Menopause Case File

Menopause Case File

Eugene C.Toy, MD, William E. Seifert, Jr., PHD, Henry W. Strobel, PHD, Konrad P. Harms, MD

❖ CASE 48

A 52-year-old female presents to your office with complaints of hot flushes, mood swings, irritability, and vaginal dryness and itching. Her last menstrual period was a little over a year ago. She denies any vaginal discharge. The patient is concerned about having thyroid problems because her friend has similar symptoms and was diagnosed with hyperthyroidism. On examination, the patient is in no acute distress with normal vital signs. Her physical is normal other than thin, atrophic vaginal mucosa. A thyroid-stimulating hormone (TSH) level is drawn and is normal. The follicle-stimulating hormone (FSH) level is drawn and is markedly elevated.

◆ What is the organ that secretes the follicle-stimulating hormone (FSH)?

◆ What is the signal that stimulates the release of FSH?

ANSWERS TO CASE 48: MENOPAUSE

Summary: A 52-year-old female presents with hot flushes, mood swings, irritability, vaginal dryness and atrophy, and last menstrual period over 1 year ago.

◆ Organ secreting follicle-stimulating hormone (FSH): Anterior pituitary gland.

◆ Signal stimulating FSH release: Gonadotropin releasing hormone from the hypothalamus binds to membrane receptors of the anterior pituitary cells, triggered phosphatidylinositol signaling to stimulate FSH production and release.

CLINICAL CORRELATION

This 52-year-old woman has symptoms of estrogen insufficiency, such as hot flushes, mood swings, and vaginal dryness. Her last menstrual period was 1 year ago, consistent with the menopause. The etiology of the hypoestrogen state is follicular atresia of the ovaries. Once in puberty, a woman usually has fairly regular menstrual cycles as dictated by the estrogen and progesterone secretion of the ovaries until about age 40 to 50 years. During a period of 2 to 4 years, some women may experience irregular menses because of irregular ovulation until finally there are no further menses. The diagnosis of the menopause is made by clinical criteria, although the gonadotropins, FSH, and luteinizing hormone (LH) are usually elevated.

APPROACH TO THE MENSTRUAL CYCLE

Objectives

1. Be familiar with the hormones that control reproduction.

2. Know about the regulation of the normal menstrual cycle.

3. Understand the hormone changes during menopause.

Definitions

Apoptosis: Programmed cell death that leads to the destruction of cells leaving membrane-bound particles that are shed or taken up by phagocytosis.

Estradiol: 17-β-Estradiol; an estrogen steroid hormone that is synthesized in the granulose cells of the ovary and secreted in response to binding of FSH released from the anterior pituitary.

FSH: Follicle-stimulating hormone; a polypeptide hormone that contains α and β subunits that is synthesized in and released from the anterior pituitary in response to binding of GnRH. When binding to receptors on the plasma membrane of the granulose cells of the ovarian follicle, it stimulates the synthesis and secretion of estradiol.

GnRH: Gonadotropin-releasing hormone; a decapeptide containing an N-terminal pyroglutaminyl residue and a C-terminal glycinamide residue. GnRH is synthesized and secreted from the hypothalamus and binds receptors on the anterior pituitary.

LH: Luteinizing hormone; a polypeptide hormone that is similar in structure to FSH and, like FSH, is synthesized and secreted from the anterior pituitary in response to binding of GnRH. It binds to receptors on the thecal cells of the ovarian follicle to increase synthesis of androgens. When binding to receptors on the corpus luteum, it increases the synthesis of progesterone.

Progesterone: A steroid hormone synthesized from cholesterol secreted from the corpus luteum in the luteal phase of the menstrual cycle.

DISCUSSION

With the onset of puberty, the normal menstrual (ovarian) cycle, as shown in Figure 48-1, is initiated by the pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. GnRH binds to plasma membrane receptors in its target cells in the anterior pituitary and triggers activation of the phosphatidylinositol signaling pathway. This in turn signals the pituitary to release both FSH and LH from the same cell. FSH binds its plasma membrane receptor in the ovarian follicle to stimulate, via adenylate cyclase activation, cyclic AMP production and protein kinase A activation, increased ovarian synthesis and secretion of 17-β-estradiol, the female sex hormone. This leads to maturation of the follicle and ovum. Estradiol also induces progesterone receptors. Estrogens circulate in the bloodstream to maintain female primary and secondary sex characteristics. The steroid hormones estradiol and progesterone act by activating their intracellular receptors (E2R and PR, respectively) to bind their response elements in promoter regions of target genes. Together they promote the thickening and vascularization of the uterine endometrium in preparation for implantation of the fertilized ovum. Ovarian synthesis of inhibin, a negative feedback regulator of FSH (but not LH) production, is also stimulated. As 17-β-estradiol levels reach a maximum, around day 13 of the cycle, they stimulate a massive release of LH and to a lesser extent FSH, from the pituitary, known as the LH spike. The LH spike, together with other factors such as prostaglandin F2α, triggers ovulation.

After ovulation, estrogen biosynthesis by the follicle declines, leading to a drop in blood levels of estrogen. The Graafian follicle now differentiates into the corpus luteum, under the mediation of LH. LH binds plasma membrane receptors in the corpus luteum, acting by the adenylate cyclase/protein kinase A signaling pathway, to stimulate progesterone biosynthesis. The uterine endometrial wall becomes secretory in preparation for implantation of the fertilized egg. In the absence of fertilization, the corpus luteum dies, because of decreased levels of LH. This leads to decreased production of progesterone

Figure 48-1. The ovarian cycle. (Reproduced, with permission, from Devlin TM, ed. Textbook of Biochemistry with Clinical Correlations, 5th ed. New York: Wiley-Liss, Copyright © 2002:935. This material is used by permission of John Wiley & Sons, Inc.)

and estradiol, culminating with apoptosis of the uterine endometrial cells, and their shedding at day 28 in menstruation. A new follicle then begins to develop. The decline in blood levels of estradiol and progesterone relieves feedback inhibition of the gonadotropes and hypothalamus, leading to GnRH release and initiation of another ovarian cycle.

If fertilization occurs, the corpus luteum remains viable and begins secretion of human chorionic gonadotropin (HCG), a function eventually taken over by the placenta. This hormone (HCG) is necessary for the maintenance of the endometrium during the first trimester of pregnancy.

At menopause, beginning on an average at age 51, ovarian production of estrogen and progesterone gradually declines. The resulting release of feedback inhibition on the pituitary leads to its greatly increased release of FSH and LH. The adrenal glands continue to produce a minor amount of estrogen. Ovulation stops, and menstruation becomes less frequent and eventually ceases. The postmenopausal ovary and the adrenal gland continue to secrete androgens. The conversion of these androgens to estrogens mainly in fat cells and skin via the enzyme aromatase provides most of circulating estrogen in postmenopausal women.

COMPREHENSION QUESTIONS

[48.1] An obese 57-year-old woman did not yet exhibit symptoms of menopause but was diagnosed with polycystic ovary syndrome (PCOS) and insulin resistance. Her plasma levels of testosterone were above normal. Which one of the following is most likely in this case?

A. Hyperinsulinemia leading to androgen overproduction by the ovary and its conversion to estrogen in fat cells

B. Androgen overproduction by the adrenal gland and its conversion to estrogen in fat cells

C. Progesterone overproduction by the polycystic ovary leading to its conversion to estrogen

D. LH/FSH ratio = 1

E. Estrogen overproduction by the ovary and conversion to testosterone

[48.2] Which one of the following changes is most likely to be observed in a  postmenopausal woman who is not taking hormone supplementation?

A. Cessation of androgen secretion

B. Increased levels of FSH and LH

C. Increased osteoblast activity

D. Decreased levels of gonadotropin-releasing hormone

E. Increased progesterone levels

[48.3] In a normal premenopausal woman, which one of the following is stimulated by progesterone?

A. Release of gonadotropin-releasing hormone by the pituitary

B. Ovulation

C. Development of the endometrium in preparation for possible pregnancy

D. Uterine contraction

E. Follicle development

Answers

[48.1] A. Hyperandrogenism is primarily ovarian in origin in PCOS women, although a minor contribution from the adrenal gland may occur. Hyperinsulinemia is the primary stimulus. Fat cells convert androgens to estrogens. This may explain the late menopause in this case. In normal postmenopausal women, ovarian production of testosterone continues and this provides the main source of circulating estrogen. Typically an LH/FSH ratio of at least 2.5 is associated with PCOS.

[48.2] B. Increased levels of FSH and LH result from decreased estrogen levels and release of feedback inhibition. Androgen secretion continues although diminished. Osteoblast activity decreases, eventually leading to risk of osteoporosis. Progesterone levels decrease, and GnRH levels increase.

[48.3] C. Progesterone is secreted by the corpus luteum under the influence of LH. Together with estrogen, it promotes the thickening and maintenance of the endometrium. Progesterone inhibits GnRH release, uterine contraction, and follicle development.

BIOCHEMISTRY PEARLS

❖ Puberty is initiated by the pulsatile release of gonadotropinreleasing hormone (GnRH) from the hypothalamus.

❖ GnRH binds to plasma membrane receptors in its target cells in the anterior pituitary and triggers activation of the phosphatidylinositol signaling pathway, stimulating the release of both folliclestimulating hormone (FSH) and luteinizing hormone (LH) from the same cell.

❖ FSH binds its plasma membrane receptor in the ovarian follicle to stimulate, via adenylate cyclase activation, cyclic AMP production, and protein kinase, increasing the ovarian synthesis and secretion of 17-β-estradiol, the female sex hormone.

❖ Follicular atresia is the cause of hypoestrogenemia in the menopause, which is associated with elevated gonadotropin levels (FSH and LH).

References

Litwack G, Schmidt TJ. Biochemistry of hormones I: polypeptide hormones. In: Devlin TM, ed. Textbook of Biochemistry with Clinical Correlations, 5th ed. New York: Wiley-Liss, 2002. 

Pathophysiology of the endocrine system. An online textbook from Colorado State University: http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/

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