Endocrinology (part 4 – reproductive endocrinology)

Some observations from chapter 4 of the book below.

“*♂. The whole process of spermatogenesis takes approximately 74 days, followed by another 12-21 days for sperm transport through the epididymis. This means that events which may affect spermatogenesis may not be apparent for up to three months, and successful induction of spermatogenesis treatment may take 2 years. *♀. From primordial follicle to primary follicle, it takes about 180 days (a continuous process). It is then another 60 days to form a preantral follicle which then proceeds to ovulation three menstrual cycles later. Only the last 2-3 weeks of this process is under gonadotrophin drive, during which time the follicle grows from 2 to 20mm.”

“Hirsutism (not a diagnosis in itself) is the presence of excess hair growth in ♀ as a result of androgen production and skin sensitivity to androgens. […] In ♀, testosterone is secreted primarily by the ovaries and adrenal glands, although a significant amount is produced by the peripheral conversion of androstenedione and DHEA. Ovarian androgen production is regulated by luteinizing hormone, whereas adrenal production is ACTH-dependent. The predominant androgens produced by the ovaries are testosterone and androstenedione, and the adrenal glands are the main source of DHEA. Circulating testosterone is mainly bound to sex hormone-binding globulin (SHBG), and it is the free testosterone which is biologically active. […] Slowly progressive hirsutism following puberty suggests a benign cause, whereas rapidly progressive hirsutism of recent onset requires further immediate investigation to rule out an androgen-secreting neoplasm. [My italics, US] […] Serum testosterone should be measured in all ♀ presenting with hirsutism. If this is <5nmol/L, then the risk of a sinister cause for her hirsutism is low.”

“Polycystic ovary syndrome (PCOS) *A heterogeneous clinical syndrome characterized by hyperandrogenism, mainly of ovarian origin, menstrual irregularity, and hyperinsulinaemia, in which other causes of androgen excess have been excluded […] *A distinction is made between polycystic ovary morphology on ultrasound (PCO which also occurs in congenital adrenal hyperplasia, acromegaly, Cushing’s syndrome, and testesterone-secreting tumours) and PCOS – the syndrome. […] PCOS is the most common endocrinopathy in ♀ of reproductive age; >95% of ♀ presenting to outpatients with hirsutism have PCOS. *The estimated prevalence of PCOS ranges from 5 to 10% on clinical criteria. Polycystic ovaries on US alone are present in 20-25% of ♀ of reproductive age. […] family history of type 2 diabetes mellitus is […] more common in ♀ with PCOS. […] Approximately 70% of ♀ with PCOS are insulin-resistant, depending on the definition. […] Type 2 diabetes mellitus is 2-4 x more common in ♀ with PCOS. […] Hyperinsulinaemia is exacerbated by obesity but can also be present in lean ♀ with PCOS. […] Insulin […] inhibits SHBG synthesis by the liver, with a consequent rise in free androgen levels. […] Symptoms often begin around puberty, after weight gain, or after stopping the oral contraceptive pill […] Oligo-/amenorrhoea [is present in] 70% […] Hirsutism [is present in] 66% […] Obesity [is present in] 50% […] *Infertility (30%). PCOS accounts for 75% of cases of anovulatory infertility. The risk of spontaneous miscarriage is also thought to be higher than the general population, mainly because of obesity. […] The aims of investigations [of PCOS] are mainly to exclude serious underlying disorders and to screen for complications, as the diagnosis is primarily clinical […] Studies have uniformly shown that weight reduction in obese ♀ with PCOS will improve insulin sensitivity and significantly reduce hyperandrogenaemia. Obese ♀ are less likely to respond to antiandrogens and infertility treatment.”

“Androgen-secreting tumours [are] [r]are tumours of the ovary or adrenal gland which may be benign or malignant, which cause virilization in ♀ through androgen production. […] Virilization […] [i]ndicates severe hyperandrogenism, is associated with clitoromegaly, and is present in 98% of ♀ with androgen-producing tumours. Not usually a feature of PCOS. […] Androgen-secreting ovarian tumours[:] *75% develop before the age of 40 years. *Account for 0.4% of all ovarian tumours; 20% are malignant. *Tumours are 5-25cm in size. The larger they are, the more likely they are to be malignant. They are rarely bilateral. […] Androgen-secreting adrenal tumours[:] *50% develop before the age of 50 years. *Larger tumours […] are more likely to be malignant. *Usually with concomitant cortisol secretion as a variant of Cushing’s syndrome. […] Symptoms and signs of Cushing’s syndrome are present in many of ♀ with adrenal tumours. […] Onset of symptoms. Usually recent onset of rapidly progressive symptoms. […] Malignant ovarian and adrenal androgen-secreting tumours are usually resistant to chemotherapy and radiotherapy. […] *Adrenal tumours. 20% 5-year survival. Most have metastatic disease at the time of surgery. *Ovarian tumours. 30% disease-free survival and 40% overall survival at 5 years. […] Benign tumours. *Prognosis excellent. *Hirsutism improves post-operatively, but clitoromegaly, male pattern balding, and deep voice may persist.”

*Oligomenorrhoea is defined as the reduction in the frequency of menses to <9 periods a year. *1° amenorrhoea is the failure of menarche by the age of 16 years. Prevalence ~0.3% *2° amenorrhoea refers to the cessation of menses for >6 months in ♀ who had previously menstruated. Prevalence ~3%. […] Although the list of causes is long […], the majority of cases of secondary amenorrhoea can be accounted for by four conditions: *Polycystic ovary syndrome. *Hypothalamic amenorrhoea. *Hyperprolactinaemia. *Ovarian failure. […] PCOS is the only common endocrine cause of amenorrhoea with normal oestrogenization – all other causes are oestrogen-deficient. Women with PCOS, therefore, are at risk of endometrial hyperplasia, and all others are at risk of osteoporosis. […] Anosmia may indicate Kallman’s syndrome. […] In routine practice, a common differential diagnosis is between mild version of PCOS and hypothalamic amenorrhoea. The distinction between these conditions may require repeated testing, as a single snapshot may not discriminate. The reason to be precise is that PCOS is oestrogen-replete and will, therefore, respond to clomiphene citrate (an antioestrogen) for fertility. HA will be oestrogen-deficient and will need HRT and ovulation induction with pulsatile GnRH or hMG [human Menopausal Gonadotropins – US]. […] […] 75% of ♀ who develop 2° amenorrhoea report hot flushes, night sweats, mood changes, fatigue, or dyspareunia; symptoms may precede the onset of menstrual disturbances.”

“POI [Premature Ovarian Insufficiency] is a disorder characterized by amenorrhoea, oestrogen deficiency, and elevated gonadotrophins, developing in ♀ <40 years, as a result of loss of ovarian follicular function. […] *Incidence – 0.1% of ♀ <30 years and 1% of those <40 years. *Accounts for 10% of all cases of 2° amenorrhoea. […] POI is the result of accelerated depletion of ovarian germ cells. […] POI is usually permanent and progressive, although a remitting course is also experienced and cannot be fully predicted, so all women must know that pregnancy is possible, even though fertility treatments are not effective (often a difficult paradox to describe). Spontaneous pregnancy has been reported in 5%. […] 80% of [women with Turner’s syndrome] have POI. […] All ♀ presenting with hypergonadotrophic amenorrhoea below age 40 should be karyotyped.”

“The menopause is the permanent cessation of menstruation as a result of ovarian failure and is a retrospective diagnosis made after 12 months of amenorrhoea. The average age of at the time of the menopause is ~50 years, although smokers reach the menopause ~2 years earlier. […] Cycles gradually become increasingly anovulatory and variable in length (often shorter) from about 4 years prior to the menopause. Oligomenorrhoea often precedes permanent amenorrhoea. in 10% of ♀, menses cease abruptly, with no preceding transitional period. […] During the perimenopausal period, there is an accelerated loss of bone mineral density (BMD), rendering post-menopausal more susceptible to osteoporotic fractures. […] Post-menopausal are 2-3 x more likely to develop IHD [ischaemic heart disease] than premenopausal , even after age adjustments. The menopause is associated with an increase in risk factors for atherosclerosis, including less favourable lipid profile, insulin sensitivity, and an ↑ thrombotic tendency. […] ♀ are 2-3 x more likely to develop Alzheimer’s disease than ♂. It is suggested that oestrogen deficiency may play a role in the development of dementia. […] The aim of treatment of perimenopausal ♀ is to alleviate menopausal symptoms and optimize quality of life. The majority of women with mild symptoms require no HRT. […] There is an ↑ risk of breast cancer in HRT users which is related to the duration of use. The risk increases by 35%, following 5 years of use (over the age of 50), and falls to never-used risk 5 years after discontinuing HRT. For ♀ aged 50 not using HRT, about 45 in every 1,000 will have cancer diagnosed over the following 20 years. This number increases to 47/1,000 ♀ using HRT for 5 years, 51/1,000 using HRT for 10 years, and 57/1,000 after 15 years of use. The risk is highest in ♀ on combined HRT compared with oestradiol alone. […] Oral HRT increases the risk [of venous thromboembolism] approximately 3-fold, resulting in an extra two cases/10,000 women-years. This risk is markedly ↑ in ♀ who already have risk factors for DVT, including previous DVT, cardiovascular disease, and within 90 days of hospitalization. […] Data from >30 observational studies suggest that HRT may reduce the risk of developing CVD [cardiovascular disease] by up to 50%. However, randomized placebo-controlled trials […] have failed to show that HRT protects against IHD. Currently, HRT should not be prescribed to prevent cardiovascular disease.”

“Any chronic illness may affect testicular function, in particular chronic renal failure, liver cirrhosis, and haemochromatosis. […] 25% of  who develop mumps after puberty have associated orchitis, and 25-50% of these will develop 1° testicular failure. […] Alcohol excess will also cause 1° testicular failure. […] Cytotoxic drugs, particularly alkylating agents, are gonadotoxic. Infertility occurs in 50% of patients following chemotherapy, and a significant number of  require androgen replacement therapy because of low testosterone levels. […] Testosterone has direct anabolic effects on skeletal muscle and has been shown to increase muscle mass and strength when given to hypogonadal men. Lean body mass is also with a reduction in fat mass. […] Hypogonadism is a risk factor for osteoporosis. Testosterone inhibits bone resorption, thereby reducing bone turnover. Its administration to hypogonadal has been shown to improve bone mineral density and reduce the risk of developing osteoporosis. […] *Androgens stimulate prostatic growth, and testosterone replacement therapy may therefore induce symptoms of bladder outflow obstruction in with prostatic hypertrophy. *It is unlikely that testosterone increases the risk of developing prostrate cancer, but it may promote the growth of an existing cancer. […] Testosterone replacement therapy may cause a fall in both LDL and HDL cholesterol levels, the significance of which remains unclear. The effect of androgen replacement therapy on the risk of developing coronary artery disease is unknown.”

“Erectile dysfunction [is] [t]he consistent inability to achieve or maintain an erect penis sufficient for satisfactory sexual intercourse. Affects approximately 10% of and >50% of >70 years. […] Erectile dysfunction may […] occur as a result of several mechanisms: *Neurological damage. *Arterial insufficiency. *Venous incompetence. *Androgen deficiency. *Penile abnormalities. […] *Abrupt onset of erectile dysfunction which is intermittent is often psychogenic in origin. *Progressive and persistent dysfunction indicates an organic cause. […] Absence of morning erections suggests an organic cause of erectile dysfunction.”

“*Infertility, defined as failure of pregnancy after 1 year of unprotected regular (2 x week) sexual intercourse, affects ~10% of all couples. *Couples who fail to conceive after 1 years of regular unprotected sexual intercourse should be investigated. […] Causes[:] *♀ factors (e.g. PCOS, tubal damage) 35%. *♂ factors (idiopathic gonadal failure in 60%) 25%. *Combined factors 25%. *Unexplained infertility 15%. […] [♀] Fertility declines rapidly after the age of 36 years. […] Each episode of acute PID causes infertility in 10-15% of cases. *Trachomatis is responsible for half the cases of PID in developed countries. […] Unexplained infertility [is] [i]nfertility despite normal sexual intercourse occurring at least twice weakly, normal semen analysis, documentation of ovulation in several cycles, and normal patent tubes (by laparoscopy). […] 30-50% will become pregnant within 3 years of expectant management. If not pregnant by then, chances that spontaneous pregnancy will occur are greatly reduced, and ART should be considered. In ♀>34 years of age, then expectant management is not an option, and up to six cycles of IUI or IVF should be considered.”


February 9, 2018 - Posted by | Books, Cancer/oncology, Cardiology, Diabetes, Genetics, Medicine, Pharmacology

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