ReproSG.docx

**[Week 12 Reproductive:]** **[Breast cancer risk factors]** Common postmenopause Arise from mammary duct epithelium or lobular glands Other less common areas -- mucinous, tublar, medullary, papillary, angiosarcoma Tissue from biopsy is tested for hormone receptors, estrogen and progesterone, g...

**[Week 12 Reproductive:]** **[Breast cancer risk factors]** Common postmenopause Arise from mammary duct epithelium or lobular glands Other less common areas -- mucinous, tublar, medullary, papillary, angiosarcoma Tissue from biopsy is tested for hormone receptors, estrogen and progesterone, growth promoting protein HER2 Tumor stage -- most important prognostic indicator: Tumor size, lymph node involvement, is metastatic disease present Most common location for breast cancer is the upper quadrant Risk factrs include: increased estrogen exposure with early menses, late menopause, nulliparity, obesity, PCOS **[Understand the normal menstrual cycle]** Menarche: 1st menstrual period Menses: the time of menstruation Perimenopause: interval (months to years) of menstrual irregularities leading up to the total cessation of cycles Menopause: cessation of menses for 12 months or more Phases The menstrual cycle is divided into 2 components: ovarian cycle and endometrial cycle: Average adult menstrual cycle is 28--35 days. "Normal" cycle length is defined as 24--38 days. "Regular" cycles are when variation in cycle length is ≤ 7‒9 days. Intervals in cycles usually remain consistent until perimenopause, when follicular phases become shorter and more frequent. *Ovarian cycle phases:* **Follicular phase:** Represents the time during which the follicle and its oocyte develop, leading up to ovulation Spans from menses onset (day 1) to the day before the surge of luteinizing hormone (LH), leading to ovulation Length: 14 to 21 days (may be shorter, especially in perimenopause) **Luteal phase:** The time after ovulation when the ovary produces hormones to support a potential pregnancy and maintain a healthy endometrium. Spans from the day of LH surge until the onset of the next menses Length: 14 days **Endometrial cycle phases:** Desquamation: shedding of the endometrial lining (menses) Proliferative phase: endometrial proliferation with straight, tubular glands Secretory phase: maturation of the spiral arteries and endometrial glands, preparing the endometrium for potential pregnancy **[Understand hormones related to menstrual cycle, pregnancy, and menopause]** The menstrual cycle is regulated by the hypothalamic-pituitary-ovarian axis. Hypothalamus: Releases gonadotropin-releasing hormone (GnRH) → stimulates gonadotropes of the anterior pituitary Secreted from the preoptic neurons of the hypothalamus in a pulsatile fashion Regulated by biologic rhythms (and to a lesser extent by other physiologic factors, such as stress) Anterior pituitary: Stimulated by GnRH → releases follicle-stimulating hormone (FSH) and luteinizing hormone (LH) FSH and LH → stimulate the ovaries FSH: Stimulates follicular development and egg maturation Stimulates the granulosa cells within the ovary to produce estradiol LH: Stimulates theca cells within the ovary to produce testosterone (most of which is converted to estradiol in the granulosa cells) A surge of LH midcycle triggers ovulation. Stimulated by GnRH → releases follicle-stimulating hormone (FSH) and luteinizing hormone (LH) FSH and LH → stimulate the ovaries FSH: Stimulates follicular development and egg maturation Stimulates the granulosa cells within the ovary to produce estradiol LH: Stimulates theca cells within the ovary to produce testosterone (most of which is converted to estradiol in the granulosa cells) A surge of LH midcycle triggers ovulation. Ovaries: Estrogens: Estradiol is the most notable. Secreted by the granulosa cells of ovarian follicles → stimulated by FSH Stimulates the endometrium to grow/develop Makes the developing follicles more sensitive to FSH Feedback/regulation: Negative feedback inhibition: During most of the menstrual cycle, estrogens inhibit further secretions of FSH, LH, and GnRH. Positive feedback: For a short time midcycle, estradiol stimulates FSH and LH secretion from the pituitary → results in ↑ estrogen production in the ovaries and causes the surge of LH, which triggers ovulation Progestins: Progesterone is the most notable. Secreted by the theca-lutein and granulosa lutein cells in the corpus luteum (stimulated by LH) after ovulation Uterine effects:↓ Endometrial growth Stabilizes and causes maturation of the endometrium → prepares the endometrium for implantation ↑ Endometrial secretions (↑ secretion thickness) Progestin withdrawal at the end of the luteal/secretory phases triggers menstrual bleeding. Breast effects: ↑ Lobular development Inhibition of milk production ↑ Body temperature → can be used to track ovulation Required for the development of the placenta during pregnancy Activins: Secreted by the granulosa cells of ovarian follicles (stimulated by FSH) Provides positive feedback to gonadotropes → stimulates secretion of LH, especially midcycle Inhibins: Secreted by the granulosa cells of ovarian follicles (stimulated by FSH) Provides negative feedback to gonadotropes → selectively inhibits further FSH secretion **PREGNANCY:** The major analyte used to establish pregnancy is β-hCG. β-hCG is a hormone produced early by the developing embryo. The presence of β-hCG indicates pregnancy. Human chorionic gonadotropin (hCG) Produced almost exclusively in the placenta, hCG levels rise rapidly during the first trimester and may contribute to nausea and vomiting. Human placental lactogen (hPL) Also known as human chorionic somatomammotropin, hPL is produced by the placenta and helps nourish the fetus and stimulate milk glands. - Estrogen Helps develop the baby\'s organs and placenta, and may cause nausea. Estrogen levels can also cause changes to your appearance, such as darkening nipples, a faint line of hair from the lower abdomen to the pubic area, and larger breasts. - Progesterone Increases blood flow to the womb, and may cause heartburn, vomiting, reflux, gas, and constipation. Progesterone levels can also cause mood swings. - Oxytocin Created toward the end of pregnancy, oxytocin eases pain during labor, encourages the cervix to open, and plays a role in milk production and bonding. - Relaxin Produced by the ovaries and the placenta, relaxin loosens and relaxes muscles, joints, and ligaments to help your body stretch and prepare for deliver **MENOPAUSE:** Anti-Müllerian hormone (AMH) ↓ Secreted by premature follicles Marker of ovarian reserve Begins to decrease 5 years prior to last menstrual period May lead to increased risk for twin pregnancies Inhibin B ↓ Inhibits FSH secretion May begin to ↓ around age 35 (earliest measurable marker) → ↑ FSH LH and FSH ↑ Inhibin B has an inhibitory effect on LH and FSH, so during menopause their levels increase. Testosterone ↓ Primary source of production shifts from ovaries to adrenals. Hypoplasia of adrenal cortex leads to a 25% decrease in testosterone. **[Review the Hypothalamic-pituitary-ovarian (HPO) axis ]** The hypothalamic-pituitary-ovarian (HPO) axis is a complex system that regulates female reproduction and the menstrual cycle through a network of communication between the hypothalamus, pituitary gland, and ovaries. The HPO axis uses hormones and neurotransmitters to create a dynamic equilibrium between the hypothalamic-pituitary unit and the gonads. This system uses both positive and negative feedback loops to regulate the production of hormones such as gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), follicular stimulating hormone (FSH), estrogen, and progesterone. The end goal of the HPO axis is to signal ovulatio **[Defining puberty and expected changes ]** Puberty is the time period from the 1st appearance of secondary sexual characteristics until achieving complete sexual development. Puberty involves a complex series of physical, psychosocial, and cognitive changes. Range: 8--13 years in girls 8--12 years in boys Hormonal control in the initiation of puberty A critical event in puberty is an increase in the pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the arcuate nucleus in the hypothalamus. Kisspeptin neurons in the arcuate nucleus release neurokinin B and dynorphin. Neurokinin B and dynorphin cause the pulsatile secretion of GnRH. GnRH causes the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland. Both LH and FSH affect the Leydig and Sertoli cells in the testes and the theca and granulosa cells of the ovary. Zona reticularis of the adrenal glands secretes androgens such as DHEA, resulting in the characteristics of adrenarche. Zona reticularis functions separately from the hypothalamic-pituitary-gonadal axis. Hormonal changes in girls: LH acts on the theca cells of the ovary to convert cholesterol into androgens. Granulosa cell converts the androgens to estradiol under the control of FSH signaling. Estradiol acts on various organs until the completion of puberty. Hormonal changes in boys: LH acts on Leydig cells convert cholesteral into terstosterone Steroid-producing cells in the interstitial tissue of the testis. They are under the regulation of pituitary hormones; luteinizing hormone; or interstitial cell-stimulating hormone. Testosterone is the major androgen (androgens) produced. **to convert cholesterol into testosterone.P** Puberty can be divided into 4 different consecutive stages, namely, thelarche, pubarche, growth spurt, and menarche. **Thelarche** Breast development with formation of the breast bud and proliferation of the duct and gland epithelium 1st sign of puberty in girls Participating hormones: estrogen, estradiol, prolactin Onset: 7--14 years of age **Pubarche** Growth of pubic and armpit hair Participating hormones: testosterone, 5α-dihydrotestosterone Onset: 8--15 years of age **Growth spurt** Onset: On average, 2 years earlier in girls than boys Approximately 1 year after the 1st indicators of puberty 3--10 cm of growth per year Participating hormones: Release of sex steroids leads to the production of growth hormones. Leads to production of insulin-like growth factor-1 in the liver **Menarche** 1st menstrual bleeding Due to estrogen withdrawal without preceding ovulation Onset: Between 9 and 16 years of age Approximately 1 year after a growth spurt Normally occurs later than other signs of puberty. **[Identifying precocious puberty or delayed puberty ]** **Precocious puberty is** diagnosed in the outpatient clinic, often prompted by parental observation. Parents note early pubertal changes (body odor, new hair growth, oily skin, changes in voice and behavior). Patients present for evaluation because they are abnormally short in stature. Precocious puberty can be a difficult subject for patients and parents to discuss. Physician tact and knowledge of culturally appropriate practices are essential. History Focused history looking for possible causes of PP: CNS: infection, perinatal asphyxia, head trauma, neoplasms and radiation, personality changes, headaches, visual field defects Exposure to endocrine disruptors: cosmetic, dietary products, or medications that may contain estrogens or androgens Family history: Strong family history in males may indicate familial male-limited PP. Clinical features in central precocious puberty Secondary sex characteristics are isosexual. Early development of breast buds in girls and of testicles (volume ≥ 4 mL) in boys. Puberty occurs with a normal sequence: Girls: thelarche (breast buds) → pubarche (pubic hair) → menarche Boys: growth of testes and thinning of scrotum → pigmentation of scrotum and growth of penis → pubarche Major growth restriction (\< 5th percentile of height as adults) occurs in 30% of girls and a larger proportion of boys: Height, weight, and osseous maturation are advanced, while mental development is normal for chronological age. 3 main patterns of pubertal progression: Rapid physical and osseous maturation with loss of linear growth (most common, especially in girls \< 6 years old) Slowly progressive osseous maturation with preserved linear growth (commonly seen in girls \> 6) Transient CPP (rarest form) Precocious is pathologic All girls less than 6yrs old who have thelarche or pubarche need evaluation Girls less than 8 with both should be evaluated Under 6 it will be a CNS issue -- headaches, neuro defects, seizures Two types: Gonadotropin Dependent: early activation of HPO axis, development is isosexual, 90% idiopathic, can be associated with CNS lesions, irradiation, trauma Gonadotropin Independent: Not reliant on FSH or LH, excess secretion of sex steroids from ovaries. Can happen if young girl is ingesting mom's birth control pills. The most common cause is autonomously functioning ovarian cysts. Sometimes ovarian tumors -- granulosa cell -- intertola leydis -rare McUne Albright Syndrome -- alpha subunit mutation of g protein or GNAS1 gene. Will have café au lait spots, polyosotic fibrous dysplasia of the bone Will see gigantism, cushing syndrome, thyrotoxosis, adrenal hyperplasia Sequence of pubertal development may be abnormal bleeding before thelarche. X Ray of left hand to get bone age, stimulation tests (GnRh test), for gonadotropin depending. If + need MRI, TSH Free T4 to rule out hypothyrodisim For Gonadatropin independent -test estradoil and testosterone, HcG, DHEAS and PM cortisol and 170HP, do an abdominal pelvic ultrasound [DELAYED PUBERTY:] Inactive hypothalamic pituitary ovarian axis "HPO" -- Hypo Hypo, GnRH deficiency Ovarian insufficiency, ovarian failure, turner syndrome Hyper Hypo = ovarian failure Can be the first sign of an occult metabolism problem -- IBS or hypothyroidism Kallman Syndrome can cause Hypothalamic/Pituitary tumors Test FSH, Estradiol, LH, Prolactin **[Know Tanner Stages]** Females: Prepubertal -- Tanner 1 Pubic hair -- villus hair only Breasts -- Evelation of papilla only Adrenarche and ovarian growth 8-11.5 years -- Tanner 2 Pubic hair -- sparse along the labia Breasts -- Buds are palpable -- first sign of puberty in females, areale are inlarged. Clitoral enlargement, labial pigmentation, growth of uterus 11.5-13 years -- Tanner 3 Pubic Hair -- coarse and curly Breast tissue -- grows with no contour or separation Axilliary hair, acne 12-15 -- Tanner 4 Pubic Hair -- adult hair that doesn't spread to thigh Breasts -- enlargement and areole form secondary mound on breast Menarche and development of menses Over 15 years old -- Tanner 5 Pubic hair -- adult hair reaching the thigh Breasts -- adult breast contours present, only papilla is raised Adult geniltalia Males: Prebubertal -- Tanner 1 Pubic Hair -- villus only Genitalia -- testes \500 no** **Stage 2: CD4 and T 200-499** **Stage 3: AIDS -- CD4 and T \