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A 25-year-old woman with menarche at 13 years and menstrual periods until about 1 year ago complains of hot flushes, skin and vaginal dryness, weakness, poor sleep, and scanty and infrequent menstrual periods of a year’s duration. She visits her gynecologist, who obtains plasma levels of follicle-stimulating hormone and luteinizing hormone, both of which are moderately elevated. She is diagnosed with premature ovarian failure, and estrogen and progesterone replacement therapy is recommended. A dual-energy absorptiometry scan (DEXA) reveals a bone density t-score of <2.5 SD, ie, frank osteoporosis. How should the ovarian hormones she lacks be replaced? What extra measures should she take for her osteoporosis while receiving treatment?


The ovary has important gametogenic functions that are integrated with its hormonal activity. In the human female, the gonad is relatively quiescent during childhood, the period of rapid growth and maturation. At puberty, the ovary begins a 30- to 40-year period of cyclic function called the menstrual cycle because of the regular episodes of bleeding that are its most obvious manifestation. It then fails to respond to gonadotropins secreted by the anterior pituitary gland, and the cessation of cyclic bleeding that occurs is called menopause.

The mechanism responsible for the onset of ovarian function at the time of puberty is thought to be neural in origin, because the immature gonad can be stimulated by gonadotropins already present in the pituitary and because the pituitary is responsive to exogenous hypothalamic gonadotropin-releasing hormone (GnRH). Despite extensive research in the field, the mechanism of puberty initiation still remains an enigma. Pulsatile pituitary gonadotropin secretion under the guidance of GnRH definitely constitutes a sine qua non for pubertal onset. However, the secretion of GnRH in the human hypothalamus is regulated by kisspeptin and its receptor, as well as by permissive or opposing signals mediated by neurokinin B and dynorphin acting on their respective receptors. These three supra-GnRH regulators compose the Kisspeptin, Neurokinin B, and Dynorphin neuron (KNDy) system, a key player in pubertal onset and progression. Recently, makorin ring finger protein 3 (MKRN3) was also implicated in pubertal onset by contributing to the regulation of the KNDy system. However, the inhibitory (gamma-amino butyric acid, neuropeptide Y, and RFamide-related peptide-3) and stimulatory (glutamate) signals acting upstream of KNDy call into question the primary role of MKRN3 as the gatekeeper of puberty. Recently, epigenetic mechanisms involving derepression of genes, such as that of kisspeptin, have been implicated in pubertal onset. Ultimately, withdrawal of a childhood-related inhibitory effect upon hypothalamic arcuate nucleus neurons allows these neurons to produce GnRH in pulses with the appropriate amplitude, which stimulate the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (see Chapter 37). At first, small amounts of the latter two hormones are released during the night, and the limited quantities of ovarian estrogen secreted in response start to cause breast development. Subsequently, FSH and LH are secreted throughout the day and night, causing secretion of higher amounts ...

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