---|---|
| Cyclophosphamide | Cisplatin | Methotrexate |
| Melphalan | Adriamycin | 5-Fluorouracil |
| Busulfan | Paclitaxel * | Vincristine |
| Chlorambucil | Bleomycin | |
| Procarbazine | Actinomycin | |
| Nitrogen mustard |
Multiple sclerosis (MS) is another autoimmune condition that merits discussion. Women are more commonly affected but usually have a less severe disease course than men ( ). Evidence is mixed regarding the effects of menstruation on disease flares. However, for women with cyclic disease flares, hormonal contraceptives are safe ( ). Women with severe multiple sclerosis have an increased risk of sexual dysfunction. Though data are limited, HRT may be useful for symptomatic postmenopausal women with MS without affecting disease activity.
Gastrointestinal disease
Estrogen and progesterone are critical in the modulation of the gastrointestinal tract. Estrogen plays a role in the secretory and absorptive function in gut epithelium, affects the gut’s microbiome composition, and has receptors on enteric neurons, which regulate neurogenic reflexes ( ). Progesterone is known to affect the motility of the gut and the growth and metabolism of the bacteria in the gastrointestinal tract ( ). It is thus no surprise that many gastrointestinal disease processes affect women differently than they affect men.
Irritable bowel syndrome (IBS) is perhaps the best example of this effect. With a female-to-male prevalence as high as 5:1, up to half of women with IBS will have exacerbations of symptoms with menses. The rapid progesterone withdrawal at the end of the luteal phase and the increase in systemic prostaglandins both lead to exacerbations of symptoms, including bloating and abdominal pain ( ). cOCPs have been shown to decrease symptoms in women with IBS. For women in whom menstrual effects become debilitating, the use of gonadotropin-releasing hormone (GnRH) agonists or continuous cOCPs has been suggested. The incidence of IBS tends to decrease after menopause.
Celiac disease, like other autoimmune diseases, tends to preferentially affect women. Women are at twice the risk for developing celiac disease ( ). Women with undiagnosed or poorly controlled celiac disease have later onset of menses, more irregular menstrual cycles, more secondary amenorrhea, and earlier age of menopause; these associations are not seen among women with treated disease ( ). A meta-analyses regarding fertility and celiac disease suggested that women with unexplained infertility should be tested for celiac disease but that women with well-controlled disease do not have decreased fertility compared with women without celiac ( ).
Women with Crohn disease and ulcerative colitis tend to have symptomatic exacerbations around the time of menses—specifically, worsening nausea, constipation, and diarrhea. Inflammatory bowel disease (IBD) has also been shown to have a negative effect on body image and sexuality ( ). Dyspareunia is also common, especially in those with Crohn disease. Women cite abdominal pain, fear of incontinence, and diarrhea as reasons for decreased levels of sexual activity ( ). Effective contraception is important for women with IBD because unplanned pregnancy in the setting of active disease is associated with worse maternal and fetal outcomes ( ). Though cOCPs are not associated with disease relapse, data suggest there is some risk of decreased absorption in women with Crohn disease and in women with increased intestinal transit secondary to previous bowel resection. For women with IBD who are at an increased risk for venous thromboembolism (VTE), including those with extensive or active disease, corticosteroid use, vitamin deficiencies, or immobilization, ECCs are not recommended ( ). LARC methods are considered safe and effective in women with IBD, independent of disease severity, and thus often are preferred over oral contraceptive options and ECCs. It is also important to note that women with IBD are at increased risk for osteoporosis and osteopenia and should be screened accordingly.
Estrogen has been noted to have a protective effect on the development and progression of liver disease. Women with hepatitis C have a better response to therapy and a slower rate of disease progression than men ( ). Research also suggests estrogen plays a significant role in preventing carcinogenesis in the liver ( ). As such, hepatocellular carcinoma is less common in women. The literature also describes the use of hormone replacement in postmenopausal women to inhibit liver fibrosis ( ). In contrast, autoimmune-mediated liver diseases, such as primary biliary cirrhosis and autoimmune hepatitis, are more common in women. It is also important to note that for women with cirrhosis or severe liver disease, ECCs are contraindicated.
Vascular and hypertensive diseases
In general, estrogens have a positive effect on the vascular system through improved lipid profiles. The presence of estrogen is associated with lower rates of atherogenic dyslipidemia, cardiovascular disease, and metabolic syndrome ( ). This effect is lost in postmenopausal women. However, women with dyslipidemias may have complications with estrogen because of its procoagulant effects, especially after the third or fourth decade. Women with dyslipidemia should avoid ECCs and HRT, although progesterone-only contraceptives, including LARC methods, are safe and effective for these women, independent of age.
In contrast, vascular and hypertensive diseases have important effects on women. Studies indicate that women with hypertension have much higher than expected levels of sexual dysfunction with impaired genital congestion and decreased arousal ( ). Data regarding the effects of antihypertensive medications on sexual function are mixed. Though beta-blockers are consistently associated with worsening sexual function, multiple studies have noted that adequate blood pressure control with medication actually leads to an improvement in sexual function ( ; ; ). Women with coronary artery disease and survivors of myocardial infarction have less sexual activity and increased sexual dysfunction ( ). Thus it is helpful for gynecologists to inquire about sexual concerns in women with cardiovascular disorders.
Hormonally based contraceptives may be problematic in women who are taking antihypertensive medications or those with poorly controlled hypertension. If there is no associated thrombosis, guidelines from the American College of Obstetricians and Gynecologists (ACOG) suggest that women may use ECCs as long as blood pressure is well controlled ( ; ). A return office visit 2 or 3 months after initiation of any ECC to assess blood pressure and potential side effects is appropriate. Studies have shown a small increase in stroke and myocardial infarction in women on oral contraceptives with hypertension, but the absolute risk is quite small ( ; ). It should also be noted that women with a history of pregnancy-related hypertension who are currently normotensive are also at a slightly increased risk for myocardial infarction and VTE, though again, the absolute risk is small ( ; ). As long as a woman does not use tobacco or does not have other aspects of vascular disease besides mild hypertension, ECCs may be reasonable. However, LARC methods are preferable, especially after age 35.
Cardiac arrhythmias are also affected by gender, though the exact pathophysiologic reasons for this are unclear. Atrioventricular nodal reentrant tachycardia occurs twice as often in women as in men, though Wolff-Parkinson-White syndrome is more common in men ( ). Supraventricular tachycardias and ectopic ventricular beats occur more often and last longer in the luteal phase of the menstrual cycle ( ). The QT interval tends to be longer in women, increasing the risk for torsades de pointes. Though rates of atrial fibrillation are lower in women, women with atrial fibrillation are less likely to be anticoagulated and to undergo ablative procedures and are more likely to suffer a stroke ( ). Menopause does not appear to affect risk of developing atrial fibrillation ( ; ). Sudden cardiac death affects both genders equally.
Renal disease
Women with end-stage renal disease (ESRD) have high prolactin levels and gonadotropin-mediated disruption of the luteinizing hormone (LH) surge ( ). These hormonal alterations result in anovulatory cycles, amenorrhea, oligomenorrhea, menorrhagia, infertility, and decreased libido. The effects of chronic disease (see Chapter 26 ) on the HPO axis also contribute to an increased likelihood of anovulatory bleeding in this population. Many, though not all, menstrual irregularities improve with renal transplant. Though many women with ESRD or on dialysis have irregular menstrual cycles and problems with infertility , many are sexually active, and thus it is critical that contraception should be discussed with them. ECCs are contraindicated in this population, whereas progesterone-only methods, especially LARCS, are safe and effective ( ).
Women with ESRD have higher rates endometrial hyperplasia, likely related to anovulatory cycles. There is also an increased incidence of cervical dysplasia, thought to be due to increased susceptibility to human papillomavirus (HPV) infection. Mammography can be challenging in this population because of increased vessel calcifications. To avoid unnecessary procedures, the patient’s history should be provided to the radiologist ( ). CA-125 is also often falsely elevated in this population and should be interpreted with caution ( ). Women with ERSD or who have undergone renal transplant have been shown to have a higher risk of surgical complications during gynecologic procedures ( ).
Up to 70% of women who are on hemodialysis, with chronic renal disease, and those who have had renal transplants have some degree of sexual dysfunction, including arousal disorders, decreased libido, and decreased genital blood flow, issues with lubrication, and orgasm problems. This may be related to lower levels of circulating estrogen. These women also go through menopause at an earlier age, 47 compared with 51 in women not undergoing dialysis, further exacerbating problems with sexual dysfunction ( ).
Peritoneal dialysis has many specific considerations in women. Fertility in this population is lower than in women receiving hemodialysis, likely related to a disruption in the ovum’s path to the fallopian tube ( ). Additionally, these women may experience cyclic hemoperitoneum, usually related to retrograde menstruation ( ). The hemoperitoneum is often asymptomatic, though rarely it may cause obstruction to the dialysis catheter ( ). If the hemoperitoneum is recurrent or problematic, it may be treated with tubal ligation or hormonal suppression of ovulation ( ). Finally, women who undergo peritoneal dialysis may be at increased risk for uterine prolapse possibly related to changes in intraabdominal pressure associated with the dialysis.
Hematologic and thrombotic diseases
Estrogen affects hematologic diseases primarily through its prothrombotic effects. Progesterone decreases smooth muscle venous tone, which leads to increased clotting potential. Routine screening for thrombophilias in women without a history of thrombosis, before the use of ECCs or hormone replacement, is not indicated. Women with a personal history of thrombosis related to estrogen should avoid estrogen-containing medications ( ). Women with known thrombophilias are great candidates for LARC methods but can also use progesterone-based oral contraceptives. Because supplemental estrogen is contraindicated in women with thrombophilias, these women may be more at risk for osteoporotic problems over time. These women should be regularly screened for a dietary history of calcium intake and for serum levels of vitamin D, with appropriate supplementation given.
Women with sickle cell disease (SCD) tend to go through menarche at a later age but do not have an increased rate of irregular cycles ( ). The menstrual cycle is often associated with increased pain crises. Progesterone stabilizes red cell membranes and significantly decreases the frequency of sickling crises; thus women with SCD may benefit from progesterone-containing contraceptives. Injectable medroxyprogesterone acetate has been used in women with frequent crises as an adjunct therapy with very good results ( ). The pain-mediating effects of progesterone-based IUDs and implants have not yet been well documented, though these are considered a safe contraceptive option for women with SCD. ECCs and HRT do not improve sickling but are not contraindicated ( ).
Women who receive oral anticoagulants (OAs), either for treatment or prophylaxis, experience increased vaginal bleeding, menorrhagia, and metrorrhagia ( ). Researchers reporting on a series of women noted that after starting the OA, the duration of bleeding increased, the percentage of women reporting heavy bleeding increased to almost 75%, and the number of women seeking medical treatment nearly doubled ( ). Anovulatory cycles may be particularly troublesome for these women. A progesterone-based IUD or progesterone supplementation for the last 14 days of the cycle may be necessary to decrease heavy bleeding. Estrogen-containing contraceptives are not recommended for women on anticoagulation ( ). Though the copper-containing IUD does not increase the risk of thrombosis, it is also generally not recommended given its association with increased menstrual bleeding ( ). Women on OAs are also at an increased risk for ovulation-related bleeding and associated hemoperitoneum.
The most common inherited bleeding diathesis is von Willebrand disease. The association of von Willebrand disease and vaginal bleeding is discussed in Chapter 26 . LARC methods are safe in these women. However, because estrogen increases von Willebrand factor, ECCs may be advantageous for women with von Willebrand disease and menorrhagia or ovarian cysts ( ). Women with rare bleeding disorders fall into this category as well, and ECCs may be helpful for them. A consensus report discussed other therapies, including endometrial ablation or hysterectomy as potential options in women with bleeding disorders who do not desire fertility ( ).
Endocrine disease
Women with type 2 diabetes or who are obese have increased rates of anovulation, infertility, and endometrial hyperplasia. ECCs are acceptable in women with isolated diabetes (type 1 or 2) without end organ damage, as are progesterone-based contraceptives ( ). However, because many women with diabetes have coexisting vascular disease or hyperlipidemia, it is recommended that ECCs be limited to women who are nonsmokers and younger than 35 with no other significant pathologic condition. LARC methods are safe, effective, and recommended for women with any form diabetes, independent of severity. In addition to the contraceptive effects, LARC methods also protect the endometrium in women who are anovulatory ( ).
Studies of sexuality in women with diabetes have noted increased sexual dysfunction, particularly for those with type 1 diabetes and those with long-standing disease. Sexual dysfunction is due to end organ disease, which leads to decreased genital blood flow, decreased lubrication, and orgasmic dysfunction. Young women with type 1 diabetes are also more likely to suffer from longer menstrual cycles and heavier menses compared with women without diabetes ( ). Though these issues are worse in women with a higher glycated hemoglobin (HbA1c), the problems persisted in women with well-controlled disease ( ). It should also be noted that insulin requirements and glycemic control vary with the hormonal fluctuations of the menstrual cycle, especially in the luteal phase and around menses. Discussion of this normal variation with younger women is important.
Obese women present an interesting conundrum regarding contraceptive options. Biologic plausibility for lower efficacy of many contraceptive options in obese women has long been stated. However, a 2016 review concluded that there did not appear to be an efficacy difference among obese and nonobese women taking cOCPs, though the review did recognize that data stratifying by body mass index (BMI) category was limited ( ). This same review also noted that the estrogen-containing patch (transdermal) has been found to be less efficacious in obese women, whereas the vaginal ring has not ( ). It should also be emphasized that given the increased risks of pregnancy-related complications in this population, some contraceptive effect is better than no contraception. The progestin-based IUD or progestin-based implant have the highest success rate, independent of weight, and should be considered a first-line treatment in the obese population ( ). Given the increased incidence of anovulation with obesity, the local effects of the progestin-based IUD are especially protective against endometrial hyperplasia as well ( ). Obese women also describe higher rates of sexual dysfunction than normal-weight women. However, this seems to improve with weight loss and improvement in body image ( ). This is true with both natural weight loss and bariatric surgery.
Obese women undergoing bariatric surgery should also be counseled about contraception and pregnancy planning. Malabsorptive procedures, particularly the Roux-en-Y procedure, have the potential to affect absorption of all oral contraception, including emergency contraception, and thus these methods should be discouraged in women who are undergoing or have undergone this sort of operations ( ). The efficacy of nonoral methods are not affected by bariatric surgery; thus the LARC methods are a good option for this population. After surgery, women may transition from being anovulatory to regular ovulation with weight loss and improved glucose control. It is recommended that women wait 12 to 18 months before attempting pregnancy after bariatric surgery, another reason that the LARC methods are a good option for these women ( ).
Women with congenital adrenal hyperplasia (CAH) are usually treated with glucocorticoid replacement. These women are exposed to an androgenic environment throughout their lives; thus hormonally based contraceptives, including OCPs, are a good form of contraception. Though many of these women have difficulties with hirsutism, they should not be treated with spironolactone because it may affect mineralocorticoid regulation. Infertility secondary to chronically increased progesterone and androgen levels may occur, though this condition is correctable with steroid maintenance therapy ( ). Women with more severe phenotypes may need mineralocorticoid and progesterone suppression ( ). Women with CAH may also have problems with dyspareunia, vaginal stenosis, and lower sexual satisfaction ( ). Sexual counseling for these women is helpful. Of note, thyroid disease is discussed in detail in Chapter 26 .
Central nervous system disease
Seizure disorders
Estrogen and progesterone have significant effects on a woman’s susceptibility to seizures. Estrogen is a proconvulsant, decreasing the seizure threshold. Estrogen increases neuronal excitability directly on nerve cells, as well as secondarily through inhibition of the GABA system. More potent, though, are the effects of progesterone, which acts primarily via its metabolite allopregnanolone, a neurosteroid. Allopregnanolone acts rapidly and directly on the GABA receptors to enhance their activity, producing potent neural inhibition throughout the central nervous system (CNS). Withdrawal of progesterone (even in small amounts such as periovulatory) leads to a significant decline in seizure threshold and an increase in seizure frequency and severity.
More than 1 million women in the United States have seizure disorders, and many have increased seizure activity related to changes in menstrual hormones. Catamenial epilepsy (from the Greek katomenios, meaning “monthly”) has been defined as seizures that occur from 3 days before to 4 days after the onset of menses. Pure catamenial epilepsy affects 10% of all women with epilepsy ( ). However, nearly 80% of women have an increase in seizure activity related to menstrual cycles ( ). Progesterone-based contraceptives or a small amount of progesterone add-back during menses has been used to decrease seizure frequency. Continuous cOCPs with an every-3-month withdrawal may also be helpful. It is unclear if the progesterone-based IUD produces systemic progesterone levels high enough to affect the seizure threshold.
Though hormonal contraception is acceptable for women with seizure disorders, estrogen affects metabolism of some antiepileptic drugs (AEDs) ( Table 8.3 ). Women who experience menstrual-related seizures should have serum levels of their anticonvulsant medications checked during menses. Some of these women will benefit from perimenstrual adjustments of their medications. In contrast, some antiepileptic drugs, referred to as enzyme-inducing AEDs (see Table 8.3 ), affect the metabolism of hormonal contraception. For women taking a medication from this family of AEDs, progesterone-only pills have decreased efficacy and are not recommended ( ). Similarly, progesterone implants are contraindicated in this population ( ). Emergency contraception can be used in women with epilepsy, but those on enzyme-inducing AEDs may need a higher dose ( ).
