Week 6

 The term “Hypogonadism” designates a deficiency in ovary or testicular function.  There are several possible origins, including, the absence of sexual development in an individual, or, feminine or masculine sterility.  This disorder can result from a congenital anomaly (Turner Syndrome) or from consuming vegetables that were grown in soil that is rich in cadmium.

In men, hypogonadism is presented by a deficiency in testicular function.  This concerns sperm production and the testosterone secretion.  This pathology is evoked in pubescent males around the age of 14 years. In women, hypogonadism manifests in three forms:  Primary hypogonadism  Secondary hypogonadism  Menopause

 In both sexes, the hypothalamus monitors and causes the release of hormones from the pituitary gland. When the reproductive hormone is required, the hypothalamus sends a gonadotropin-releasing hormone (GnRH) to the anterior pituitary.  This causes the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary into the blood.  Note that the body must reach puberty in order for the adrenals to release the hormones that must be present for GnRH to be produced

Sex hormone binding globulin (SHBG) is a protein that affects the function of some sex hormones,including testosterone and estrogen  It is primarily made in the liver . In short, SHBG binds to specific sex hormones, removing them from direct circulation in the body. It binds tightly to testosterone, dihydrotestosterone (DHT), and estradiol (an estrogen) and transports them in the blood in an inactive form.

 At the onset of puberty, the hypothalamus causes the release of FSH and LH into the male system for the first time.  FSH enters the testes and stimulates the Sertoli cells to begin facilitating spermatogenesis using negative feedback.  LH also enters the testes and stimulates the interstitial cells of Leydig to make and release testosterone into the testes and the blood. Testosterone, the hormone responsible for the secondary sexual characteristics that develop in the male during adolescence, stimulates spermatogenesis.  These secondary sex characteristics include a deepening of the voice, the growth of facial, axillary, and pubic hair, and the beginnings of the sex drive.

As with the male, the anterior pituitary hormones cause the release of the hormones FSH and LH.  In addition, estrogens and progesterone are released from the developing follicles.  Estrogen is the reproductive hormone in females that assists in endometrial regrowth, ovulation, and calcium absorption; it is also responsible for the secondary sexual characteristics of females.  These include breast development, flaring of the hips, and a shorter period necessary for bone maturation.  Progesterone assists in endometrial re-growth and inhibition of FSH and LH release.  In females, FSH stimulates development of egg cells, called ova, which develop in structures called follicles.  Follicle cells produce the hormone inhibin, which inhibits FSH production.  LH also plays a role in the development of ova, induction of ovulation, and stimulation of estradiol and progesterone production by the ovaries.  Estradiol and progesterone are steroid hormones that prepare the body for pregnancy.  Estradiol produces secondary sex characteristics in females, while both estradiol and progesterone regulate the menstrual cycle.

A decrease in either of the two major functions of the testes:  sperm production  testosterone production Primary hypogonadism  Testes  Serum Testosterone↓, FSH & LH ↑ Secondary hypogonadism  Pituitary gland or Hypothalamus  Serum Testosterone↓, FSH & LH ↔ , ↓

 Male sexual differentiation  Secondary sex characteristic in puberty and adult  Spermatogenesis  Muscle strength, Muscle volume  Bone density  Erythropoeisis

Musculoskeletal • Decreased vigour and physical energy • Diminished muscle strength Sexuality • Decreased interest in sex • Reduction in frequency of sexual activity • Poor erectile function/arousal • Loss of nocturnal erections • Reduced quality of orgasm • Reduced volume of ejaculate

Postpubertal onset  Loss of libido  Impotence  Infertility

Postpubertal onset  Infections — Mumps orchitis  Radiation  Drugs  Trauma  Bilateral orchiectomy  Autoimmune damage  Chronic systemic diseases (Cirrhosis, Chronic renal failure, HIV)

Prepubertal onset  Isolated idiopathic hypogonadotropic hypogonadism  Kallmann's syndrome  Idiopathic hypogonadotropic hypogonadism associated with mental retardation  Abnormal ß-subunit of LH  Abnormal ß-subunit of FSH  Idiopathic hypogonadotropic hypogonadism associated with other hypothalamic pituitary hormonal deficits Postpubertal onset  Sella or suprasellar tumor  Infiltrative disease > Sarcoidosis, eosinophilic granuloma → hypothalamic hypogonad > Hemochromatosis → pituitary hypogonad  Infection: meningitis  Trauma  Critical illness: surgery, MI, head trauma  Chronic systemic illness : cirrhosis, CKD, HIV  Drugs

Serum Testosterone, FSH,LH Semen analysis Others  Peripheral leukocyte karyotype  Other pituitary hormones  Serum prolactin  Iron saturation  MRI brain

 Intramuscular preparations  Transdermal patch  Transdermal gel  Oral agent  Testosterone pellet  Buccal testosterone tablets

Describes the inadequate function of the ovaries, with impaired production of germ cells (eggs) and sex hormones (oestrogen and progesterone).  Primary hypogonadism refers to a condition of the ovaries (primary ovarian insufficiency/hypergonadotropic hypogonadism).  Secondary hypogonadism refers to the failure of the hypothalamus or pituitary gland (hypogonadotropic hypogonadism).

 Ovaries do not regularly release eggs and do not produce enough sex hormones despite high levels of circulating gonadotropins (especially follicle-stimulating hormone [FSH]) in women < 40.  Diagnosis is by measuring FSH and estradiol levels.

 Also called primary hypogonadism, is a disorder of abnormal function of gonads with decreased estradiol in females, which results in delayed sexual development.  Diagnosis is by measuring FSH and estradiol levels.

Primary amenorrhea is failure of menses to occur by age 15 years in patients with normal growth and secondary sexual characteristics. Secondary amenorrhea is the absence of menses for ≥ 6 months or the length of 3 cycles after the establishment of regular menstrual cycles.

During normal female menstruation cycle:  Gonadotropin-releasing hormone (GnRH) is released from hypothalamus, and it works on pituitary to release follicle- stimulating hormone (FSH) and luteinizing hormone (LH)  These 2 hormones from pituitary act on ovaries and ovaries finally make estrogen and progesterone to work on the uterus to carry out the follicular and secretory phase of menstrual cycle. Any defect at any level of this normal physiology of female can cause amenorrhea.

These hormones do the following:  Follicle-stimulating hormone activates aromatase in granulosa cells around the developing oocytes to convert androgens to estradiol.  Estrogen stimulates the endometrium, causing it to proliferate.  Luteinizing hormone, when it surges during the menstrual cycle, promotes maturation of the dominant oocyte, release of the oocyte, and formation of the corpus luteum, which produces progesterone.  Progesterone changes the endometrium into a secretory structure and prepares it for egg implantation (endometrial decidualization).

 In late reproductive life, menopause occurs after 12 months of amenorrhea and represents the near complete cessation of ovarian hormone secretion.  The Menopausal Transition (MT) is the time in each woman’s reproductive life that precedes the final menstrual period (FMP).  MT is associated with changes in bleeding pattern and hormone profiles.

Follicle stimulating hormone (FSH), anti-Mullerian hormone (AMH), inhibin B and estradiol represent the four primary hormone measures of these investigations.  AMH appears to be the first marker to change, followed by FSH and inhibin B.  Estradiol declines in late MT.  FSH is secreted by the anterior pituitary gonadtrophes and is regulated in part through negative feedback by inhibin B and estradiol, hence an “indirect measure”.  As inhibin B and estradiol vary through each menstrual cycle, FSH levels fluctuate accordingly.  With ovarian aging, lower inhibin B also results in decreased negative feedback to the pituitary, resulting in increased FSH secretion and higher early follicular FSH.  Current data show an increase in FSH and decreases in AMH, inhibin B and estradiol over MT