The Yentl Syndrome: An Endocrine Perspective

Introduction

In 1983, a popular movie named “Yentl” starring Barbra Streisand was released. In this, she portrayed a woman who pretended to be a man and secretly received education in Jewish Religious Law, The Talmud, since girls were forbidden to study religious scriptures in those days. This film’s title was described in 1991, in an article in NEJM, by Dr Bernadine Healy, the first female Director of NIH, as under- diagnosis, under- treatment and adverse outcomes in women with ischemic heart disease, because symptoms of their disease were not classic nor conformed to that of men.¹ Taking it further, many authors have used “Yentl Syndrome” to explain the nuances between diseases in women as compared to diseases in men.²

Differences in anatomy and physiology between the sexes implies that diseases may affect them differently. Women’s health is not limited to reproductive medicine alone. Some diseases are unique to women, some have higher prevalence in women, some show different symptoms and response to medications. We must be mindful of all these aspects.

Very simply stated, ‘Sex’ refers to biological differences, whereas ‘gender’ refers to social differences. Sex is defined, based on chromosomes, hormones, and reproductive anatomy. Gender is a way of life, shaped by socially constructed roles and behaviours.

Every medical speciality is influenced by sex related differences. In this review, we will focus on some Metabolic and Endocrine Disorders. As men and women age, they suffer from similar types of illnesses but men tend to suffer more from acute illnesses for relatively shorter periods before they die. Generally, men are more vulnerable to life-threatening diseases, like coronary heart disease, cancer, cerebrovascular disease, emphysema, cirrhosis and kidney disease.

Women have a longer life marked by many chronic non-life-threatening disabilities that can affect quality of their lives. For example, osteoporosis, due to a natural decline in bone density after menopause, affects mainly women. Women suffer more from chronic disorders, like anaemia, thyroid problems, gall stones, migraine headaches, arthritis and endometriosis. The biological advantage of women’s longer lives, appears to be related to behaviours like less smoking, less alcohol use, more social connections, their ability to bear children and their stronger immune system. By age 85 yrs. there are roughly 6 women to every 4 men. At the age of 100, the ratio escalates to 2 to 1.3 Human endocrine system is very interesting. It involves maintaining harmony with cyclical and circadian release of hormones at different life events like puberty, ovulation, pregnancy, with different stresses of life, or simple daily routines and juggling with feedback loops. It almost resembles a world class orchestra making music under a brilliant master conductor. Each hormone performs its own task and yet listens and reacts to each other in many amazing ways. Endocrine disorders e.g. hypothyroidism have a higher prevalence in women. Conditions like gestational diabetes, polycystic ovarian syndrome, menopause are found only in women. Other health problems like cerebrovascular diseases (CVD), osteoporosis and diabetes mellitus have increased risk factors because of ethnicity, race and sex, leading to different clinical outcomes in men and women.

Auto immunity forms the basis for many endocrine diseases that are more prevalent in the female sex. It is said that women have a strong immune system, which at times can attack one’s own body. 78% of all autoimmune diseases occur in only women.⁴

Sex steroid hormones e.g. oestrogen and testosterone, their site of production, blood concentration, interactions on various organs is different in both the sexes. For Instance, in males, testosterone comes from male gonads, in a ‘circadian rhythm’, daily. Small amounts of oestrogen and progesterone are also produced by testis and adrenal glands, or in the peripheral tissues like adipose tissue and liver by enzymatic conversion. In contrast, females make oestrogen and progesterone from female gonads, in a ‘cyclical pattern’ monthly. Small amounts of testosterone are also made in the ovary, adrenal gland and peripheral tissues. In female bodies, testosterone is converted quickly to oestrogen, while in men it remains as testosterone.

Triglycerides, HDL, glucose metabolism and even hepatic synthesis of many enzyme systems e.g. CP450 family, differ in males and females. This can lead to differences in drug distribution and different pathways, which in turn cause variation in efficacy of medications in males and females and also differences in appearance of adverse effects.⁵ Let us review some of the endocrine diseases.

Thyroid diseases

Thyroid diseases are at least 5-8 times more common in females, that includes hypothyroid, hyperthyroid, nodular disease and autoimmune condition. Significantly higher proportion of adult female vs male were diagnosed with hypothyroidism 15.86% vs 5.02%.6 Differentiated thyroid cancer (DTC) is the most common endocrine neoplasm. It is 2.9 times more common in females.7 The peak incidence is at about 40-49 years in women, while in men it peaks at 60-69 years. Overall, 10-year survival of DTC is 90 %. Females have a better survival rate than age adjusted males.

Thyroid physiology changes in pregnancy. Receptors on the gland are stimulated by placental human chorionic gonadotropin (HCG) and suppresses TSH in some women. Oestrogens stimulate the formation of TBG which causes high total T3 / T4. Hypothyroidism, if inadequately treated may increase pregnancy loss, high blood pressure in pregnancy and the woman is prone to develop gestational diabetes. Some earlier studies showed lower Intelligence quotient (IQ) and impaired psychomotor development in the child too. It is very important to keep TSH levels in trimester specific range. Newborn screening for congenital hypothyroidism is extremely essential.

Diabetes mellitus (DM)

It has been shown that diabetes is different in the sexes. The life time risk of diabetes is higher in women. In Indians at age 20 years, the risk was 55.5 % in men and 64.6 % in women in metro cities.8 The children of mothers with high glycaemia are at risk of early onset obesity and cardio metabolic disorders as a result of intra uterine programming. Women with DM in the reproductive age group are at very high risk for pregnancy related complications e.g. pregnancy loss, preterm babies and in uncontrolled diabetes, diabetic embryopathy, skeletal problems, neural defects and renal agenesis in the baby. Pregnancy can worsen pre-existing retinopathy and nephropathy. Physicians should strictly advise their female patients to use contraception till blood sugars are in target range for planning a pregnancy. This is of paramount importance.

Diabetes Mellitus is a strong risk factor for congenital heart disease (CHD), CVD and all-cause mortality in women, more than men. Women have a 44 % excess risk for CHD and 27 % higher relative risk for stroke.9 36.9 % of women with DM and myocardial infarction (MI) died within one-year vs 20.2 % of women without DM.

Pre-menopausal women with diabetes lose the protection against heart disease that non diabetic women have. Women have significantly higher risk of ischemic cardiomyopathy. They have worse prognosis after MI and a higher mortality rate from CVD than diabetic men. Changes in hormone levels before and during menstrual periods can make blood sugars unpredictable. Vigilance is required at such times. Menopause or use of oral contraceptives represents a risk factor for insulin resistance in women. Diabetic women are at high risk for urinary tract infection (UTI)/genital infections with SGLT2 inhibitor drugs. Thiazolidine drugs increase the risk of bone fracture in post-menopausal women. All females need tailor made treatment protocols to keep in perspective their unique situations e.g. contraception, pre conception care, post-partum, safety of medication in pregnancy, lactation, bone health and of course mental health.

Osteoporosis

Historically, osteoporosis was regarded as a woman’s disease, though it occurs in men too. In fact, men have a worse outcome after fractures than women and are twice as likely to die after hip fracture compared to women. Worldwide, 1 in 3 women over age 50 years will have a fracture and 1 in 5 men over 50 years will suffer the same fate. In 2022, the prevalence of osteoporosis and osteopenia was 30.50% and 44.2% in postmenopausal women of Punjab.10 The higher risk for osteoporosis and fractures in women is thought to stem from lower peak bone mass attained, biologically smaller muscle mass, bone loss at menopause, food fads and dieting, and the effect of pregnancies on bone health.

In the ESOPO Study, an Italian epidemiological study on prevalence of osteoporosis in Italy, in 40-79 years old, osteoporosis was found to be prevalent in 18.5% in women and 10% in men. Prevalence of osteopenia was 44.7 % in women and 36% in males.11 Men tend to have higher peak bone mineral density (BMD) and bone content. They reach bone peak mass in late 20’s, at an older age than females in early 20’s.12 This suggests that improving bone health by paying attention to calcium and Vitamin D intake, adequate exercise and healthy lifestyle, especially in young women, much before age 20, will help delay or defer osteoporosis. Post-menopausal women have higher bone resorption markers. In males, bone degradation seems to increase but bone formation markers are stable suggesting a low bone remodelling rate.¹¹

Both sex hormones keep bones strong, but here, men actually have the edge. As men age, testosterone levels decline slowly, about 1% a year, but oestrogen levels drop abruptly at menopause, escalating the risk of osteoporosis. As far as therapy for osteoporosis is concerned, it has been reported that, females have higher cases of atypical fractures compared to men, almost a 3-fold higher risk.¹⁴ Alendronate users had higher risk than Risendronate users in women; cause of this discrepancy is not known.

Heart disease

Heart disease is the leading cause of death globally. It accounts for 1 in every 5 female deaths, far exceeding death from breast cancer. However, heart disease still is thought of as a man’s disease. Research has focussed on symptoms of male heart attacks, causing misdiagnosis in women because they may have no chest pain, the classic “Yentl Syndrome”. Young women may present with stomach discomfort, nausea, fatigue or breathlessness. Physicians often refer to these as “atypical “because men don’t report them.¹

Sex specific risk factors for women include reproductive factors e.g. Peripartum cardiomyopathy, breast cancer therapy, anthracyclines and radiation therapy specially to left side of the chest. The prevalence of Heart Failure with preserved Ejection fraction (HFpEF) is higher in women.¹⁵ It is suggested that Troponin diagnostic threshold levels may be too high for women. Women appropriate threshold values should be introduced, whose presence can be a biological marker and diagnostic test for heart attacks in women. Complex cardio protective effects of oestrogens limit release of Troponin from cardiac muscles.¹⁶

In 2007 a research study found that Aspirin is less efficacious in women (for reduction of MI) and raises the possibility that women are more susceptible to ‘Aspirin Resistance’. A meta-analysis of 43 studies in 2 million patients in Journal of American Heart Association (2020), reported that women were significantly less likely to be prescribed Aspirin, statins, ACE I compared to men.¹⁷ In fact, Women on atorvastatin had more side effects, more increase in liver enzymes, more myalgia than men and may discontinue it earlier.

These variations and many more, create challenges in management of cardio metabolic diseases in women.

Polycystic ovary syndrome (PCOS)

Polycystic ovary syndrome (PCOS) is the most common endocrine-metabolic abnormality among reproductive age women. The worldwide prevalence is about 15%, depending on diagnostic criteria. PCOS is not just a reproductive and cosmetic disorder, but has widespread metabolic ramifications and trans-generational impact. It is a public health ‘wakeup call’ which unfortunately has no definite cure as yet. It can lead to Obesity, CVD, T2 DM, infertility and endometrial cancer in the future.

70 % of PCOS patients are not identified in society. Women with PCOS have a 47 % increased risk for death at a younger age compared to those without PCOS.¹⁸ Even though the exact aetiology of PCOS is unknown so far, addressing each issue will go a long way in improving lives of PCOS patients.

Menopause and andropause

Age related hormone changes in men are different from those in women. In women, there is a deep dive of oestrogen levels at menopause compared to the gradual decline of Testosterone in men. Ovulation ceases quite dramatically. Testosterone declines with age in all men at the rate of 1-3% per year. Levels are below normal range in only 20% at age 60 years.¹⁹ So, is Andropause real? What are the ramifications? The debate continues regarding this.

Menopause is an important transition from a social and biological perspective. A woman’s experience of menopause may be influenced by sociocultural factors. Vasomotor and genitourinary symptoms of menopause, may significantly impair quality of life. Shared decision making of patient and physician will help individualise treatment to keep doses low of HRT, seek best route of treatment for the shortest duration, keeping in mind all the other co- morbidities of the post-menopausal woman, hence reduce serious side effects from menopausal hormone therapy.

Endometriosis and premenstrual syndrome (PMS)

In the Indian context, menstrual health discussion is often considered a taboo in society. Endometriosis, a disease that affects roughly 10% of women and girls of reproductive age worldwide, is highly underreported in our country. Globally it is under researched. This has come to symbolise how illnesses that affect only women have been ignored by a historically male-focused medical system.

Premenstrual Syndrome, is a group of symptoms that includes anxiety, mood swings, bloating, breast tenderness and sleep disturbances. Exact cause is unknown, but fluctuations in oestrogen, progesterone and serotonin may be involved. In India, it affects over 14.3% to 74.4 % women.²⁰ Erectile Dysfunction, is reported in 10 to 52 % of men. According to a 2024 report by World Economic Forum and McKinsey Health Institute, as of 2015 there were 5 times more research papers on erectile dysfunction than PMS. A plethora of medications are available to treat ED, very little is available to help women with PMS. Is it really the case that woman’s health is taken less seriously than a man’s? Sadly, an average woman spends 25 % more time in poor health compared to a man.

Gestational diabetes mellitus (GDM)

GDM is one of the most challenging disorders, in terms of diagnosis, treatment and future repercussions. Gynaecologists/Obstetricians, Foetal Medicine Experts, Primary Care, Endocrinologists and Dieticians all are involved to improve the outcomes of a GDM pregnancy. Risk of developing T2 DM is 10-fold higher in women with GDM compared to women without GDM.²¹ It is imperative that national and international organizations come to a consensus for diagnosis and management of this condition. This uniformity will reduce the controversies and confusion that exists at present.

Obesity

Females have higher percentage of fat mass, especially in subcutaneous and lower extremities. Female sex hormones play a major role in the amount, distribution, and metabolism of fat in women. Males have more visceral fat in the abdominal region. In puberty and pregnancy, adipose tissue increases as a result of gonadal steroids. Oestrogen protects against obesity, through suppression of appetite and increasing energy expenditure. Oestrogen deficiency leads to fat accumulation in an android fashion.

Obesity in females is associated with a high risk for development of cardio metabolic diseases, endometrial, breast and colon cancers, musculoskeletal disorders, depression, obstructive sleep apnoea etc. Obesity in adolescent girls need to be addressed at school, community and grassroots level at almost a war footing.