A condition, known commonly as "black urine disease" or Alkaptonuria is a rare genetic disorder involving protein metabolism, and it has its root in the mutation of the homogentisate 1,2-dioxygenase gene, which in turn causes homogentisic acid accumulation in the body. The appearance of dark urine after exposure to air is due to this kind of accumulation; however, a variety of symptoms can be expected, such as joint stiffness, changes in pigmentation, and other long-term health complications. Although the prevalence has been estimated to be between 1 in 250,000 and 1 in 1 million people in the United States, its effects are indeed high on those affected.

Alkaptonuria is an autosomal recessive disease, meaning that the child must inherit a defective copy of the HGD gene from both parents. If both parents are carriers, their offspring have a 25% chance of inheriting two faulty genes and developing alkaptonuria. The condition is genetic but is often not diagnosed for years because it progresses slowly and its early symptoms appear to be harmless.

Symptoms of Alkaptonuria

The most characteristic and common initial symptom of alkaptonuria is dark urine. The reason for this is due to the fact that excess HGA is excreted in the urine and upon oxidation in the presence of air, it gives the urine a brown or black color. Though it is often considered cosmetic, the long-term accumulation of HGA within the connective tissues produces more complicated health problems.

Progressive joint pain and stiffness: The accumulation of HGA in cartilage leads to early-onset osteoarthritis, making movement increasingly difficult over time.

Skin and eye pigmentation changes: Affected individuals may develop bluish or grayish discoloration of the sclera (white part of the eye) and the skin, particularly in areas exposed to friction.

Cardiovascular and respiratory problems: With age, HGA accumulation can lead to valve calcifications in the heart and stiffening of connective tissues in the respiratory tract, which can cause problems in middle and old age.

Decreased mobility and spinal problems: The spine may become stiff and painful due to chronic cartilage degeneration.

These symptoms usually begin to manifest during adulthood, leading to severe complications in a person's 40s or 50s and significantly affecting the quality of their life.

How is Alkaptonuria Diagnosed?

Because of its rarity, alkaptonuria is often mistaken or overlooked early in life. However, there are several ways to confirm the condition:

Urine Testing: The gold standard in the diagnosis is the testing of urine samples for high levels of homogentisic acid via gas chromatography. In case of oxidation, which changes the color of urine to black, it is indicative of alkaptonuria.

Genetic Testing: Confirmatory genetic testing reveals mutations of the HGD gene to diagnose the condition conclusively.

Blood Tests: High levels of HGA in the blood can be used as further evidence.

Imaging Studies: X-rays and MRIs will expose cartilage and joint damage characteristic of alkaptonuria.

Management of Alkaptonuria: Is There A Cure?

At present, there is no cure for alkaptonuria; however, various treatment approaches can reduce its symptoms and slow the disease's progress:

Nitisinone Therapy: Nitisinone is a drug that inhibits the production of HGA. It has been shown to reduce HGA levels and slow tissue damage. However, it needs to be taken under close medical supervision because of potential side effects.

Low-Protein Diet: Since HGA is a byproduct of protein metabolism, reducing protein intake—especially foods rich in tyrosine and phenylalanine—may help decrease HGA production.

Pain Management: OTC pain relievers and anti-inflammatory medications can be used to relieve joint pain and stiffness.

Physical Therapy: Exercise regularly, as it may improve mobility and strengthen muscles, thus reducing strain on affected joints.

Surgical Interventions: Most people with alkaptonuria develop severe osteoarthritis necessitating joint replacement in their old age. Also, some may require heart valve replacement surgery if cardiovascular complications develop.

Life with Alkaptonuria

Although alkaptonuria is not fatal, it severely affects the quality of life. The progressive deterioration of the joints and associated symptoms can make everyday activities difficult, requiring lifestyle changes and medical interventions. The disease may cause premature aging of the joints, requiring walking aids and mobility assistance earlier than expected.

Ongoing research will continue to work on improving the treatment options by focusing on gene therapy and alternative enzyme replacement therapies. However, because of its rarity, the clinical trials and research remain sparse.

As genetic research advances, more hope for better management and possible curative approaches for alkaptonuria exists. Scientists are searching extensively for enzyme replacement therapies and innovative drugs that can target the root cause of the disorder. Being aware and being diagnosed early helps individuals better their condition and ultimately have better long-term health outcomes.

Alkaptonuria is a striking example of how one gene mutation can have widespread effects on the body. Though still a rare and often misunderstood condition, growing awareness and advances in treatment are paving the way for better care. If you or a loved one suspect symptoms of alkaptonuria, it is essential to seek early diagnosis and medical guidance to manage the disease effectively and preserve quality of life.

Menopause typically occurs between the ages of 45 and 55. However, the hormonal changes leading up to it can begin earlier, with some women reporting symptoms in their 30s.

A 2025 study published in NPJ Women's Health examined 4,400 American women aged 30 and older. It found that roughly 55% of women aged 30-35 reported moderate or severe symptoms on the Menopause Rating Scale. The proportion rose to just over 64% among women aged 36-40. Despite these symptoms, most women did not seek treatment until they were 56 or older.

Speaking to HealthandMe, Dr. Kajal Parikh is an Obstetrician and a Gynecologist based in Mumbai, explained how hormonal changes can begin in the mid-to-late 30s, the signs women should watch for, and why monitoring symptoms and maintaining healthy habits matter during this transition.

Perimenopause Can Begin In Your Mid-To-Late 30s

From the first menstrual period to menopause, the body undergoes significant hormonal changes. Estrogen and progesterone are among the hormones involved in this process.

“These hormones don't exit overnight. The exit starts much earlier. Starting mid-30s to late 30s, the hormone levels start depleting. Now, when that level starts depleting, you're going to see signals.”

According to Dr Parikh, changes in menstrual cycles can be among the first signs. Periods may become heavier or lighter, while cycles may become shorter or longer.

Being mindful of these changes can help women identify patterns and discuss persistent or concerning symptoms with a healthcare professional. However, these symptoms alone do not confirm that a woman is in perimenopause.

Also read: Menopause Abruptly Shifts Bones, Liver And Blood Fats, Study Finds

Brain Fog, Sleep Problems And Other Signs To Watch For

Perimenopause symptoms can extend beyond menstrual changes. Women may notice dry skin, pigmentation, hair thinning, increased hair fall, low energy, brain fog and disturbed sleep.

Some women who previously slept well may begin waking up at 3 or 4 a.m. and find it difficult to return to sleep, Dr Parikh told HealthandMe.

“That's your body asking for some help, or rather the body signaling that we are going through some crisis, see how we can fix it.”

Other possible symptoms include breast tenderness, worsening premenstrual symptoms, headaches, migraines, and bone and joint pain. Vaginal dryness, changes in urinary habits and reduced libido may also occur.

Symptoms vary considerably between individuals, and many of these changes can have causes other than perimenopause, the expert said,

When Should Women Seek Medical Advice?

Read More: ‘I Was Vocal About Cancer But Silent About Menopause Out Of Shame’, Says Actress Lisa Ray

Dr Parikh recommended annual gynecological visits to monitor changes over time. She also advised women to track their symptoms and seek medical advice if they worsen or do not improve with treatment.

Although menstrual changes may become noticeable in the late 30s and early 40s, the timing of the menopausal transition varies. Some women experience menopause earlier than expected, while others continue menstruating into their 50s.

For women without symptoms, Dr Parikh identified 40 as an appropriate age to begin regular monitoring and annual screening.

“40 is that golden age when you start monitoring, when you start getting your annual screenings done.”

The need for specific tests depends on a woman's age, symptoms and medical history. Women experiencing menstrual changes or possible menopausal symptoms at a younger age should consult a healthcare professional rather than waiting until 40.

What Tests And Lifestyle Changes Can Help?

Dr Parikh said doctors may assess iron levels, thyroid function, blood sugar and lipid levels while reviewing a woman's diet, nutrition and exercise habits. These assessments can help identify other conditions that may contribute to symptoms.

She also emphasised the importance of sleep, nutrition and exercise during the menopausal transition.

“The only thing that will save you from this transition are your three strong pillars, which is your sleep, your nutrition, and your exercise regimen.”

Treatment depends on the symptoms and individual health needs. After assessing symptoms and ruling out other possible causes, doctors can discuss appropriate options, including hormone therapy when indicated.

READ: Can Menopause Be Delayed? What Science Says About Slowing Ovarian Aging

Can Genetics Influence Menopause Timing?

Dr Parikh said genetics can play a role in determining when menopause occurs. A family history of early menopause, including in a woman's mother or grandmother, may be relevant when discussing her own reproductive health.

She also raised concerns about potential environmental exposures, including endocrine-disrupting chemicals found in some products and packaging. However, their individual contribution to the timing of menopause is difficult to establish, and these exposures should not be presented as proven causes of early menopause.

Maintaining a balanced diet, exercising regularly and prioritising sleep can support overall health during the menopausal transition.

For a patient with advanced heart failure, there comes a point when medicines, devices and repeated hospitalisations can no longer control the disease. For some, a heart transplant may offer the only realistic path to long-term survival. Yet in India, the challenge often begins much earlier than the waiting list: many patients who could potentially benefit from transplantation never reach an advanced heart-failure or transplant centre for evaluation.

The scale of the problem is enormous. A recent study found that 83,000 heart transplantations were required annually in India in 2021, although only a very small proportion of that need was met. In comparison, according to the National Organ and Tissue Transplant Organisation (NOTTO), 221 heart transplants were performed in 2023.

Why Patients With Advanced Heart Failure Miss Out

The first issue is delayed referral. Patients with advanced heart failure may continue to be treated repeatedly for breathlessness, fluid retention or hospital admissions without being assessed early for advanced therapies.

A transplant evaluation is not a last-minute decision. It requires time to assess the patient's medical condition, other organs, infection risk, nutrition, psychosocial circumstances and ability to undergo lifelong follow-up.

The second challenge is the limited availability of donor hearts. Heart transplantation depends almost entirely on deceased organ donation. India has made substantial progress in transplantation overall, but the national deceased organ donation rate remains less than one donor per million population.

How Geography And Cost Affect Access To Transplants

Geography and affordability also matter. Advanced heart-failure programmes and transplant centres are concentrated in selected regions, meaning that patients from smaller cities and rural areas may face substantial travel, financial and logistical barriers.

The cost of evaluation, repeated hospitalisations, mechanical circulatory support and post-transplant medicines can further influence whether a patient can realistically pursue transplantation.

Also read: “You’ve Got A Pig’s Heart!” Genetically Modified Pigs with Human-like Organs Transforming Organ Donation; Details Inside

When Should Patients Be Referred To A Transplant Centre?

We therefore need to change the way advanced heart failure is recognised. A patient with recurrent hospitalisations, persistent symptoms despite optimal therapy, progressive kidney or liver dysfunction, low blood pressure limiting medications, or dependence on intravenous therapies should trigger consideration of referral to an advanced heart-failure centre.

Early referral gives specialists more time to evaluate the patient, assess treatment options and determine whether transplantation or another advanced therapy is appropriate.

Heart Transplant Is Not The Only Advanced Treatment

Importantly, transplantation is not the only advanced therapy. Left ventricular assist devices (LVADs) can serve as a bridge to transplantation or, in selected patients, as long-term therapy.

These devices can help support the heart's pumping function in patients with advanced heart failure who meet the criteria for their use. The appropriate option depends on the patient's condition, overall health and treatment goals.

India has demonstrated that transplantation can grow rapidly when infrastructure, coordination and public awareness improve. The next step is to ensure that patients are identified early enough to be evaluated, and that a shortage of donor organs does not remain the only reason they never get the opportunity to reach the transplant list.

By Dr. Pravin Kulkarni, MBBS, MS (General Surgery), MCh (Cardiovascular and Thoracic Surgery), Fellowship in CTS, Director, Advanced Cardiac Surgery and Heart and Lung Transplant Program

According to the latest National Family Health Survey (NFHS-6), 30.7% of women aged 15-49 years in India are reported as overweight or obese, highlighting the growing importance of lifestyle factors in women’s reproductive and overall health. Along with nutrition and physical activity, sleep is another important factor for overall menstrual health and the ovulation cycle.

Ovulation is controlled by a complex interaction between the brain, pituitary gland and ovaries. This reproductive hormone system is closely connected to the body's circadian rhythm, which regulates the sleep-wake cycle and influences the timing of several hormonal processes. When sleep becomes consistently irregular or insufficient, these signals may become disrupted, potentially affecting the hormonal coordination required for normal ovulation.

How Sleep Disturbances May Affect Reproductive Hormones

Also read: Andrew Huberman’s Sleep Trick: Can Eye Movements Help You Fall Back Asleep?

One of the ways this may occur is through interference with the functioning of the hypothalamic-pituitary-adrenal (HPA) axis. The reproductive system relies on communication between the hypothalamus and pituitary gland to regulate the hormones involved in follicle development and egg release.

Melatonin is another hormone linked to sleep and circadian rhythm. It also has antioxidant properties in the ovaries. This is why the relationship between sleep and fertility may involve more than simply the number of hours a woman sleeps.

A 2025 study published in Chronobiology International found that a later chronotype, or a tendency to sleep and wake later, was associated with a higher risk of sporadic anovulation among women with regular menstrual cycles.

Each one-hour increase in later chronotype was associated with a 5% higher relative risk of anovulation (RR 1.05; 95% CI 1.00–1.11), while women in the third chronotype tertile had a 33% higher relative risk compared with those in the second tertile (RR 1.33; 95% CI 1.05–1.68).

Interestingly, sleep duration itself was not associated with anovulation, suggesting that sleep timing and circadian patterns may also matter.

Poor Sleep Quality May Also Matter During IVF

Sleep may also be relevant during fertility treatment. A 2025 prospective cohort study of 174 women undergoing IVF/ICSI reported that women with poor sleep quality had 22.89% fewer retrieved oocytes and 22.01% fewer matured oocytes after adjustment for relevant factors.

The study also reported associations between certain sleep patterns and other IVF outcomes. However, these findings are observational and do not establish that poor sleep directly causes poorer fertility outcomes.